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TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury | Acta Neuropathologica
<!DOCTYPE html> <html lang="en" class="no-js"> <head> <meta charset="UTF-8"> <meta http-equiv="X-UA-Compatible" content="IE=edge"> <meta name="applicable-device" content="pc,mobile"> <meta name="viewport" content="width=device-width, initial-scale=1"> <meta name="robots" content="max-image-preview:large"> <meta name="access" content="Yes"> <meta name="360-site-verification" content="1268d79b5e96aecf3ff2a7dac04ad990" /> <title>TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury | Acta Neuropathologica </title> <meta name="twitter:site" content="@SpringerLink"/> <meta name="twitter:card" content="summary_large_image"/> <meta name="twitter:image:alt" content="Content cover image"/> <meta name="twitter:title" content="TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury"/> <meta name="twitter:description" content="Acta Neuropathologica - Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear..."/> <meta name="twitter:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig1_HTML.png"/> <meta name="journal_id" content="401"/> <meta name="dc.title" content="TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury"/> <meta name="dc.source" content="Acta Neuropathologica 2024 149:1"/> <meta name="dc.format" content="text/html"/> <meta name="dc.publisher" content="Springer"/> <meta name="dc.date" content="2024-12-16"/> <meta name="dc.type" content="OriginalPaper"/> <meta name="dc.language" content="En"/> <meta name="dc.copyright" content="2024 The Author(s)"/> <meta name="dc.rights" content="2024 The Author(s)"/> <meta name="dc.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="dc.description" content="Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206)&nbsp;were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain."/> <meta name="prism.issn" content="1432-0533"/> <meta name="prism.publicationName" content="Acta Neuropathologica"/> <meta name="prism.publicationDate" content="2024-12-16"/> <meta name="prism.volume" content="149"/> <meta name="prism.number" content="1"/> <meta name="prism.section" content="OriginalPaper"/> <meta name="prism.startingPage" content="1"/> <meta name="prism.endingPage" content="21"/> <meta name="prism.copyright" content="2024 The Author(s)"/> <meta name="prism.rightsAgent" content="journalpermissions@springernature.com"/> <meta name="prism.url" content="https://link.springer.com/article/10.1007/s00401-024-02840-9"/> <meta name="prism.doi" content="doi:10.1007/s00401-024-02840-9"/> <meta name="citation_pdf_url" content="https://link.springer.com/content/pdf/10.1007/s00401-024-02840-9.pdf"/> <meta name="citation_fulltext_html_url" content="https://link.springer.com/article/10.1007/s00401-024-02840-9"/> <meta name="citation_journal_title" content="Acta Neuropathologica"/> <meta name="citation_journal_abbrev" content="Acta Neuropathol"/> <meta name="citation_publisher" content="Springer Berlin Heidelberg"/> <meta name="citation_issn" content="1432-0533"/> <meta name="citation_title" content="TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury"/> <meta name="citation_volume" content="149"/> <meta name="citation_issue" content="1"/> <meta name="citation_publication_date" content="2025/06"/> <meta name="citation_online_date" content="2024/12/16"/> <meta name="citation_firstpage" content="1"/> <meta name="citation_lastpage" content="21"/> <meta name="citation_article_type" content="Original Paper"/> <meta name="citation_fulltext_world_readable" content=""/> <meta name="citation_language" content="en"/> <meta name="dc.identifier" content="doi:10.1007/s00401-024-02840-9"/> <meta name="DOI" content="10.1007/s00401-024-02840-9"/> <meta name="size" content="284018"/> <meta name="citation_doi" content="10.1007/s00401-024-02840-9"/> <meta name="citation_springer_api_url" content="http://api.springer.com/xmldata/jats?q=doi:10.1007/s00401-024-02840-9&api_key="/> <meta name="description" content="Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So fa"/> <meta name="dc.creator" content="Hartmannsberger, Beate"/> <meta name="dc.creator" content="Ben-Kraiem, Adel"/> <meta name="dc.creator" content="Kramer, Sofia"/> <meta name="dc.creator" content="Guidolin, Carolina"/> <meta name="dc.creator" content="Kazerani, Ida"/> <meta name="dc.creator" content="Doppler, Kathrin"/> <meta name="dc.creator" content="Thomas, Dominique"/> <meta name="dc.creator" content="Gurke, Robert"/> <meta name="dc.creator" content="Sisignano, Marco"/> <meta name="dc.creator" content="Kalelkar, Pranav P."/> <meta name="dc.creator" content="García, Andrés J."/> <meta name="dc.creator" content="Monje, Paula V."/> <meta name="dc.creator" content="Sammeth, Michael"/> <meta name="dc.creator" content="Nusrat, Asma"/> <meta name="dc.creator" content="Brack, Alexander"/> <meta name="dc.creator" content="Krug, Susanne M."/> <meta name="dc.creator" content="Sommer, Claudia"/> <meta name="dc.creator" content="Rittner, Heike L."/> <meta name="dc.subject" content="Pathology"/> <meta name="dc.subject" content="Neurosciences"/> <meta name="citation_reference" content="citation_journal_title=J Cell Biol; 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Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, USA"/> <meta name="citation_author" content="Monje, Paula V."/> <meta name="citation_author_institution" content="Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, USA"/> <meta name="citation_author" content="Sammeth, Michael"/> <meta name="citation_author_institution" content="Department of Applied Sciences and Health, Coburg University of Applied Sciences and Art, Coburg, Germany"/> <meta name="citation_author_institution" content="Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany"/> <meta name="citation_author" content="Nusrat, Asma"/> <meta name="citation_author_institution" content="Department of Pathology, University of Michigan, Ann Arbor, USA"/> <meta name="citation_author" content="Brack, Alexander"/> <meta name="citation_author_institution" content="Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany"/> <meta name="citation_author" content="Krug, Susanne M."/> <meta name="citation_author_institution" content="Charité-Universitätsmedizin Berlin, Clinical Physiology/Nutritional Medicine, Berlin, Germany"/> <meta name="citation_author" content="Sommer, Claudia"/> <meta name="citation_author_institution" content="Department of Neurology, University Hospital Würzburg, Würzburg, Germany"/> <meta name="citation_author" content="Rittner, Heike L."/> <meta name="citation_author_email" content="rittner_h@ukw.de"/> <meta name="citation_author_institution" content="Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany"/> <meta name="format-detection" content="telephone=no"/> <meta name="citation_cover_date" content="2025/06/01"/> <meta property="og:url" content="https://link.springer.com/article/10.1007/s00401-024-02840-9"/> <meta property="og:type" content="article"/> <meta property="og:site_name" content="SpringerLink"/> <meta property="og:title" content="TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury - Acta Neuropathologica"/> <meta property="og:description" content="Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain."/> <meta property="og:image" content="https://static-content.springer.com/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig1_HTML.png"/> <meta name="format-detection" content="telephone=no"> <link rel="apple-touch-icon" sizes="180x180" href=/oscar-static/img/favicons/darwin/apple-touch-icon-92e819bf8a.png> <link rel="icon" type="image/png" sizes="192x192" href=/oscar-static/img/favicons/darwin/android-chrome-192x192-6f081ca7e5.png> <link rel="icon" type="image/png" sizes="32x32" href=/oscar-static/img/favicons/darwin/favicon-32x32-1435da3e82.png> <link rel="icon" type="image/png" sizes="16x16" href=/oscar-static/img/favicons/darwin/favicon-16x16-ed57f42bd2.png> <link rel="shortcut icon" data-test="shortcut-icon" 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Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.","datePublished":"2024-12-16T00:00:00Z","dateModified":"2024-12-16T00:00:00Z","pageStart":"1","pageEnd":"21","license":"http://creativecommons.org/licenses/by/4.0/","sameAs":"https://doi.org/10.1007/s00401-024-02840-9","keywords":["Blood–nerve barrier","Fibrinogen","Pain resolution","Resolvin D1","Chronic constriction injury","TAM receptors","Nanoparticles","Pathology","Neurosciences"],"image":["https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig1_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig2_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig3_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig4_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig5_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig6_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig7_HTML.png","https://media.springernature.com/lw1200/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig8_HTML.png"],"isPartOf":{"name":"Acta Neuropathologica","issn":["1432-0533"],"volumeNumber":"149","@type":["Periodical","PublicationVolume"]},"publisher":{"name":"Springer Berlin Heidelberg","logo":{"url":"https://www.springernature.com/app-sn/public/images/logo-springernature.png","@type":"ImageObject"},"@type":"Organization"},"author":[{"name":"Beate Hartmannsberger","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Adel Ben-Kraiem","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"},{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research, Diet-Induced Metabolic Alterations Group","address":{"name":"Helmholtz Institute for Metabolic, Obesity and Vascular Research, Diet-Induced Metabolic Alterations Group, Leipzig, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Sofia Kramer","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Carolina Guidolin","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Ida Kazerani","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Kathrin Doppler","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Department of Neurology, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Dominique Thomas","affiliation":[{"name":"Goethe University, Frankfurt, Faculty of Medicine, Institute of Clinical Pharmacology","address":{"name":"Goethe University, Frankfurt, Faculty of Medicine, Institute of Clinical Pharmacology, Frankfurt Am Main, Germany","@type":"PostalAddress"},"@type":"Organization"},{"name":"Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence 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Monje","affiliation":[{"name":"University of Kentucky","address":{"name":"Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Michael Sammeth","affiliation":[{"name":"Coburg University of Applied Sciences and Art","address":{"name":"Department of Applied Sciences and Health, Coburg University of Applied Sciences and Art, Coburg, Germany","@type":"PostalAddress"},"@type":"Organization"},{"name":"University Hospital Würzburg","address":{"name":"Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Asma Nusrat","affiliation":[{"name":"University of Michigan","address":{"name":"Department of Pathology, University of Michigan, Ann Arbor, USA","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Alexander Brack","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"@type":"Person"},{"name":"Susanne M. 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Rittner","affiliation":[{"name":"University Hospital Würzburg","address":{"name":"Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany","@type":"PostalAddress"},"@type":"Organization"}],"email":"rittner_h@ukw.de","@type":"Person"}],"isAccessibleForFree":true,"@type":"ScholarlyArticle"},"@context":"https://schema.org","@type":"WebPage"}</script> </head> <body class="" > <!-- Google Tag Manager (noscript) --> <noscript> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript> <!-- End Google Tag Manager (noscript) --> <!-- Google Tag Manager (noscript) --> <noscript data-test="gtm-body"> <iframe src="https://www.googletagmanager.com/ns.html?id=GTM-MRVXSHQ" height="0" width="0" style="display:none;visibility:hidden"></iframe> </noscript> <!-- End Google Tag Manager (noscript) --> 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class="c-context-bar__title"> TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury </div> <div data-test="inCoD" data-track-context="sticky banner"> <div class="c-pdf-container"> <div class="c-pdf-download u-clear-both u-mb-16"> <a href="/content/pdf/10.1007/s00401-024-02840-9.pdf" class="u-button u-button--full-width u-button--primary u-justify-content-space-between c-pdf-download__link" data-article-pdf="true" data-readcube-pdf-url="true" data-test="pdf-link" data-draft-ignore="true" data-track="content_download" data-track-type="article pdf download" data-track-action="download pdf" data-track-label="button" data-track-external download> <span class="c-pdf-download__text">Download PDF</span> <svg aria-hidden="true" focusable="false" width="16" height="16" class="u-icon"><use xlink:href="#icon-eds-i-download-medium"/></svg> </a> </div> </div> </div> </div> </div> <div class="c-article-header"> <header> <ul class="c-article-author-list 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Monje</a><sup class="u-js-hide"><a href="#Aff7">7</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Michael-Sammeth-Aff8-Aff9" data-author-popup="auth-Michael-Sammeth-Aff8-Aff9" data-author-search="Sammeth, Michael">Michael Sammeth</a><sup class="u-js-hide"><a href="#Aff8">8</a>,<a href="#Aff9">9</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Asma-Nusrat-Aff10" data-author-popup="auth-Asma-Nusrat-Aff10" data-author-search="Nusrat, Asma">Asma Nusrat</a><sup class="u-js-hide"><a href="#Aff10">10</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Alexander-Brack-Aff1" data-author-popup="auth-Alexander-Brack-Aff1" data-author-search="Brack, Alexander">Alexander Brack</a><sup class="u-js-hide"><a href="#Aff1">1</a></sup>, </li><li class="c-article-author-list__item c-article-author-list__item--hide-small-screen"><a data-test="author-name" data-track="click" data-track-action="open author" data-track-label="link" href="#auth-Susanne_M_-Krug-Aff11" data-author-popup="auth-Susanne_M_-Krug-Aff11" data-author-search="Krug, Susanne M.">Susanne M. 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Rittner<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-mail-medium"></use></svg></a><sup class="u-js-hide"><a href="#Aff1">1</a></sup> </li></ul><button aria-expanded="false" class="c-article-author-list__button"><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-down-medium"></use></svg><span>Show authors</span></button> <div data-test="article-metrics"> <ul class="app-article-metrics-bar u-list-reset"> <li class="app-article-metrics-bar__item"> <p class="app-article-metrics-bar__count"><svg class="u-icon app-article-metrics-bar__icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-accesses-medium"></use> </svg>432 <span class="app-article-metrics-bar__label">Accesses</span></p> </li> <li class="app-article-metrics-bar__item app-article-metrics-bar__item--metrics"> <p class="app-article-metrics-bar__details"><a href="/article/10.1007/s00401-024-02840-9/metrics" data-track="click" data-track-action="view metrics" data-track-label="link" rel="nofollow">Explore all metrics <svg class="u-icon app-article-metrics-bar__arrow-icon" width="24" height="24" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-arrow-right-medium"></use> </svg></a></p> </li> </ul> </div> <div class="u-mt-32"> </div> </header> </div> <div data-article-body="true" data-track-component="article body" class="c-article-body"> <section aria-labelledby="Abs1" data-title="Abstract" lang="en"><div class="c-article-section" id="Abs1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Abs1">Abstract</h2><div class="c-article-section__content" id="Abs1-content"><p>Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers—perineurium, capillaries and myelin—only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (<i>Cd206)</i> were boosted and fibrinolytic pathways (<i>Plat)</i> were induced, while inflammation (<i>Tnfα)</i> and inflammasomes (<i>Nlrp3)</i> were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2–Cd206–TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.</p></div></div></section> <div data-test="cobranding-download"> </div> <section aria-labelledby="inline-recommendations" data-title="Inline Recommendations" class="c-article-recommendations" data-track-component="inline-recommendations"> <h3 class="c-article-recommendations-title" id="inline-recommendations">Similar content being viewed by others</h3> <div class="c-article-recommendations-list"> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1007%2Fs00109-021-02091-1/MediaObjects/109_2021_2091_Figa_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1007/s00109-021-02091-1?fromPaywallRec=false" data-track="select_recommendations_1" data-track-context="inline recommendations" data-track-action="click recommendations inline - 1" data-track-label="10.1007/s00109-021-02091-1">Selective blood-nerve barrier leakiness with claudin-1 and vessel-associated macrophage loss in diabetic polyneuropathy </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">21 May 2021</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1186%2Fs40478-019-0762-y/MediaObjects/40478_2019_762_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1186/s40478-019-0762-y?fromPaywallRec=false" data-track="select_recommendations_2" data-track-context="inline recommendations" data-track-action="click recommendations inline - 2" data-track-label="10.1186/s40478-019-0762-y">Nanomedicine-driven neuropathic pain relief in a rat model is associated with macrophage polarity and mast cell activation </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">05 July 2019</span> </div> </div> </article> </div> <div class="c-article-recommendations-list__item"> <article class="c-article-recommendations-card" itemscope itemtype="http://schema.org/ScholarlyArticle"> <div class="c-article-recommendations-card__img"><img src="https://media.springernature.com/w215h120/springer-static/image/art%3A10.1038%2Fs41420-021-00529-6/MediaObjects/41420_2021_529_Fig1_HTML.png" loading="lazy" alt=""></div> <div class="c-article-recommendations-card__main"> <h3 class="c-article-recommendations-card__heading" itemprop="name headline"> <a class="c-article-recommendations-card__link" itemprop="url" href="https://link.springer.com/10.1038/s41420-021-00529-6?fromPaywallRec=false" data-track="select_recommendations_3" data-track-context="inline recommendations" data-track-action="click recommendations inline - 3" data-track-label="10.1038/s41420-021-00529-6">Gasdermin D in peripheral nerves: the pyroptotic microenvironment inhibits nerve regeneration </a> </h3> <div class="c-article-meta-recommendations" data-test="recommendation-info"> <span class="c-article-meta-recommendations__item-type">Article</span> <span class="c-article-meta-recommendations__access-type">Open access</span> <span class="c-article-meta-recommendations__date">14 June 2021</span> </div> </div> </article> </div> </div> </section> <script> window.dataLayer = window.dataLayer || []; window.dataLayer.push({ recommendations: { recommender: 'semantic', model: 'specter', policy_id: 'NA', timestamp: 1735086248, embedded_user: 'null' } }); </script> <div class="app-card-service" data-test="article-checklist-banner"> <div> <a class="app-card-service__link" data-track="click_presubmission_checklist" data-track-context="article page top of reading companion" data-track-category="pre-submission-checklist" data-track-action="clicked article page checklist banner test 2 old version" data-track-label="link" href="https://beta.springernature.com/pre-submission?journalId=401" data-test="article-checklist-banner-link"> <span class="app-card-service__link-text">Use our pre-submission checklist</span> <svg class="app-card-service__link-icon" aria-hidden="true" focusable="false"><use xlink:href="#icon-eds-i-arrow-right-small"></use></svg> </a> <p class="app-card-service__description">Avoid common mistakes on your manuscript.</p> </div> <div class="app-card-service__icon-container"> <svg class="app-card-service__icon" aria-hidden="true" focusable="false"> <use xlink:href="#icon-eds-i-clipboard-check-medium"></use> </svg> </div> </div> <div class="main-content"> <section data-title="Introduction"><div class="c-article-section" id="Sec1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec1">Introduction</h2><div class="c-article-section__content" id="Sec1-content"><p>Traumatic peripheral nerve injury elicits neuropathic pain followed by regeneration, with axonal regrowth, remyelination and target organ innervation. While many patients recuperate, some fail to recover and suffer long-lasting chronic pain. In the last few decades, research has provided valuable insights into chronification mechanisms, but healing and resolution of pain are less well understood [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 12" title="Cohen SP, Vase L, Hooten WM (2021) Chronic pain: an update on burden, best practices, and new advances. Lancet 397:2082–2097. 
 https://doi.org/10.1016/s0140-6736(21)00393-7
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR12" id="ref-link-section-d431148989e780">12</a>]. Regeneration failure includes incomplete restoration or miswiring of sensory and nociceptive fibres, causing neuropathic pain [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 21" title="Gangadharan V, Zheng H, Taberner FJ, Landry J, Nees TA, Pistolic J et al (2022) Neuropathic pain caused by miswiring and abnormal end organ targeting. Nature 606:137–145. 
 https://doi.org/10.1038/s41586-022-04777-z
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR21" id="ref-link-section-d431148989e783">21</a>].</p><p>The initial pathology after chronic constriction injury (CCI) includes oedema, Wallerian degeneration and disruption of the perineurium, with macrophage infiltration and endothelial proliferation observed within the first week. The long-term effects involve significant loss of nerve fibres, axonal sprouting and fibrous tissue formation around the ligatures [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Sommer C, Galbraith JA, Heckman HM, Myers RR (1993) Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223–233. 
 https://doi.org/10.1097/00005072-199305000-00006
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR60" id="ref-link-section-d431148989e789">60</a>]. Vascular changes are evident as endothelial cell proliferation and vessel narrowing in a distinct time course: distended vessels 1 day after surgery, followed by progressive thickening of vessel walls and reduced luminal size from day 7 [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 59" title="Sommer C, Myers RR (1996) Vascular pathology in CCL neuropathy: a quantitative temporal study. Experim Neurol 141:113–119. 
 https://doi.org/10.1006/S0014-4886(96)92000-2
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR59" id="ref-link-section-d431148989e792">59</a>].</p><p>Immune cells are believed to play an important role in the switch to pain resolution which can occur independently of the recovery of tissue architecture and function [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Sommer C, Galbraith JA, Heckman HM, Myers RR (1993) Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223–233. 
 https://doi.org/10.1097/00005072-199305000-00006
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR60" id="ref-link-section-d431148989e798">60</a>]. While sensory or motor defects persist, the regeneration phase can emerge with mild or no pain. Immune cells control the pro-resolution switch, including macrophages and T cells, releasing anti-inflammatory cytokines [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 20" title="Fiore NT, Debs SR, Hayes JP, Duffy SS, Moalem-Taylor G (2023) Pain-resolving immune mechanisms in neuropathic pain. Nat Rev Neurol 19:199–220. 
 https://doi.org/10.1038/s41582-023-00777-3
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR20" id="ref-link-section-d431148989e801">20</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 30" title="Kavelaars A, Heijnen CJ (2021) Immune regulation of pain: Friend and foe. Sci Transl Med 13: eabj7152 
 https://doi.org/10.1126/scitranslmed.abj7152
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR30" id="ref-link-section-d431148989e804">30</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 58" title="Sim J, O’Guin E, Monahan K, Sugimoto C, McLean SA, Albertorio-Sáez L et al (2023) Interleukin-10-producing monocytes contribute to sex differences in pain resolution in mice and humans. bioRxiv: 
 https://doi.org/10.1101/2023.11.03.565129
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR58" id="ref-link-section-d431148989e807">58</a>], specific subtypes of spinal microglia [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 17" title="Donovan LJ, Bridges CM, Nippert AR, Wang M, Wu S, Forman TE et al (2024) Repopulated spinal cord microglia exhibit a unique transcriptome and contribute to pain resolution. Cell Rep 43:113683. 
 https://doi.org/10.1016/j.celrep.2024.113683
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR17" id="ref-link-section-d431148989e810">17</a>] and mitochondria or extracellular vesicles from anti-inflammatory macrophages [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 69" title="van der Vlist M, Raoof R, Willemen H, Prado J, Versteeg S, Martin Gil C et al (2022) Macrophages transfer mitochondria to sensory neurons to resolve inflammatory pain. Neuron 110:613-626.e619. 
 https://doi.org/10.1016/j.neuron.2021.11.020
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR69" id="ref-link-section-d431148989e814">69</a>]. These highly regulated processes balance the switch for chronification or resolution [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 44" title="Parisien M, Lima LV, Dagostino C, El-Hachem N, Drury GL, Grant AV et al (2022) Acute inflammatory response via neutrophil activation protects against the development of chronic pain. Sci Transl Med 14: eabj9954 
 https://doi.org/10.1126/scitranslmed.abj9954
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR44" id="ref-link-section-d431148989e817">44</a>]. However, the temporal course in nerve tissues is not thoroughly understood.</p><p>Nerve barriers are composed of perineurial, endothelial and Schwann cells that shield the delicate nerve milieu from external stimuli [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 40" title="Moreau N, Mauborgne A, Bourgoin S, Couraud PO, Romero IA, Weksler BB et al (2016) Early alterations of Hedgehog signaling pathway in vascular endothelial cells after peripheral nerve injury elicit blood-nerve barrier disruption, nerve inflammation, and neuropathic pain development. Pain 157:827–839. 
 https://doi.org/10.1097/j.pain.0000000000000444
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR40" id="ref-link-section-d431148989e823">40</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH et al (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73:729–742. 
 https://doi.org/10.1016/j.neuron.2011.11.031
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR42" id="ref-link-section-d431148989e826">42</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Reinhold AK, Hartmannsberger B, Burek M, Rittner HL (2023) Stabilizing the neural barrier - a novel approach in pain therapy. Pharmacol Ther 249:108484. 
 https://doi.org/10.1016/j.pharmthera.2023.108484
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR52" id="ref-link-section-d431148989e829">52</a>]. Under homeostatic conditions, nerve barriers ensure proper nerve function and conduction through tight junction proteins, such as claudins, pericytes and endoneurial macrophages [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Malong L, Napoli I, Casal G, White IJ, Stierli S, Vaughan A et al (2023) Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery. Dev Cell 58:174-191.e178. 
 https://doi.org/10.1016/j.devcel.2023.01.002
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR37" id="ref-link-section-d431148989e832">37</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 52" title="Reinhold AK, Hartmannsberger B, Burek M, Rittner HL (2023) Stabilizing the neural barrier - a novel approach in pain therapy. Pharmacol Ther 249:108484. 
 https://doi.org/10.1016/j.pharmthera.2023.108484
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR52" id="ref-link-section-d431148989e835">52</a>]. Endoneurial oedema represents one of the earliest signs of nerve damage and barrier leakage in patients with inflammatory and non-inflammatory polyneuropathy and preclinical models [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Sommer C, Galbraith JA, Heckman HM, Myers RR (1993) Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223–233. 
 https://doi.org/10.1097/00005072-199305000-00006
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR60" id="ref-link-section-d431148989e839">60</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 67" title="Üçeyler N, Necula G, Wagemann E, Toyka KV, Sommer C (2016) Endoneurial edema in sural nerve may indicate recent onset inflammatory neuropathy. Muscle Nerve 53:705–710. 
 https://doi.org/10.1002/mus.24930
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR67" id="ref-link-section-d431148989e842">67</a>], which manifests as endoneurial deposition of plasma proteins, such as fibrinogen [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Schenone A, De Martini I, Tabaton M, Romagnoli P, Akkad Wattar AS, Bianchini D et al (1988) Direct immunofluorescence in sural nerve biopsies. Eur Neurol 28:262–269. 
 https://doi.org/10.1159/000116281
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR56" id="ref-link-section-d431148989e845">56</a>], and loss of myelin barrier proteins [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 10" title="Chen JT, Hu X, Otto IUC, Schürger C, von Bieberstein BR, Doppler K et al (2023) Myelin barrier breakdown, mechanical hypersensitivity, and painfulness in polyneuropathy with claudin-12 deficiency. Neurobiol Dis 185:106246. 
 https://doi.org/10.1016/j.nbd.2023.106246
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR10" id="ref-link-section-d431148989e848">10</a>].</p><p>After nerve injury, barrier breakdown—evident as tight junction protein loss and immune cell infiltration—facilitates the proper removal of myelin debris. Following successful clearance, nerve barriers need to be resealed to protect the regenerated sensitive structures of the nerve milieu. The proposed factors that promote barrier resealing are TAM receptors (Tyro3, Axl and Mer), which are part of a group of receptor tyrosine kinases that control efferocytosis in both macrophages and Schwann cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 5" title="Brosius Lutz A, Chung WS, Sloan SA, Carson GA, Zhou L, Lovelett E et al (2017) Schwann cells use TAM receptor-mediated phagocytosis in addition to autophagy to clear myelin in a mouse model of nerve injury. Proc Natl Acad Sci USA 114:E8072-e8080. 
 https://doi.org/10.1073/pnas.1710566114
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR5" id="ref-link-section-d431148989e855">5</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 19" title="Elliott MR, Koster KM, Murphy PS (2017) Efferocytosis signaling in the regulation of macrophage inflammatory responses. J Immunol 198:1387–1394. 
 https://doi.org/10.4049/jimmunol.1601520
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR19" id="ref-link-section-d431148989e858">19</a>]. TAM receptors mediate the resolution of inflammation and promote the production and synthesis of anti-inflammatory and specialized pro-resolving mediators [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Vago JP, Amaral FA, van de Loo FAJ (2021) Resolving inflammation by TAM receptor activation. Pharmacol Ther 227:107893. 
 https://doi.org/10.1016/j.pharmthera.2021.107893
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR68" id="ref-link-section-d431148989e861">68</a>]. These SPMs—other factors for barrier resealing—derived from omega-3 and omega-6 polyunsaturated fatty acids, actively resolve inflammation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Tao X, Lee MS, Donnelly CR, Ji RR (2020) Neuromodulation, specialized proresolving mediators, and resolution of pain. Neurotherapeutics 17:886–899. 
 https://doi.org/10.1007/s13311-020-00892-9
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR63" id="ref-link-section-d431148989e864">63</a>]. SPMs such as maresins, protectins and resolvins activate seven different cell surface G-protein coupled receptors (GPCRs), including formyl peptide receptor 2 (FPR2) and G protein-coupled receptor 37-like 1 (GPR37L1), thereby ameliorating inflammatory and neuropathic pain [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 4" title="Bang S, Jiang C, Xu J, Chandra S, McGinnis A, Luo X et al (2024) Satellite glial GPR37L1 and its ligand maresin 1 regulate potassium channel signaling and pain homeostasis. J Clin Invest. 
 https://doi.org/10.1172/jci173537
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR4" id="ref-link-section-d431148989e867">4</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 62" title="Su CJ, Zhang JT, Zhao FL, Xu DL, Pan J, Liu T (2023) Resolvin D1/N-formyl peptide receptor 2 ameliorates paclitaxel-induced neuropathic pain through the activation of IL-10/Nrf2/HO-1 pathway in mice. Front Immunol 14:1091753. 
 https://doi.org/10.3389/fimmu.2023.1091753
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR62" id="ref-link-section-d431148989e871">62</a>], endothelial cell activation and vascular smooth muscle cell remodelling [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 15" title="Díaz Del Campo LS, Rodrigues-Díez R, Salaices M, Briones AM, García-Redondo AB (2022) Specialized pro-resolving lipid mediators: new therapeutic approaches for vascular remodeling. Int J Mol Sci. 
 https://doi.org/10.3390/ijms23073592
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR15" id="ref-link-section-d431148989e874">15</a>].</p><p>In this study, we explored the interplay between the nervous system, barrier function and the immune system to create a temporal signature of pain resolution after traumatic nerve injury. Specifically, we employed in-depth lipidomics, barrier mapping and pathway analysis and therapeutically used SPM-laden nanoparticles to foster pain resolution.</p></div></div></section><section data-title="Materials and methods"><div class="c-article-section" id="Sec2-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec2">Materials and methods</h2><div class="c-article-section__content" id="Sec2-content"><h3 class="c-article__sub-heading" id="Sec3">Animal model</h3><p>All animal experiments were approved by the Government of Lower Franconia, Germany (55.2.2-2532-2-612–06.04.2018 and 55.2.2-2532-2-1547–25.04.2022, Regierung von Unterfranken). Wistar rats (Janvier Labs, Le Genest-Saint-Isle, France) were maintained under pathogen-free conditions with a controlled light cycle, temperature and humidity (14:10 h light/dark cycle, 20–24 °C, 45–65% humidity). Rats (200–250 g) were provided standard chow and water ad libitum and were randomly assigned to the experimental groups. For chronic constriction injury (CCI), the rats were deeply anaesthetized with 2–4% isoflurane. The right sciatic nerve was surgically exposed, and four loose silk ligatures were placed around it with a spacing of approximately 1 mm. The incision was closed using sutures. Animals with auto-mutilation were excluded from the experiments. Sham-operated rats served as controls. All experiments were performed in accordance with ethical regulations.</p><h3 class="c-article__sub-heading" id="Sec4">Perineurial injection</h3><p>Perineurial injections were performed under isoflurane anaesthesia. A blunt cannula attached to a nerve stimulator was inserted through the skin after prepuncture with a 22-Gauge cannula. When proximity to the nerve was confirmed by foot twitching, 0.3 ml of 500 nmol BML-111/phosphate-buffered saline (PBS; Merck KGaA, Darmstadt, Germany, cat. no. SML0215-25MG) or 1 mg RU-301/64% DMSO/PBS (Biozol, cat. no. MCE-HY-119039) or vehicle was injected. For the injection of nanoparticles, the volume was 0.1 ml.</p><h3 class="c-article__sub-heading" id="Sec5">Behavioural testing, reflexive and non-reflexive</h3><p>The von Frey test was performed to assess mechanical allodynia using the Dixon’s up-and-down method. Von Frey filaments (Aesthesio® set, Ugo Basile SRL, Gemonio, Italy) were applied to the plantar surface of each hind paw for 1–3 s so that the filaments were bent to a 45° angle. Single paws were tested with a recovery time of at least 30 s between applications. For analysis, the means of the filament forces with positive reactions were averaged per paw.</p><p>Thermal hypersensitivity was assessed by the Hargreaves test. The light source of a Plantar Analgesia Meter (Model 400 Heated Base from IITC Life Science, Woodland Hills, California, USA) was applied to the plantar surface of each hind paw with a cut-off latency of 20 s. Withdrawal latencies were recorded twice (at least 30 s intervals) and averaged for analysis.</p><p>Motor activity was assessed by voluntary wheel running (Model BIO-ACTIVW; Bioseb, Vitrolles, France). Once per week, the rats were individually placed in cages with voluntary running wheels for 24 h. The activity parameters, including distance, speed and acceleration, were recorded using the BIO-ACTIVW-SOFT software (Bioseb).</p><p>The CatWalk XT system (Noldus, Wageningen, the Netherlands) was used for gait analysis. The rats were allowed to move freely on the CatWalk until three valid runs were recorded with a camera. Runs with a run duration of 0.5–5 s and a maximal run speed variation of 60% were classified as valid. The ratios of footprint area and standing time between the right and left hind paws were calculated. Data from three valid runs were averaged for the analysis.</p><h3 class="c-article__sub-heading" id="Sec6">Reverse transcription-quantitative PCR</h3><p>To isolate RNA from the snap-frozen sciatic nerve tissue (the site of ligation in CCI), we used the RNeasy Micro Kit (#74,004, Qiagen, Venlo, the Netherlands) according to the manufacturer’s instructions. RNA concentration was determined using a NanoDrop ND 2000 spectrophotometer (Thermo Fisher Scientific). 1000 ng (for the 1–6-week characterization) and 500 ng of total RNA were reverse-transcribed to cDNA using the High-Capacity cDNA Reverse Transcription Kit, according to the manufacturer’s instructions (Thermo Fisher Scientific). For quantitative polymerase chain reaction (qPCR), the following TaqMan gene expression assays with FAM-labelled probes were used (Applied Biosystems, Thermo Fisher Scientific): <i>Gapdh</i> (Rn01462662_g1), <i>Tnfα</i> (Rn99999017_m1), <i>Cd68</i> (Rn01495634_g1), <i>Plat</i> (Rn01482578_m1), <i>Tjp1</i> (Rn02116071_s1), <i>Cldn1</i> (Rn00581740_m1), <i>Cldn5</i> (Rn01753146_s1), <i>Cldn12</i> (Rn04219013_m1), <i>Cldn19</i> (Rn01416537_m1), <i>Mpz</i> (Rn00566746_m1), <i>Gpr18</i> (Rn01493247_m1), <i>Gpr37</i> (Rn00589441_m1), <i>Gpr37l1</i> (Rn00595762_m1), <i>CmklR1/ChemR23</i> (Rn00573616_s1)<i>, Fpr2</i> (Rn03037051_gH), <i>Lgr6</i> (Rn01490727_m1), <i>Arg1</i> (Rn00691090_m1), <i>Mrc-1/Cd206</i> (Rn01487342_m1) and <i>Nlrp3</i> (Rn04244620_m1). qPCRs were run on a StepOnePlus real-time PCR system (Applied Biosystems) using the following program: 40 cycles at 95 °C for 1 s and 60 °C for 20 s. The samples were run in triplicate and averaged for the analysis. mRNA abundance relative to the reference gene <i>Gapdh</i> was presented as 2<sup>−ΔCt</sup>.</p><h3 class="c-article__sub-heading" id="Sec7">Permeability assessment: perineurial barrier, myelin barrier and endoneurial vessels</h3><p>To assess perineurial permeability, endings of the sciatic nerve were sealed with Vaseline and immersed in 1 ml of 5% Evan’s Blue albumin (EBA; 5% bovine serum albumin, 1% Evans Blue) and 3% sodium fluorescein (NaFlu) in PBS for 15 min, followed by 5% EBA for 45 min at room temperature (RT). After washing with PBS, the nerves were fixed in 4% paraformaldehyde (PFA) for 1–3 h, cryoprotected in 30% sucrose at 4°C overnight and frozen in Tissue-Tek® O.C.T.™ Compound (Sakura, Alphen aan den Rijn, the Netherlands). Ten-micrometre sections were cut using a cryostat (Leica CM3050S; Leica Biosystems, Wetzlar, Germany). Immunofluorescence images were acquired using a microscope (BZ-9000, Keyence Deutschland GmbH, Neu-Isenburg, Germany), and the intensity was measured.</p><p>For myelin barrier assessment, the epi-perineurium was removed from the nerves proximal from the ligation, which were sealed with Vaseline at their endings [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 9" title="Chen JT-C, Schmidt L, Schürger C, Hankir MK, Krug SM, Rittner HL (2021) Netrin-1 as a multitarget barrier stabilizer in the peripheral nerve after injury. Int J Mol Sci 22:10090" href="/article/10.1007/s00401-024-02840-9#ref-CR9" id="ref-link-section-d431148989e1002">9</a>]. After incubation in artificial cerebrospinal fluid (10 mM HEPES, 110 mM NaCl, 17.8 mM NaHCO<sub>3</sub>, 4 mM MgSO<sub>4</sub>, 3.9 mM KCl, 3 mM KH<sub>2</sub>PO<sub>4</sub>, 1.2 mM CaCl<sub>2</sub> and 10 mM dextrose) containing 0.5% 70 kDa fluorescein isothiocyanate-dextran (FITC-Dextran; Sigma-Aldrich, St. Louis, MO, USA) for 1 h at 37 °C, the nerves were washed, fixed in 4% PFA for 5 min at RT and teased to single nerve fibres on microscopy slides. Until mounting with Aqua-Poly/Mount medium, the slides were stored at -20 °C. Fluorescence images were then acquired for the analysis.</p><p>To assess the permeability of the endoneurial blood vessels, rats received an intravenous injection of 1 ml 5% EBA per 100 g body weight [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 43" title="Omura K, Ohbayashi M, Sano M, Omura T, Hasegawa T, Nagano A (2004) The recovery of blood-nerve barrier in crush nerve injury–a quantitative analysis utilizing immunohistochemistry. Brain Res 1001:13–21. 
 https://doi.org/10.1016/j.brainres.2003.10.067
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR43" id="ref-link-section-d431148989e1019">43</a>]. After 30 min, the proximal and distal parts of the sciatic nerve were snap-frozen in Tissue-Tek® O.C.T.™ Compound. Immunofluorescence images of 10-µm sections were acquired, and the endoneurial intensity was measured.</p><h3 class="c-article__sub-heading" id="Sec8">In vitro assessment of barrier recovery by resolvin D1 and permeability for fibrinogen</h3><p>Primary human dermal microvascular cells (HDMECs; PromoCell, Heidelberg, Germany) were employed as endothelial/endoneurial model and seeded on Millipore filter inserts (Merck-Millipore, PCF-filters, pore size 0.45 µm, area 0.6 cm<sup>2</sup>) and grown until confluent and stable in transendothelial resistance (TER). The cells were then challenged with 500 U/ml TNF-α (Peprotech) for 24 h in parallel to untreated controls. Then, TNF-α concentration was reduced to avoid the induction of apoptosis to 100 U/ml, and some filters were additionally incubated with 500 nM RvD1 (Cayman Chemicals/Biomol GmbH, Hamburg, Germany) for a further 24 h. Permeability for fibrinogen was determined, using FITC-labelled fibrinogen (LOXO GmbH, Dossenheim, Germany), which was added at a concentration of 0.58 µM apically to the filters. After 4, 5 or 6 h, concentrations of FITC-fibrinogen in the basal compartments were measured fluorometrically (Tecan Infinite M200, Tecan, Switzerland). To analyse potential changes in the transcellular passage, e.g. by endocytosis, the cells were harvested from the filters after washing with PBS and were dissolved using total lysate buffer (10 mM Tric-Cl pH 7.5, 150 mM NaCl, 0.5% Triton X-100, 0.1% SDS, protease inhibitors). The intracellular concentration of FITC-fibrinogen was detected at the Tecan photometer. Tracer fluxes and apparent permeabilities were calculated from the concentrations of FITC-fibrinogen.</p><h3 class="c-article__sub-heading" id="Sec9">Liquid chromatography-tandem mass spectrometry</h3><p>The SPMs were determined as described in a previous study by <i>Toewe </i>et al<i>.</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 65" title="Toewe A, Balas L, Durand T, Geisslinger G, Ferreirós N (2018) Simultaneous determination of PUFA-derived pro-resolving metabolites and pathway markers using chiral chromatography and tandem mass spectrometry. Anal Chim Acta 1031:185–194. 
 https://doi.org/10.1016/j.aca.2018.05.020
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR65" id="ref-link-section-d431148989e1046">65</a>] after some modifications of the extraction method. After dissection, sciatic nerve tissues were snap-frozen in liquid nitrogen. The tissue samples were homogenized in water:ethanol (75:25, v/v) to a tissue homogenate of 0.1 mg/μl using a swing mill (Retsch, Haan, Germany) with five zirconium oxide grinding balls (25 Hz for 2.5 min). Three hundred microlitres of the tissue homogenates (in total 30 mg tissue) was spiked with the internal standard solution and extracted using solid-phase extraction with Express ABN cartridges and Extrahera (both from Biotage). Afterwards, the sample extracts were measured using a liquid chromatography-tandem mass spectrometry (LC-MSMS) system comprising an Agilent 1200 LC system and a 5500 QTRAP mass spectrometer (Sciex). Chiral chromatographic separation was achieved using a Lux Amylose-1 column (250 × 4.6 mm, 3 µm, Phenomenex) with water:FA (99.9:0.1, v/v) as solvent A and ACN:MeOH:FA (95:4.9:0.1, v/v/v) as solvent B in gradient elution mode. Data acquisition and evaluation were performed using Analyst 1.6.2 and MultiQuant 3.0, respectively (both from Sciex).</p><h3 class="c-article__sub-heading" id="Sec10">Production of nanoparticles</h3><p>Nanoparticles were produced as previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 50" title="Quiros M, Feier D, Birkl D, Agarwal R, Zhou DW, García AJ et al. (2020) Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing. Proc Natl Acad Sci 117: 9477–9482 
 https://doi.org/10.1073/pnas.1921335117
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR50" id="ref-link-section-d431148989e1057">50</a>]. Briefly, PLGA-PEG-biotin (Nanosoft Polymers; PLGA molecular weight = 10 kDa, PEG molecular weight = 2 kDa) was dissolved in dimethylformamide (100 mg/ml), and 3.76 μg of RvD1 (Cayman Chemical, Ann Arbor, USA; dissolved in ethanol at 0.1 mg/ml) was added to the polymer solution. Next, 500 µL of this polymer–resolvin mixture was added dropwise to 10 mL of PBS. Unloaded control nanoparticles were prepared by dropwise addition of a polymer solution (without resolvin) to PBS. The nanoparticles were stirred for 4–5 h, concentrated by centrifugation using Amicon Ultra-15 centrifugal filter units and filtered through sterile 0.45-μm syringe filters.</p><h3 class="c-article__sub-heading" id="Sec11">Dialysis of nanoparticles to measure resolvin D1 release</h3><p>Slide-A-Lyzer™ mini dialysis unit 20 K MWCO (Thermo Fisher Scientific, Darmstadt, Germany; ref: 69,590) was loaded with 100 µL of RvD1-laden nanoparticles. The devices were placed in 1.1 mL of PBS. The prepared tubes were stirred in a thermomixer at 300 rpm and 37 °C for 1, 3 and 6 h or 1, 2 and 3 days. The dialysates were stored at -80 °C until shipment for analysis by LC-MSMS.</p><h3 class="c-article__sub-heading" id="Sec12">Immunofluorescence of rat nerve tissues</h3><p>The nerves were snap-frozen in Tissue-Tek® O.C.T.™ Compound. The 10-µm sections were fixed in a -20 °C acetone bath. Blocking and permeabilization were performed using PBS containing 0.3% Triton X-100, 0.1% Tween20 and 10% donkey serum for 1 h at RT. The sections were incubated with goat anti-fibrinogen (1:100; antibodies-online GmbH, Aachen, Germany, cat. no. ABIN458743) primary antibodies overnight at 4 °C. Suitable secondary antibodies were applied for 1 h at RT: donkey anti-goat IgG Alexa Fluor 594 (1:600; cat. no. A32758, Thermo Fisher Scientific). Before mounting with Aqua-Poly/Mount medium (Vector Labs, Burlingame, CA, USA), nuclei were stained with DAPI. In this study, we used a polyclonal fibrinogen antibody that binds to various fibrin(ogen) (degradation) products. In the following section, we will use the term fibrinogen for fibrin.</p><h3 class="c-article__sub-heading" id="Sec13">Human nerve tissues</h3><p>The human sural nerves were obtained for diagnostic purposes. Nerve material that was left after diagnostic workup was used for the study with approval from the Ethical Committee of the University of Würzburg (238/17). For patient details, please refer to Supplementary Table ST1. Sixteen biopsies from patients with neuropathies were obtained for immunofluorescence, freshly frozen in OCT and stored at – 80 °C. The 10-µm sections were cut. For staining, the sections were thawed, dried and fixed in 4% PFA for 10 min at RT. After washing, the sections were blocked with 10% donkey serum, 0.1% TritonX-100 and 0.3% Tween20 in PBS for 1 h at RT. Rabbit anti-tissue plasminogen activator (tPA; 1:100; 10,147–1-AP, Proteintech) and sheep anti-fibrinogen (1:200; ab118533, Abcam) antibodies were incubated overnight at 4 °C. Suitable secondary antibodies (1:600; anti-rabbit Alexa Fluor 488, Invitrogen, #A32731; anti-sheep Alexa Fluor 647, Invitrogen, #A21448) were incubated for 1 h at room temperature. Before mounting with Aqua-Poly/Mount medium (Vector Labs), the nuclei were stained with Hoechst33342.</p><p>RNAseq datasets from human intact and transected sural nerve fibres obtained from the participants of a nerve transplantation clinical trial for Parkinson’s disease were reported by Welleford et al. [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Welleford AS, Quintero JE, Seblani NE, Blalock E, Gunewardena S, Shapiro SM et al (2020) RNA sequencing of human peripheral nerve in response to injury: distinctive analysis of the nerve repair pathways. Cell Transplant 29:963689720926157. 
 https://doi.org/10.1177/0963689720926157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR72" id="ref-link-section-d431148989e1088">72</a>] and made publicly available via the UK knowledge website (<a href="https://uknowledge.uky.edu">https://uknowledge.uky.edu</a>).</p><h3 class="c-article__sub-heading" id="Sec15">Image analysis</h3><p>Nerves from the permeability assays and fibrinogen staining were imaged using a fluorescence microscope (BZ-9000; Keyence Deutschland GmbH, Neu-Isenburg, Germany). The images were further analysed using ImageJ software [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 57" title="Schneider CA, Rasband WS, Eliceiri KW (2012) NIH Image to ImageJ: 25 years of image analysis. Nat Methods 9:671–675. 
 https://doi.org/10.1038/nmeth.2089
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR57" id="ref-link-section-d431148989e1106">57</a>]. The endoneurial region of each image was manually selected, and the mean intensity was measured. For each sample, three images were analysed and averaged.</p><p>For the teased fibres, brightfield images were acquired to place a 5-µm-diameter circle as the region of interest (ROI) in the internodal region of the fibres and three ROIs for background subtraction. These ROIs were transferred to their corresponding fluorescence images, and the mean intensities of the ROIs were measured. The intensity of the background ROIs was averaged and subtracted from each internodal ROI.</p><p>Image acquisition for human nerve tissues was performed using an Axio Imager.M2 fluorescence microscope coupled with an Axiocam 506 mono camera (Zeiss, Oberkochen, Germany). For each sample, 2–3 images were analysed and averaged.</p><h3 class="c-article__sub-heading" id="Sec16">Statistical analysis</h3><p>Statistical analyses were performed using GraphPad Prism version 9.3.0 Windows (GraphPad Software, San Diego, CA, USA). For animal behaviour tests, two-way repeated-measures ANOVA with Tukey’s multiple comparison test was performed. The tests performed included Mann–Whitney U test as a non-parametric test or Student’s t test (incl. Welch’s correction for unequal variance) and two-way ANOVA and post-hoc test for multiple groups (see figure legends). Statistical significance was set at p < 0.05. All data were expressed as mean ± SEM.</p></div></div></section><section data-title="Results"><div class="c-article-section" id="Sec17-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec17">Results</h2><div class="c-article-section__content" id="Sec17-content"><h3 class="c-article__sub-heading" id="Sec18">Resolution of thermal and mechanical hyperalgesia in chronic constriction injury from 4 to 6 weeks</h3><p>We characterized the pain course using reflexive and non-reflexive tests over 9 weeks to determine the period of resolution of neuropathic pain after CCI in Wistar rats (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig1">1</a>a). Mechanical and thermal thresholds decreased until week 4 after CCI compared with sham animals and completely recovered at week 6 in both males (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig1">1</a>b, c) and females (SFig. 1). Assessment of the mean print area and the stand time in gait analysis can serve as a measure of pain [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 24" title="Heinzel J, Langle G, Oberhauser V, Hausner T, Kolbenschlag J, Prahm C et al (2020) Use of the CatWalk gait analysis system to assess functional recovery in rodent models of peripheral nerve injury - a systematic review. J Neurosci Methods 345:108889. 
 https://doi.org/10.1016/j.jneumeth.2020.108889
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR24" id="ref-link-section-d431148989e1142">24</a>]. The gait pattern drastically changed after CCI, while the gait of the sham-operated rats remained unaffected (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig1">1</a>d, e). Gait recovery took a similar but delayed course compared with reflexive tests. The stand time did not completely return to baseline levels after 9 weeks, which is thought to result from nerve damage rather than pain. Despite their impaired gait, CCI animals demonstrated normal physical activity throughout the entire time course, using a voluntary running wheel (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig1">1</a>f, g).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-1" data-title="Fig. 1"><figure><figcaption><b id="Fig1" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 1</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/1" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig1_HTML.png?as=webp"><img aria-describedby="Fig1" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig1_HTML.png" alt="figure 1" loading="lazy" width="685" height="1323"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-1-desc"><p>Neuropathic pain resolves 6 weeks after nerve injury. <b>a</b> Schematic illustration of the experimental setup: Male and female Wistar rats underwent CCI or sham surgery and were examined using the displayed tests throughout 9 weeks. <b>b</b> Mechanical allodynia and <b>c</b> thermal hypersensitivity were assessed weekly (n = 6–8). <b>d</b> The print area and <b>e</b> stand time presented as the ratios of values from right to left hindpaws were recorded using the Catwalk gait analysis system (<i>n</i> = 6–7). <b>f</b> The covered distance and <b>g</b> the mean speed of CCI and sham animals were recorded with voluntary running wheels (<i>n</i> = 8). <b>h</b> The summary of all behavioural tests including von Frey and Hargreaves from both male and female rats. The heatmap shows the ratios between the arithmetic means of CCI and sham groups. Data in graphs are shown as mean ± SEM, *p < 0.05. Two-way repeated-measures ANOVA with Tukey’s multiple comparison. <i>PWT</i> paw withdrawal threshold, <i>PWL</i> paw withdrawal latency, <i>CCI</i> chronic constriction injury, <i>VWR</i> voluntary wheel running, <i>ANOVA</i> analysis of variance</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/1" data-track-dest="link:Figure1 Full size image" aria-label="Full size image figure 1" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Based on the curves for mechanical and thermal hyperalgesia and footprint analysis, pain resolution started from week 3 to week 4 after CCI, whereas the end of the resolution was evident at week 6 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig1">1</a>h). Thus, we defined week 1 after surgery as maximal hypersensitivity, week 3 as the flexion point of resolution, week 6 as the end of pain resolution and week 9 as the nerve regeneration phase.</p><h3 class="c-article__sub-heading" id="Sec19">Capillaries reseal for fibrinogen in parallel to pain resolution</h3><p>To determine whether pain resolution coincided with the resealing of any of the nerve barriers, we performed a battery of permeability tests and tight junction protein analysis (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig2">2</a>a).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-2" data-title="Fig. 2"><figure><figcaption><b id="Fig2" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 2</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/2" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig2_HTML.png?as=webp"><img aria-describedby="Fig2" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig2_HTML.png" alt="figure 2" loading="lazy" width="685" height="914"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-2-desc"><p>The perineurial barrier remains open up to 9 weeks, while the myelin barrier stays intact. <b>a</b> Depiction of two ex vivo immersion techniques for analysing the perineurial and myelin barriers after CCI or sham. <b>b</b> Representative images of sciatic nerve cross sections and <b>c, d</b> quantification of endoneurial fluorescence intensity of nerves immersed in Fluo (332 Da) and Evans blue albumin (EBA, 68 kDA) ex vivo. Dashed lines indicate the endoneurial regions. Scale bar: 300 µm. <b>e</b> Representative brightfield and fluorescence images of teased nerve fibres from the proximal part of the sciatic nerve after immersion in 70 kDa FITC-dextran. Scale bar: 100 µm. <b>f</b> Quantification of the fluorescence intensity measured in the internodal regions of the teased fibres. (<i>n</i> = 138–296 from 5 to 6 animals per group, pairwise Mann–Whitney U tests). The relative gene expression of <b>g</b> <i>Cldn1</i>, <b>h</b> <i>Tjp1</i> and <b>i</b> <i>Cldn19</i> in the ligation parts of ipsilateral and contralateral sciatic nerves after 1, 3 and 6 weeks after CCI (n = 5–6). All data are shown as mean ± SEM, *<i>p</i> < 0.05 compared to control at the indicated time points, two-way ANOVA with Šidák’s multiple comparisons unless indicated otherwise</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/2" data-track-dest="link:Figure2 Full size image" aria-label="Full size image figure 2" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Hyperpermeability of the perineurium persisted for Fluo (332 Da) and EBA (69 kDa) for up to 9 weeks after CCI (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig2">2</a>b–d). To assess the state of the myelin barrier in the proximal, non-degenerating part of the nerve, we immersed desheathed nerve fibres in FITC-dextran (70 kDa). Dye leakage through the myelin barrier was similar after nerve injury compared with that in the sham group (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig2">2</a>e, f). Perineurium breakdown was reflected by low levels of <i>Cldn1</i> and <i>Tjp1</i> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig2">2</a>g, h) in the ligated region, whereas <i>Cldn19</i> expression was heavily reduced (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig2">2</a>i) in accordance with <i>Mpz</i> levels (SFig. 2b).</p><p>The integrity of the intraneural blood vessel barrier was compromised from weeks 1–6 for EBA and reestablished at week 9 (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig3">3</a>a–d). Intravenously injected EBA leaked through the blood vessels at the ligation and distal parts, whereas the blood–nerve barrier (BNB) in the proximal parts further away from the ligations was unaffected. Accordingly, <i>Cldn5</i> was reduced in the ligated region (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig3">3</a>h); exemplary fluorescence images of Cldn5 are depicted in SFig. 3. <i>Cldn12</i>, another tight junction protein, was also reduced and did not recover with pain resolution (SFig. 2a).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-3" data-title="Fig. 3"><figure><figcaption><b id="Fig3" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 3</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/3" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig3_HTML.png?as=webp"><img aria-describedby="Fig3" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig3_HTML.png" alt="figure 3" loading="lazy" width="685" height="718"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-3-desc"><p>The capillary barrier reseals specifically for fibrinogen in parallel with neuropathic pain. <b>a</b> Schematic illustration of the capillary permeability test: Evans blue albumin (EBA, 68 kDa) was intravenously injected. Cross sections at distinct positions distal and proximal from the ligations were collected and analysed. <b>b</b> Representative images of sciatic nerve cross sections. The dashed lines indicate the endoneurial regions. Scale bar: 300 µm. <b>c</b> Depiction of the spatial and temporal EBA extravasation into the endoneurium through endoneurial vessels. Sham values were averaged and plotted on each position as reference. Dashed lines mark the positions that were used for the calculations for the areas under the curve in <b>d</b> Quantification analysis of the areas under the curves distal and proximal from 0 to 6 mm from the ligations were plotted (<i>n</i> = 3–6). *distal vs. sham; #distal vs. proximal <i>p</i> < 0.05 two-way ANOVA with Bonferroni’s multiple comparison test. <b>e</b> Representative images of fibrinogen immunoreactivity in the sciatic nerve 1 week after surgery. The dashed lines indicate the endoneurial region. <b>f</b> Quantification of the intensity of fibrinogen immunoreactivity within the endoneurial regions (<i>n</i> = 5–6). Scale bar: 300 µm. Relative gene expression of <b>g</b> <i>Plat</i> and <b>h</b> <i>Cldn5</i> in sciatic nerves after CCI (<i>n</i> = 5–6). <b>i</b> Summary of all permeability tests. The heatmap displays the ratios between the arithmetic means of CCI and sham groups. All data are shown as mean ± SEM, *<i>p</i> < 0.05 two-way ANOVA with Šidák’s multiple comparisons</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/3" data-track-dest="link:Figure3 Full size image" aria-label="Full size image figure 3" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Endoneurial leakage of blood proteins is a well-known hallmark of polyneuropathy [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 56" title="Schenone A, De Martini I, Tabaton M, Romagnoli P, Akkad Wattar AS, Bianchini D et al (1988) Direct immunofluorescence in sural nerve biopsies. Eur Neurol 28:262–269. 
 https://doi.org/10.1159/000116281
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR56" id="ref-link-section-d431148989e1407">56</a>]. Fibrinogen (340 kDa) is a blood coagulation factor, produced in the liver, which polymerizes to fibrin upon tissue damage. tPA (gene: <i>Plat</i>) activates plasminogen to degrade fibrin. In injured nerves, fibrinogen accumulated endoneurially and <i>Plat</i> was upregulated until 3 weeks (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig3">3</a>e–g). When hypersensitivity was resolved, both fibrinogen and <i>Plat</i> returned to sham levels, indicating complete recovery of the BNB in terms of fibrinogen leakage. The capillary barrier was impermeable to fibrinogen at the time of complete pain resolution.</p><p>To detect endoneurial fibrinogen, we used an antibody binding to various fibrin(ogen) (degradation) products. Endoneurial fibrinogen correlated with the pain course in the analysis of the barrier portfolio (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig3">3</a>i), indicating that the presence of fibrinogen, a pro-inflammatory and pro-nociceptive molecule [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Akassoglou K, Kombrinck KW, Degen JL, Strickland S (2000) Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 149:1157–1166. 
 https://doi.org/10.1083/jcb.149.5.1157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR1" id="ref-link-section-d431148989e1429">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Lim TKY, Shi XQ, Martin HC, Huang H, Luheshi G, Rivest S et al (2014) Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief. Pain 155:954–967. 
 https://doi.org/10.1016/j.pain.2014.01.026
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR31" id="ref-link-section-d431148989e1432">31</a>] that penetrates the capillary of the BNB into the endoneurium, might explain the pathophysiology of the switch to pain resolution.</p><h3 class="c-article__sub-heading" id="Sec20">Human nerves contained more endoneurial fibrinogen in painful neuropathy</h3><p>To validate our preclinical findings in a translational approach, we analysed sural nerve biopsies of patients with different polyneuropathies (Table <a data-track="click" data-track-label="link" data-track-action="table anchor" href="/article/10.1007/s00401-024-02840-9#Tab1">1</a>). Patients were aged 69 ± 7.8 years and were mainly male (10 males and 6 females), with a disease duration of 52 ± 44.1 months and a clinical severity of neuropathy of 2 ± 1.2 (Overall Disability Sum Score [ODSS] score, 0 = no sign of disability to 12 = most severe disability). The demyelinating and axonal neuropathies were almost evenly distributed. Half of the patients (8 of 16) had pain at the time of nerve biopsy, while the other half did not. Follow-up information was available from only six patients. Three of them had pain, of which only one was painless several years later. We immunostained the nerves and compared the fibrinogen and tPA signal intensities (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig4">4</a>a, c). Patients with painful polyneuropathy showed higher fibrinogen immunoreactivity in the endoneurium, whereas the tPA levels did not differ (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig4">4</a>b, d). These results suggest that fibrinogen may also play a role in the persistence of pain in human patients with painful neuropathy with longer duration and lack of clearance.</p><div class="c-article-table" data-test="inline-table" data-container-section="table" id="table-1"><figure><figcaption class="c-article-table__figcaption"><b id="Tab1" data-test="table-caption">Table 1 Patient demographic and clinical characteristics of painful and non-painful neuropathies</b></figcaption><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="table-link" data-track="click" data-track-action="view table" data-track-label="button" rel="nofollow" href="/article/10.1007/s00401-024-02840-9/tables/1" aria-label="Full size table 1"><span>Full size table</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-4" data-title="Fig. 4"><figure><figcaption><b id="Fig4" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 4</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/4" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig4_HTML.png?as=webp"><img aria-describedby="Fig4" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig4_HTML.png" alt="figure 4" loading="lazy" width="685" height="453"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-4-desc"><p>More endoneurial fibrinogen in sural nerve biopsies from patients with painful polyneuropathies. Sural nerve biopsies from patients were immunofluorescently stained. Representative images of human sural nerves stained for <b>a</b> fibrinogen and <b>c</b> tissue plasminogen activator (tPA). The dashed lines indicate the endoneurial regions. Scale bar: 300 µm. <b>b, d</b> Quantifications of the signal intensity of fibrinogen and tPA. Patients were grouped by pain occurrence (<i>n</i> = 16, Student’s t tests with Welch’s correction)</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/4" data-track-dest="link:Figure4 Full size image" aria-label="Full size image figure 4" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><h3 class="c-article__sub-heading" id="Sec21">Lipidomics: 15R-HETE culminates selectively at the switch for pain resolution</h3><p>We hypothesized that pain resolution is initiated by resealing of the nerve barriers which in turn might be induced by SPMs [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 35" title="Luo J, Zhang WY, Li H, Zhang PH, Tian C, Wu CH et al (2022) Pro-resolving mediator resolvin E1 restores alveolar fluid clearance in acute respiratory distress syndrome. Shock 57:565–575. 
 https://doi.org/10.1097/shk.0000000000001865
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR35" id="ref-link-section-d431148989e2191">35</a>]. To identify the lipids driving the lipid mediator class switch from pro-inflammatory to pro-resolving and their respective receptors, we performed a lipidomic analysis by LC-MSMS and qPCR of the sciatic nerve (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>a). We analysed 34 lipids derived from arachidonic acid (AA), docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and detected 11 of them. Although pro-inflammatory prostaglandin E2 (PGE2) and thromboxane B2 (TXB2) were more abundant after injury, prostaglandin D2 (PGD2) levels were reduced. Among the three hydroxyeicosatetraenoic acid (HETE) precursor lipoxins (5S-, 15S- and 15R-HETE), only 15R-HETE selectively increased at the beginning of pain resolution (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>b). Specialized pro-resolving mediators, such as neuroprotection D1 (NPD1), resolvin D1 (RvD1), resolving D2 (RvD2) and maresin 1 (MaR1), could not be detected. Other lipids from pro-resolving synthesis pathways, such as 17S-HDHA (a precursor of RvD1 and 2) and 14S-HDHA (derived from DHA), showed higher concentrations, but not selectively, at 3 weeks (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>b). Lipids derived from EPA (18R-HEPE) were not detected.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-5" data-title="Fig. 5"><figure><figcaption><b id="Fig5" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 5</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/5" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig5_HTML.png?as=webp"><img aria-describedby="Fig5" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig5_HTML.png" alt="figure 5" loading="lazy" width="685" height="745"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-5-desc"><p>Unbiased lipidomic analysis selectively identified higher levels of the LXA4 precursor 15R-HETE at 3 weeks, initiating the resolution phase. <b>a</b> Arachidonic-, docosahexaenoic- and eicosapentaenoic acids-derived metabolites were measured by LC-MSMS in the sciatic nerve, and their cognate receptors were assessed using qPCR. <b>b</b> Relative levels of the 11 detected lipid metabolites are depicted. Only 15R-HETE (circled in red) had a significant upregulation in CCI specifically at 3 weeks compared with sham. <b>c</b> Relative mRNA expression of the respective SPM receptor after CCI; <i>CL</i> contralateral, <i>IL</i> ipsilateral. All data are shown as mean ± SEM, <i>n</i> = 5–6, two-way ANOVA with Šidák’s multiple comparisons. *<i>p</i> < 0.05; ANOVA: analysis of variance. <b>d</b> Expression levels as counts per million (CPM) of the SPM receptors from intact and injured human sural nerve tissues collected 2 weeks after a full transection injury (<i>n</i> = 6, Student’s <i>t</i> tests with Welch’s correction), as obtained from previously published bulk RNAseq data [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Welleford AS, Quintero JE, Seblani NE, Blalock E, Gunewardena S, Shapiro SM et al (2020) RNA sequencing of human peripheral nerve in response to injury: distinctive analysis of the nerve repair pathways. Cell Transplant 29:963689720926157. 
 https://doi.org/10.1177/0963689720926157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR72" id="ref-link-section-d431148989e2244">72</a>]</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/5" data-track-dest="link:Figure5 Full size image" aria-label="Full size image figure 5" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>To further evaluate the potential of the aspirin-triggered lipoxin A4 (AT-LXA4) precursor 15R-HETE to resolve pain, we determined the mRNA expression of its receptor, formyl peptide receptor 2 (<i>Fpr2</i>), and other known SPM receptors <i>Gpr18, Chem23r, Gpr37</i> and <i>Lgr6</i> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig4">5</a>c)<i>. Gpr18</i> and <i>ChemR23</i> were upregulated, whereas <i>Lgr6</i>, <i>Gpr37</i> and <i>Gpr37l1</i> were downregulated in the rat sciatic nerve. <i>Fpr2</i> was not abundant but was increased at 1 week and decreased 6 weeks after injury (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>c), but it is known to be expressed in rat macrophages [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 53" title="Rittner HL, Hackel D, Voigt P, Mousa S, Stolz A, Labuz D et al (2009) Mycobacteria attenuate nociceptive responses by formyl peptide receptor triggered opioid peptide release from neutrophils. PLoS Pathog 5:e1000362. 
 https://doi.org/10.1371/journal.ppat.1000362
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR53" id="ref-link-section-d431148989e2293">53</a>]. To assess the translatability of our findings, we reanalysed data from bulk RNA sequencing (RNAseq) experiments from human transected nerves compared to naive human nerves [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 72" title="Welleford AS, Quintero JE, Seblani NE, Blalock E, Gunewardena S, Shapiro SM et al (2020) RNA sequencing of human peripheral nerve in response to injury: distinctive analysis of the nerve repair pathways. Cell Transplant 29:963689720926157. 
 https://doi.org/10.1177/0963689720926157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR72" id="ref-link-section-d431148989e2296">72</a>]. In human nerves, <i>FPR2</i> and <i>CHEMR23</i> were increased, <i>GPR37L1</i> was downregulated, while <i>LGR6</i> was unchanged after injury (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>d). To further elucidate which cell type expresses the different receptors, we analysed receptor expression in purified in vitro cultured Schwann cells, the most abundant endoneurial cell type. <i>FPR2/Fpr2</i> was not expressed in human or rat Schwann cells before and after differentiation (SFig. 4) [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 6" title="Camarena V, Sant DW, Huff TC, Mustafi S, Muir RK, Aron AT et al (2017) cAMP signaling regulates DNA hydroxymethylation by augmenting the intracellular labile ferrous iron pool. Elife. 
 https://doi.org/10.7554/eLife.29750
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR6" id="ref-link-section-d431148989e2318">6</a>]. All other receptors (<i>CHEMR23</i>, <i>GPR18</i>, <i>LGR6, GPR37</i> and <i>GPR37L1</i>) were expressed in Schwann cells of human and/or rat origin as shown in SFig. 4. Since <i>Fpr2</i> was absent in Schwann cells, we next explored the cellular source of <i>Fpr2</i> after CCI. To this end, we reanalysed a previously published single-cell RNAseq (scRNAseq) dataset [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 33" title="Lovatt D, Tamburino A, Krasowska-Zoladek A, Sanoja R, Li L, Peterson V et al (2022) scRNA-seq generates a molecular map of emerging cell subtypes after sciatic nerve injury in rats. Commun Biol 5:1105. 
 https://doi.org/10.1038/s42003-022-03970-0
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR33" id="ref-link-section-d431148989e2340">33</a>] employing publicly available experimental results on gene expression at different time points after CCI (i.e. naive nerves as well as nerves 3, 12 and 60 days after CCI; SFig. 5a). In our reanalysis, we were able to identify the types of major cell populations, such as macrophages, Schwann cells and epineurial fibroblasts (SFig. 5b, c). Similar to our previous observations (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig5">5</a>c), <i>Fpr2</i> abundance was in general very low (SFig. 5d) but was significantly enriched in macrophages when compared to other cell types (SFig. 5e), indicating that the activation of Fpr2 primarily occurs in macrophages.</p><h3 class="c-article__sub-heading" id="Sec22">Fpr2 activation by BML-111 accelerates pain resolution and the degradation of fibrinogen</h3><p>Since we identified the AT-LXA4 precursor at the pain resolution switch, we further investigated Fpr2 at 2.5 weeks preceding ‘natural’ pain resolution. To specifically activate Fpr2 in the sciatic nerve, we applied the Fpr2 agonist BML-111 perineurially twice daily for 1 week and tested its analgesic effects using the von Frey and Hargreaves tests (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>a). The analgesic effect of 500 nmol BML-111 arose from 1 to 3 h after injection and vanished after 6 h (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>b). Therefore, we decided to administer a second dose after the behavioural test. Cumulative analgesic effects (measured before the first injections of the day) appeared on the 3rd day of injections and gradually increased during the 7-day injection period. While mechanical hypersensitivity significantly improved on day 6, thermal hypersensitivity significantly improved on day 2 and later reached the contralateral paw withdrawal thresholds (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>c, d). After 1 week of treatment, fibrinogen deposition was reduced in BML-111-treated nerves compared to that in vehicle-treated nerves (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>e, f). Elevated <i>Plat</i> levels in BML-111-treated nerves suggest that fibrinolysis was still in process (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>g) and not terminated, as observed in CCI animals after 6 weeks (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig3">3</a>g).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-6" data-title="Fig. 6"><figure><figcaption><b id="Fig6" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 6</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/6" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig6_HTML.png?as=webp"><img aria-describedby="Fig6" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig6_HTML.png" alt="figure 6" loading="lazy" width="685" height="707"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-6-desc"><p>Local application of the Fpr2 agonist BML-111 initiates pain resolution, macrophage polarization and fibrinogen clearance. <b>a</b> CCI-operated animals received a perineurial injection of BML-111 or vehicle (PBS). The animals were retested with Hargreaves and von Frey at 1, 2, 3 and 6 h. As soon as reflexive tests at 6 h were finished, the animals received a second injection from day 18 to 24 and were killed at day 25. Blue arrows indicate the daily injection/test programme. T: reflexive testing; syringe: injection. <b>b</b> Mechanical allodynia was measured after the first BML-111 injection on day 18 (<i>n</i> = 6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). Paw withdrawal thresholds for <b>c</b> mechanical and <b>d</b> thermal hypersensitivities of baseline measurements show an accumulative effect of perineurial BML-111 (<i>n</i> = 5–6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). <b>e, f</b> Representative images and quantification of fibrinogen immunostaining in the sciatic nerve after BML-111 injections. The dashed lines indicate the endoneurial region. Scale bar: 300 µm (<i>n</i> = 6, Student’s t tests with Welch’s correction). <b>g-k</b> Relative mRNA expression of <i>Tnfα</i>, <i>Arg1</i>, <i>Cd206,</i> <i>Nlrp3</i> and <i>Plat</i> after BML-111 injections (<i>n</i> = 6, Student’s <i>t</i> tests with Welch’s correction). <b>l</b> Mechanical allodynia was assessed daily for 1 week after injections were discontinued (<i>n</i> = 6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). <i>ANOVA</i> analysis of variance. All data are shown as mean ± SEM, *<i>p</i> < 0.05</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/6" data-track-dest="link:Figure6 Full size image" aria-label="Full size image figure 6" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>Fpr2 inhibits pro-inflammatory and pro-nociceptive genes such as <i>Tnfα</i> and <i>Nlrp3</i> and promotes anti-inflammatory macrophages expressing <i>Arg1</i> and <i>Cd206</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 7" title="Cao Y, Zhou X, Yin Z, Yu X, Yang Q, Guo Q et al (2018) The anti-inflammatory effect of BML-111 on COPD may be mediated by regulating NLRP3 inflammasome activation and ROS production. Prostaglandins Other Lipid Mediat 138:23–30. 
 https://doi.org/10.1016/j.prostaglandins.2018.08.001
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR7" id="ref-link-section-d431148989e2476">7</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 74" title="Yuan J, Lin F, Chen L, Chen W, Pan X, Bai Y et al (2022) Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2–IRF pathway. Inflammopharmacology 30:487–498. 
 https://doi.org/10.1007/s10787-022-00942-y
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR74" id="ref-link-section-d431148989e2480">74</a>]. In our system, only <i>Cd206</i> expression was increased (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>h–k), highlighting the role of endoneurial fibrinogen. Over the course of 6 weeks, the increased abundance of <i>Tnfα</i>, which is known to induce pain, in the CCI nerve compared to sham suggests that <i>Tnfα</i> might not be critically involved in pain resolution (SFig. 6). We checked whether <i>Cd206</i> was upregulated in the phase of pain resolution; however, <i>Cd206</i> levels mirrored the <i>Plat</i> levels, while <i>Cd68</i> remained stably elevated after 6 weeks (SFig. 6).</p><p>To determine whether the activation of Fpr2 induces permanent or irreversible pain relief, we tested the mechanical allodynia of BML-111-administered animals for 1 week after injections. After the last BML-111 treatment, mechanical thresholds remained stable for 3 days and re-approached the levels of vehicle animals, which showed slowly resolving pain (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig6">6</a>l).</p><h3 class="c-article__sub-heading" id="Sec23">RvD1 nanoparticles also accelerate resolution in male and female rats</h3><p>Analgesia by BML-111 ceased rapidly, and SPMs were even shorter-lasting. To evaluate SPMs as therapeutic long-lasting Fpr2 agonists, we applied RvD1-laden polymeric nanoparticles (RvD1-NPs, Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>a). The nanoparticles released RvD1 with maximum concentrations between 3 and 24 h (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>b). Based on these kinetics, RvD1-NPs only needed to be applied once daily to ensure continuous RvD1 supply. RvD1-NPs elicited analgesic effects on mechanical allodynia (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>c, d). RvD1-NPs caused fibrinogen degradation in the endoneurium and a trend for increased <i>Plat</i> (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>e–g). Similar to BML-111-treated animals, <i>Tnfα</i>, <i>Nlrp3</i> and <i>Arg1</i> levels did not change after RvD1-NP injection, and <i>Cd206</i> was upregulated (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>h–k). Similar effects were observed after RvD1-NP treatment in female rats, suggesting a similar mechanism in male and female rats (SFig. 7).</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-7" data-title="Fig. 7"><figure><figcaption><b id="Fig7" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 7</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/7" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig7_HTML.png?as=webp"><img aria-describedby="Fig7" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig7_HTML.png" alt="figure 7" loading="lazy" width="685" height="743"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-7-desc"><p>Locally applied RvD1-laden nanoparticles (NPs) induce pain resolution, macrophage polarization and fibrinogen clearance after CCI. <b>a</b> Treatment plan for RvD1-NPs in CCI-operated male rats: The animals received a perineurial injection of RvD1-NPs or empty NPs. They were tested at baseline, 1, 2, 3 and 6 h from days 18 to 24, and killed on day 25. Blue arrows indicate daily injection/test programme. <i>T</i> reflexive testing; syringe: injection. <b>b</b> Estimated amount of released RvD1 from NPs by a dialysis experiment. The NP solution was diluted in PBS and incubated at 37 °C in dialysis tubes. The RvD1 concentration of the dialysates was subsequently determined by LC-MSMS (<i>n</i> = 1). <b>c</b> Mechanical allodynia was measured after the first RvD1-NP injection on day 18 (<i>n</i> = 6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). <b>d</b> Mechanical hypersensitivities measured before the injections during the injection period (<i>n</i> = 6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). <b>e</b> Representative images of fibrinogen immunostaining in sciatic nerve cross sections after RvD1-NP injections. The dashed lines indicate the endoneurial region. Scale bar: 300 µm. <b>f</b> Quantification of the intensity of fibrinogen immunoreactivity within the endoneurial regions (<i>n</i> = 6, Student’s <i>t</i> tests with Welch’s correction). <b>g-k</b> Relative mRNA expression of <i>Tnfα</i>, <i>Arg1</i>, <i>Cd206,</i> <i>Nlrp3</i> and <i>Plat</i> after daily RvD1-NP injections (<i>n</i> = 6, Student’s <i>t</i> tests with Welch’s correction). <b>l</b> Fluxes of FITC-labelled fibrinogen through monolayers of primary HDMECs were measured in vitro. Extracellular FITC-fibrinogen fluorescence intensity was assessed to evaluate paracellular barrier integrity, while intracellular FITC-fibrinogen was assessed to evaluate transcellular passage, potentially via endocytosis (<i>n</i> = 7–9, one-way ANOVA with multiple comparisons). <i>NP</i> empty nanoparticles, <i>RvD1-NP</i> RvD1-laden nanoparticles, <i>ANOVA</i> analysis of variance, <i>PBS</i> phosphate-buffered saline, <i>CCI</i> chronic constriction injury, <i>HDMECs</i> human dermal microvascular endothelial cells. Scale bar: 300 µm. All data are shown as mean ± SEM, *<i>p</i> < 0.05</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/7" data-track-dest="link:Figure7 Full size image" aria-label="Full size image figure 7" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div><p>To assess the effects on the endothelial barrier, we conducted experiments employing HDMECs, which are of endothelial origin and possess typical features that are present in endoneurial vessels as well. Fluxes of FITC-labelled fibrinogen through a monolayer of HDMECs were assessed to study the barrier after challenge with TNF-α and treatment with RvD1. Treatment with TNF-α significantly increased the paracellular permeability for FITC-fibrinogen, while transcellular routes remained unaffected (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>l). RvD1 was able to completely restore this TNF-α-induced barrier defect (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig7">7</a>l).</p><h3 class="c-article__sub-heading" id="Sec24">Fpr2-fibrinogen clearance pathway is inhibited by TAM receptor blocking</h3><p>Schwann cells are the main drivers of fibrinogen clearance through tPA secretion [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Akassoglou K, Kombrinck KW, Degen JL, Strickland S (2000) Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 149:1157–1166. 
 https://doi.org/10.1083/jcb.149.5.1157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR1" id="ref-link-section-d431148989e2679">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Pellegatta M, Canevazzi P, Forese MG, Podini P, Valenzano S, Carro U et al (2022) ADAM17 regulates p75NTR-mediated fibrinolysis and nerve remyelination. J Neurosci 42:2433–2447. 
 https://doi.org/10.1523/jneurosci.1341-21.2022
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR47" id="ref-link-section-d431148989e2682">47</a>] but do not express Fpr2. Growth arrest-specific 6 (Gas6), the cognate glycoprotein ligand for TAM receptors secreted by macrophages, is necessary for Schwann cell maturation after nerve injury [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 61" title="Stratton JA, Holmes A, Rosin NL, Sinha S, Vohra M, Burma NE et al (2018) Macrophages regulate Schwann cell maturation after nerve injury. Cell Rep 24:2561-2572.e2566. 
 https://doi.org/10.1016/j.celrep.2018.08.004
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR61" id="ref-link-section-d431148989e2685">61</a>]. Thus, we hypothesized that Fpr2 activation induces Gas6 release from macrophages, which triggers tPA secretion in Schwann cells and leads to fibrinogen clearance (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig8">8</a>a). In a previously published scRNAseq dataset (Supplementary Methods), we found <i>Gas6</i> expression in macrophages and epineurial fibroblasts (SFig. 8a). A lot of macrophages were <i>Cd206</i><sup>+</sup> anti-inflammatory macrophages, while <i>Cd80</i><sup>+</sup> pro-inflammatory macrophages were not abundant (SFig. 8a). We further found that <i>Gas6</i> expression was more prevalent in <i>Cd206</i><sup>+</sup> than in <i>Cd206</i><sup><i>−</i></sup> macrophages (SFig. 8b, c). In addition, the Gas6 receptors <i>Axl</i> and <i>Mertk</i> were expressed in Schwann cells (SFig. 8d). Further functional evidence supported the TAM pathway: Co-injection of the TAM inhibitor RU-301 to block TAM signalling before each BML-111 injection inhibited the analgesic effects of BML-111 on mechanical and thermal hypersensitivity (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig8">8</a>b, c). Under TAM blockade conditions, endoneurial fibrinogen was not cleared although <i>Plat</i> levels were not reduced (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig8">8</a>d–f). <i>Cd206</i> was not upregulated (Fig. <a data-track="click" data-track-label="link" data-track-action="figure anchor" href="/article/10.1007/s00401-024-02840-9#Fig8">8</a>g). We expected that <i>Cd206</i> would not be changed by TAM blocking since we hypothesized that the <i>Cd206</i> and macrophage polarization increase was mainly caused by Fpr2 stimulation. But TAM receptors also mediate the macrophage phenotype shift [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Vago JP, Amaral FA, van de Loo FAJ (2021) Resolving inflammation by TAM receptor activation. Pharmacol Ther 227:107893. 
 https://doi.org/10.1016/j.pharmthera.2021.107893
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR68" id="ref-link-section-d431148989e2745">68</a>] and are also necessary for the Fpr2-mediated macrophage phenotype shift. In the scRNAseq dataset, only very few pro-inflammatory <i>Cd80</i><sup>+</sup> macrophages were present. In our nerve samples, we found many CD206<sup>+</sup> and basically no CD80<sup>+</sup> cells throughout 1–6 weeks after CCI (SFig. 9). Instead of a macrophage phenotype shift, we propose a pro-resolving boost of macrophages. These results indicate that TAMs and their ligands are critically involved in pain resolution and fibrinolysis.</p><div class="c-article-section__figure js-c-reading-companion-figures-item" data-test="figure" data-container-section="figure" id="figure-8" data-title="Fig. 8"><figure><figcaption><b id="Fig8" class="c-article-section__figure-caption" data-test="figure-caption-text">Fig. 8</b></figcaption><div class="c-article-section__figure-content"><div class="c-article-section__figure-item"><a class="c-article-section__figure-link" data-test="img-link" data-track="click" data-track-label="image" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/8" rel="nofollow"><picture><source type="image/webp" srcset="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig8_HTML.png?as=webp"><img aria-describedby="Fig8" src="//media.springernature.com/lw685/springer-static/image/art%3A10.1007%2Fs00401-024-02840-9/MediaObjects/401_2024_2840_Fig8_HTML.png" alt="figure 8" loading="lazy" width="685" height="1230"></picture></a></div><div class="c-article-section__figure-description" data-test="bottom-caption" id="figure-8-desc"><p>Blocking TAM receptors inhibits Fpr2-mediated pain resolution and fibrinogen clearance. <b>a</b> Proposed model of pain relief through Fpr2 activation and involvement of the TAM receptor family of receptor tyrosine kinases (Tyro3, Axl and MerTK) in macrophages and Schwann cells leading to fibrinogen clearance: For details, see text. <b>b, c</b> Male Wistar rats received BML-111 injections combined with prior injections of the TAM receptor inhibitor RU-301 for 1 week. Paw withdrawal thresholds for <b>b</b> mechanical and <b>c</b> thermal hypersensitivities (<i>n</i> = 6, two-way repeated-measures ANOVA with Tukey’s multiple comparisons). <b>d, e</b> Representative images of fibrinogen immunostaining and quantification within the endoneurial regions in sciatic nerve cross sections after BML-111 with or without RU-301 injections. The dashed lines indicate the endoneurial region (<i>n</i> = 6, Student’s <i>t</i> tests with Welch’s correction). Scale bar: 300 µm. <b>f, g</b> Relative mRNA expression of <i>Cd206</i> and <i>Plat</i> after 1 week of BML-111 administration with and without TAM blocking</p></div></div><div class="u-text-right u-hide-print"><a class="c-article__pill-button" data-test="article-link" data-track="click" data-track-label="button" data-track-action="view figure" href="/article/10.1007/s00401-024-02840-9/figures/8" data-track-dest="link:Figure8 Full size image" aria-label="Full size image figure 8" rel="nofollow"><span>Full size image</span><svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-chevron-right-small"></use></svg></a></div></figure></div></div></div></section><section data-title="Discussion"><div class="c-article-section" id="Sec25-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec25">Discussion</h2><div class="c-article-section__content" id="Sec25-content"><p>In this study, we characterized the pathophysiology of the injured sciatic nerve at the switch towards pain resolution and identified local treatment options for its acceleration. Beyond the known pathways, we included neural barriers, the coagulation system and TAM receptors in this process. Pain resolution and functional recovery were independent processes in both male and female rats. Hyperalgesia was intertwined with enhanced diffusion and failed removal of endoneurial fibrinogen, whereas all other neural barriers were intact or persistently open. Using a translational approach, we further showed that—in line with the findings of the rat model of neuropathy—fibrinogen immunoreactivity was enhanced in nerve biopsies from neuropathic patients with pain in comparison with those without pain. Lipidomic screening of SPMs and their receptors identified Fpr2 ligand precursors at switch points. Fpr2 ligands, such as BML-111 and RvD1-NPs, profoundly boosted fibrinogen clearance and pain resolution beyond immediate application. TAM receptors mediated this signalling cascade through fibrinolysis. In patients with painful polyneuropathies, endoneurial fibrinogen deposition and anti-inflammatory activity were increased, which might indicate similar mechanisms. These novel findings provide new options for the treatment of unresolved neuropathic pain when fibrinogen deposition is prevalent.</p><p>The course of thermal and mechanical allodynia after CCI in male and female rats was similar to that previously described [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 60" title="Sommer C, Galbraith JA, Heckman HM, Myers RR (1993) Pathology of experimental compression neuropathy producing hyperesthesia. J Neuropathol Exp Neurol 52:223–233. 
 https://doi.org/10.1097/00005072-199305000-00006
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR60" id="ref-link-section-d431148989e2821">60</a>]. Gait patterns did not completely recover, which might be attributed to residual muscle weakness or coordination deficits and possibly higher sensitivity compared to von Frey in CCI rats [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 11" title="Chiang CY, Sheu ML, Cheng FC, Chen CJ, Su HL, Sheehan J et al (2014) Comprehensive analysis of neurobehavior associated with histomorphological alterations in a chronic constrictive nerve injury model through use of the CatWalk XT system. J Neurosurg 120:250–262. 
 https://doi.org/10.3171/2013.9.JNS13353
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR11" id="ref-link-section-d431148989e2824">11</a>]. However, CCI rats still reached similar distances and speeds on the voluntary running wheel, suggesting that their overall activity was unaffected.</p><p>In our permeability assays, none of the nerve barriers completely recovered with the resolution of pain. The perineurium remained leaky until week 9, which was also reflected by the low expression of tight junction proteins. Similar findings have been previously reported [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 25" title="Hirasawa Y, Saiki T, Nakao Y, Katsumi Y (1994) Regeneration of perineurium after nerve injury and autografting. An experiment study. Int Orthop 18:229–235. 
 https://doi.org/10.1007/bf00188327
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR25" id="ref-link-section-d431148989e2830">25</a>]. The open perineurium most likely enabled the diffusion of the perineurally applied substances, which would not be possible in conditions with a sealed perineurium. The perineurial barrier can be transiently opened with hypertonic saline. Simultaneous application allows for the delivery of therapeutics [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 22" title="Hackel D, Krug SM, Sauer RS, Mousa SA, Bocker A, Pflucke D et al (2012) Transient opening of the perineurial barrier for analgesic drug delivery. Proc Natl Acad Sci U S A 109:E2018-2027. 
 https://doi.org/10.1073/pnas.1120800109
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR22" id="ref-link-section-d431148989e2833">22</a>].</p><p>Interestingly, the capillary barrier remained permeable to the EBA tracer until 6 weeks; however, at this time point, fibrinogen deposition was already cleared from the endoneurium. We postulate that fibrinogen clearance from the endoneurium is necessary for complete recovery of the capillary barrier. Endoneurial fibrinogen drives axonal degeneration and prevents Schwann cell redifferentiation [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 1" title="Akassoglou K, Kombrinck KW, Degen JL, Strickland S (2000) Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. J Cell Biol 149:1157–1166. 
 https://doi.org/10.1083/jcb.149.5.1157
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR1" id="ref-link-section-d431148989e2839">1</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Akassoglou K, Yu W-M, Akpinar P, Strickland S (2002) Fibrin inhibits peripheral nerve remyelination by regulating schwann cell differentiation. Neuron 33:861–875. 
 https://doi.org/10.1016/S0896-6273(02)00617-7
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR2" id="ref-link-section-d431148989e2842">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 13" title="Davalos D, Akassoglou K (2012) Fibrinogen as a key regulator of inflammation in disease. Semin Immunopathol 34:43–62. 
 https://doi.org/10.1007/s00281-011-0290-8
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR13" id="ref-link-section-d431148989e2845">13</a>], while successful clearance of fibrinogen and myelin debris allows Schwann cell remyelination [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 2" title="Akassoglou K, Yu W-M, Akpinar P, Strickland S (2002) Fibrin inhibits peripheral nerve remyelination by regulating schwann cell differentiation. Neuron 33:861–875. 
 https://doi.org/10.1016/S0896-6273(02)00617-7
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR2" id="ref-link-section-d431148989e2848">2</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 47" title="Pellegatta M, Canevazzi P, Forese MG, Podini P, Valenzano S, Carro U et al (2022) ADAM17 regulates p75NTR-mediated fibrinolysis and nerve remyelination. J Neurosci 42:2433–2447. 
 https://doi.org/10.1523/jneurosci.1341-21.2022
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR47" id="ref-link-section-d431148989e2851">47</a>]. In turn, dedifferentiated Schwann cells induce opening of the capillary barrier, as evidenced by immune cell infiltration and EBA tracer extravasation, both of which recover when Schwann cells redifferentiate [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 42" title="Napoli I, Noon LA, Ribeiro S, Kerai AP, Parrinello S, Rosenberg LH et al (2012) A central role for the ERK-signaling pathway in controlling Schwann cell plasticity and peripheral nerve regeneration in vivo. Neuron 73:729–742. 
 https://doi.org/10.1016/j.neuron.2011.11.031
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR42" id="ref-link-section-d431148989e2855">42</a>], indicating that barrier closure is dependent on fibrinogen clearance. This could explain the delayed complete recovery of the EBA tracer permeability. The tight junction mRNA expression was in accordance with the results of the permeability assay. However, <i>Malong </i>et al<i>.</i> showed in a non-injury model that Schwann cells exclusively induce barrier breakdown by increasing transcytosis rates, while tight junctions remain intact [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Malong L, Napoli I, Casal G, White IJ, Stierli S, Vaughan A et al (2023) Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery. Dev Cell 58:174-191.e178. 
 https://doi.org/10.1016/j.devcel.2023.01.002
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR37" id="ref-link-section-d431148989e2864">37</a>]. The exact mechanism of leakage remains unknown in our analysis.</p><p>Pain resolution coincided with the clearance of endoneurial fibrinogen rather than with inflammation or resealing of capillary vessels for smaller molecules. Possible indirect pro-nociceptive mechanisms of fibrinogen might involve cytokine release from Schwann cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 27" title="Hu Z, Deng N, Liu K, Zhou N, Sun Y, Zeng W (2020) CNTF-STAT3-IL-6 axis mediates neuroinflammatory cascade across Schwann cell-neuron-microglia. Cell Reports 31:107657. 
 https://doi.org/10.1016/j.celrep.2020.107657
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR27" id="ref-link-section-d431148989e2871">27</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 71" title="Wang Q, Li H-y, Ling Z-m, Chen G, Wei Z-Y (2022) Inhibition of Schwann cell pannexin 1 attenuates neuropathic pain through the suppression of inflammatory responses. J Neuroinflammation 19:244. 
 https://doi.org/10.1186/s12974-022-02603-x
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR71" id="ref-link-section-d431148989e2874">71</a>] or inhibited anti-nociceptive mechanisms [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 54" title="Sadri M, Hirosawa N, Le J, Romero H, Martellucci S, Kwon HJ et al (2021) Tumor necrosis factor receptor-1 is selectively sequestered into Schwann cell extracellular vesicles where it functions as a TNFα decoy. Glia. 
 https://doi.org/10.1002/glia.24098
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR54" id="ref-link-section-d431148989e2877">54</a>] when in contact with fibrinogen. In addition, fibrinogen might directly interact with neuronal axons via toll-like receptor 4, as suggested by <i>Lim </i>et al<i>.</i> [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Lim TKY, Shi XQ, Martin HC, Huang H, Luheshi G, Rivest S et al (2014) Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief. Pain 155:954–967. 
 https://doi.org/10.1016/j.pain.2014.01.026
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR31" id="ref-link-section-d431148989e2887">31</a>]. Macrophages or microglia are activated by fibrinogen through the CD11b/CD18 receptor and induce inflammatory mechanisms in the CNS [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 48" title="Petersen MA, Ryu JK, Akassoglou K (2018) Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat Rev Neurosci 19:283–301. 
 https://doi.org/10.1038/nrn.2018.13
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR48" id="ref-link-section-d431148989e2890">48</a>], but to our knowledge, there is no study investigating the effect of fibrinogen on macrophages in the PNS. As fibrinogen is a pro-nociceptive and pro-inflammatory molecule [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 31" title="Lim TKY, Shi XQ, Martin HC, Huang H, Luheshi G, Rivest S et al (2014) Blood-nerve barrier dysfunction contributes to the generation of neuropathic pain and allows targeting of injured nerves for pain relief. Pain 155:954–967. 
 https://doi.org/10.1016/j.pain.2014.01.026
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR31" id="ref-link-section-d431148989e2893">31</a>], its degradation<b>,</b> together with less diffusion, alleviates hypersensitivity.</p><p>In the case of fibrinogen deposition, pain relief could also be achieved by targeting fibrinogen. Intravenous recombinant tissue plasminogen activator (rtPA) is used clinically for stroke treatment. To overcome half-life issues and adverse effects such as haemorrhaging, researchers have been developing nanoparticles as carriers for rtPA [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 8" title="Chen HA, Ma YH, Hsu TY, Chen JP (2020) Preparation of peptide and recombinant tissue plasminogen activator conjugated Poly(Lactic-Co-Glycolic Acid) (PLGA) magnetic nanoparticles for dual targeted thrombolytic therapy. Int J Mol Sci. 
 https://doi.org/10.3390/ijms21082690
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR8" id="ref-link-section-d431148989e2902">8</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 14" title="Deng J, Mei H, Shi W, Pang ZQ, Zhang B, Guo T et al (2018) Recombinant tissue plasminogen activator-conjugated nanoparticles effectively targets thrombolysis in a rat model of middle cerebral artery occlusion. Curr Med Sci 38:427–435. 
 https://doi.org/10.1007/s11596-018-1896-z
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR14" id="ref-link-section-d431148989e2905">14</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 16" title="Dong MX, Hu QC, Shen P, Pan JX, Wei YD, Liu YY et al (2016) Recombinant tissue plasminogen activator induces neurological side effects independent on thrombolysis in mechanical animal models of focal cerebral infarction: a systematic review and meta-analysis. PLoS One 11:e0158848. 
 https://doi.org/10.1371/journal.pone.0158848
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR16" id="ref-link-section-d431148989e2908">16</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 28" title="Huang L, Wang J, Huang S, Siaw-Debrah F, Nyanzu M, Zhuge Q (2019) Polyacrylic acid-coated nanoparticles loaded with recombinant tissue plasminogen activator for the treatment of mice with ischemic stroke. Biochem Biophys Res Commun 516:565–570. 
 https://doi.org/10.1016/j.bbrc.2019.06.079
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR28" id="ref-link-section-d431148989e2911">28</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Ma H, Jiang Z, Xu J, Liu J, Guo ZN (2021) Targeted nano-delivery strategies for facilitating thrombolysis treatment in ischemic stroke. Drug Deliv 28:357–371. 
 https://doi.org/10.1080/10717544.2021.1879315
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR36" id="ref-link-section-d431148989e2914">36</a>]. One of the proposed advantages of nanoparticles is that they can be developed to not penetrate the blood–brain barrier [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 36" title="Ma H, Jiang Z, Xu J, Liu J, Guo ZN (2021) Targeted nano-delivery strategies for facilitating thrombolysis treatment in ischemic stroke. Drug Deliv 28:357–371. 
 https://doi.org/10.1080/10717544.2021.1879315
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR36" id="ref-link-section-d431148989e2918">36</a>]. Since nanoparticles might be too large to penetrate the open BNB, perineurial injection, as we did, could be considered. Considering the adverse effects of the current rtPA therapy or analgesic drugs, SPMs could serve as promising alternative in pain therapy as they do not induce any analgesic effects in sham models or naïve rodents [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 26" title="Hu S, Mao-Ying Q-L, Wang J, Wang Z-F, Mi W-L, Wang X-W et al (2012) Lipoxins and aspirin-triggered lipoxin alleviate bone cancer pain in association with suppressing expression of spinal proinflammatory cytokines. J Neuroinflammation 9:278. 
 https://doi.org/10.1186/1742-2094-9-278
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR26" id="ref-link-section-d431148989e2921">26</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 64" title="Tian Y, Liu M, Mao-Ying QL, Liu H, Wang ZF, Zhang MT et al (2015) Early single Aspirin-triggered Lipoxin blocked morphine anti-nociception tolerance through inhibiting NALP1 inflammasome: Involvement of PI3k/Akt signaling pathway. Brain Behav Immun 50:63–77. 
 https://doi.org/10.1016/j.bbi.2015.06.016
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR64" id="ref-link-section-d431148989e2924">64</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 70" title="Wang ZF, Li Q, Liu SB, Mi WL, Hu S, Zhao J et al (2014) Aspirin-triggered Lipoxin A4 attenuates mechanical allodynia in association with inhibiting spinal JAK2/STAT3 signaling in neuropathic pain in rats. Neuroscience 273:65–78. 
 https://doi.org/10.1016/j.neuroscience.2014.04.052
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR70" id="ref-link-section-d431148989e2927">70</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 73" title="Xu ZZ, Berta T, Ji RR (2013) Resolvin E1 inhibits neuropathic pain and spinal cord microglial activation following peripheral nerve injury. J Neuroimmune Pharmacol 8:37–41. 
 https://doi.org/10.1007/s11481-012-9394-8
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR73" id="ref-link-section-d431148989e2930">73</a>], but adverse effects need to be properly assessed.</p><p>In our lipidomic analysis, only 11 out of 34 lipids were detected in the sciatic nerve of CCI or sham animals. SPMs themselves were undetectable. This may be because of nutritional or technical reasons. First, the standard chow is probably not rich in omega-3 acids. Indeed, feeding fish oil drastically increases RvD1 levels [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 32" title="Lobo BW, Lima CK, Teixeira MS, Silva NL, Takiya CM, Ramos MF et al (2016) Fish oil attenuates persistent inflammatory pain in rats through modulation of TNF-α and resolvins. Life Sci 152:30–37. 
 https://doi.org/10.1016/j.lfs.2016.03.034
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR32" id="ref-link-section-d431148989e2936">32</a>]. Second, the methods to measure endogenous SPMs and their detectability in the context of their instability and low concentrations are controversial [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 55" title="Schebb NH, Kühn H, Kahnt AS, Rund KM, O’Donnell VB, Flamand N et al (2022) Formation, signaling and occurrence of specialized pro-resolving lipid mediators—what is the evidence so far? Front Pharmacol. 
 https://doi.org/10.3389/fphar.2022.838782
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR55" id="ref-link-section-d431148989e2939">55</a>]. Exogenously applied SPMs and their analogues have shown pro-resolving effects in different tissue types and conditions in numerous studies, including ours [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 49" title="Poblete RA, Arenas M, Sanossian N, Hong Y-K, Freeman WD, Lyden PD et al (2022) Pro-resolving lipid mediators in traumatic brain injury: emerging concepts and translational approach. Am J Transl Res 14:1482–1494" href="/article/10.1007/s00401-024-02840-9#ref-CR49" id="ref-link-section-d431148989e2942">49</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 63" title="Tao X, Lee MS, Donnelly CR, Ji RR (2020) Neuromodulation, specialized proresolving mediators, and resolution of pain. Neurotherapeutics 17:886–899. 
 https://doi.org/10.1007/s13311-020-00892-9
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR63" id="ref-link-section-d431148989e2945">63</a>]. In fact, the encapsulation of SPMs into nanoparticles seems to be a promising technology for the delivery of anti-inflammatory substances [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 39" title="Miranda J, Brazil JC, Morris AH, Parkos CA, Quiros M, Nusrat A (2023) Maresin-2 promotes mucosal repair and has therapeutic potential when encapsulated in thermostable nanoparticles. Proc Natl Acad Sci USA 120:e2218162120. 
 https://doi.org/10.1073/pnas.2218162120
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR39" id="ref-link-section-d431148989e2948">39</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 51" title="Quiros M, Feier D, Birkl D, Agarwal R, Zhou DW, García AJ et al (2020) Resolvin E1 is a pro-repair molecule that promotes intestinal epithelial wound healing. Proc Natl Acad Sci USA 117:9477–9482. 
 https://doi.org/10.1073/pnas.1921335117
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR51" id="ref-link-section-d431148989e2952">51</a>].</p><p>The effect of Fpr2 activation is most likely multifactorial and reciprocal. In our in vitro barrier model, RvD1 protected the monolayer against fibrinogen flux after TNF-α challenge. But also, TAM signalling and fibrinogen act on endothelial cells [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 3" title="Avanzi GC, Gallicchio M, Bottarel F, Gammaitoni L, Cavalloni G, Buonfiglio D et al (1998) GAS6 inhibits granulocyte adhesion to endothelial cells. Blood 91:2334–2340. 
 https://doi.org/10.1182/blood.V91.7.2334
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR3" id="ref-link-section-d431148989e2958">3</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 23" title="Happonen KE, Tran S, Mörgelin M, Prince R, Calzavarini S, Angelillo-Scherrer A et al (2016) The Gas6-Axl protein interaction mediates endothelial uptake of platelet microparticles *. J Biol Chem 291:10586–10601. 
 https://doi.org/10.1074/jbc.M115.699058
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR23" id="ref-link-section-d431148989e2961">23</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 41" title="Muradashvili N, Benton RL, Tyagi R, Tyagi SC, Lominadze D (2014) Elevated level of fibrinogen increases caveolae formation; role of matrix metalloproteinase-9. Cell Biochem Biophys 69:283–294. 
 https://doi.org/10.1007/s12013-013-9797-z
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR41" id="ref-link-section-d431148989e2964">41</a>]. Fibrinogen increases endothelial permeability [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 45" title="Patibandla PK, Tyagi N, Dean WL, Tyagi SC, Roberts AM, Lominadze D (2009) Fibrinogen induces alterations of endothelial cell tight junction proteins. J Cell Physiol 221:195–203. 
 https://doi.org/10.1002/jcp.21845
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR45" id="ref-link-section-d431148989e2967">45</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 46" title="Paul J, Strickland S, Melchor JP (2007) Fibrin deposition accelerates neurovascular damage and neuroinflammation in mouse models of Alzheimer’s disease. J Exp Med 204:1999–2008. 
 https://doi.org/10.1084/jem.20070304
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR46" id="ref-link-section-d431148989e2970">46</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 66" title="Tyagi N, Roberts AM, Dean WL, Tyagi SC, Lominadze D (2008) Fibrinogen induces endothelial cell permeability. Mol Cell Biochem 307:13–22. 
 https://doi.org/10.1007/s11010-007-9579-2
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR66" id="ref-link-section-d431148989e2974">66</a>], whereas TAM signalling strengthens barrier integrity [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 38" title="Miner JJ, Daniels BP, Shrestha B, Proenca-Modena JL, Lew ED, Lazear HM et al (2015) The TAM receptor Mertk protects against neuroinvasive viral infection by maintaining blood-brain barrier integrity. Nat Med 21:1464–1472. 
 https://doi.org/10.1038/nm.3974
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR38" id="ref-link-section-d431148989e2977">38</a>]. The role of macrophages as guardians of the capillary barrier involves uptake of infiltrating molecules. Under homeostatic conditions, the endothelial barrier in the nerve and dorsal root ganglion allows minimal amounts of blood molecules to pass through, which are taken up by macrophages [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 34" title="Lund H, Hunt MA, Kurtović Z, Sandor K, Kägy PB, Fereydouni N et al (2024) CD163+ macrophages monitor enhanced permeability at the blood-dorsal root ganglion barrier. J Exp Med. 
 https://doi.org/10.1084/jem.20230675
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR34" id="ref-link-section-d431148989e2980">34</a>, <a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 37" title="Malong L, Napoli I, Casal G, White IJ, Stierli S, Vaughan A et al (2023) Characterization of the structure and control of the blood-nerve barrier identifies avenues for therapeutic delivery. Dev Cell 58:174-191.e178. 
 https://doi.org/10.1016/j.devcel.2023.01.002
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR37" id="ref-link-section-d431148989e2983">37</a>]. TAMs can shift macrophages to a phenotype with pro-resolving properties [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 68" title="Vago JP, Amaral FA, van de Loo FAJ (2021) Resolving inflammation by TAM receptor activation. Pharmacol Ther 227:107893. 
 https://doi.org/10.1016/j.pharmthera.2021.107893
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR68" id="ref-link-section-d431148989e2986">68</a>]. In our case, Fpr2 activation might lead to pain resolution through the macrophage phenotype boost, which further activates TAM signalling, leading to sustained <i>Cd206</i>-expressing macrophage population, fibrinolysis, plasmin synthesis, debris removal and BNB resealing, alleviating neuroinflammation and thereby neuropathic pain.</p><p>The strengths of this study include the diverse array of experimental approaches used to examine the mechanical and thermal hyperalgesia in male and female rats. Furthermore, we examined fully established neuropathic pain and developed a suitable intervention option not only for prevention. We provide evidence that neuropathic pain is triggered by fibrinogen deposition both in an animal model of and in humans with neuropathic pain. We provided a promising treatment option (Fpr2 activation) and an optimized delivery system (RvD1-laden nanoparticles) to resolve neuropathic pain. In addition, we investigated the potential downstream therapeutic targets for therapeutic intervention (TAM receptors and fibrinolysis).</p><p>The limitations of this study include missing follow-up investigations of patients. We did not elucidate whether the patients’ pain resolved and lacked healthy controls. Furthermore, the patients were relatively old and did not suffer from nerve injury; therefore, different mechanisms might apply. Human nerve biopsies are rarely performed, and regulations are strictly defined. Therefore, we could not restrict patient inclusion to stringent criteria. We only investigated the CCI model. While similar mechanisms could apply to other models with Wallerian degeneration such as nerve crush or spared nerve injuries, this might not be translatable to other neuropathic pain conditions, such as metabolic or hereditary neuropathies. When transferring our animal results to humans, it needs to be considered that isolated nerve injury is rare and most nerve injuries are accompanied by additional tissue damage, e.g. to muscles or connective tissue. Damage to the surrounding tissue could also induce inflammatory processes that contribute to neuropathic pain. Tissue oedema and inflammation induced by tissue damage might interfere with therapeutic resealing of the barrier. Another limitation was the underlying role of fibrinogen in the maintenance of hypersensitivity. Our study lacks direct proof that fibrinogen causes neuropathic pain in the rat CCI model. Conceptually, direct and conclusive evidence for the role of fibrinogen in neuropathic pain could be obtained by examining fibrinogen-deficient mice [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 18" title="Drew AF, Liu H, Davidson JM, Daugherty CC, Degen JL (2001) Wound-healing defects in mice lacking fibrinogen. Blood 97:3691–3698. 
 https://doi.org/10.1182/blood.v97.12.3691
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR18" id="ref-link-section-d431148989e2998">18</a>] or by lipid nanoparticle-encapsulated siRNA-mediated suppression of fibrinogen production [<a data-track="click" data-track-action="reference anchor" data-track-label="link" data-test="citation-ref" aria-label="Reference 29" title="Juang LJ, Hur WS, Silva LM, Strilchuk AW, Francisco B, Leung J et al (2022) Suppression of fibrin(ogen)-driven pathologies in disease models through controlled knockdown by lipid nanoparticle delivery of siRNA. Blood 139:1302–1311. 
 https://doi.org/10.1182/blood.2021014559
 
 " href="/article/10.1007/s00401-024-02840-9#ref-CR29" id="ref-link-section-d431148989e3001">29</a>]. In a translational approach, fibrinogen deposition was elevated in nerve biopsies from patients with painful vs. non-painful neuropathy but, again, this evidence is not conclusive.</p><p>The mechanistic pathway presented in this study serves as the basis for the development of therapeutic targets for neuropathic pain. The regulation of macrophage phenotypes and coagulation factors by SPMs and TAM ligands might be a promising approach for inflammatory polyneuropathies in which macrophages accumulate. Tackling the local effects of fully developed neuropathic pain has the potential to resolve chronic neuropathic pain, as it boosts the pain resolution switch. The use of nanoparticles as a delivery system further enables the application of short-lived substances and broadens the molecular toolbox for patient treatment.</p></div></div></section><section data-title="Conclusion"><div class="c-article-section" id="Sec26-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Sec26">Conclusion</h2><div class="c-article-section__content" id="Sec26-content"><p>This study links neuropathic pain after nerve injury to capillary leakage in male and female rats. Both pain and diffused endoneurial fibrinogen subsided after local intervention with Fpr2 ligands delivered by nanoparticles. The functional pathway includes an anti-inflammatory/pro-resolving macrophage boost and TAM receptor signalling. This is a novel concept in the field of pain resolution and may shed light on new targets for the treatment of peripheral neuropathies.</p></div></div></section> </div> <section data-title="Data availability"><div class="c-article-section" id="data-availability-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="data-availability">Data availability</h2><div class="c-article-section__content" id="data-availability-content"> <p>Data is provided within the manuscript or supplementary information files.</p> </div></div></section><div id="MagazineFulltextArticleBodySuffix"><section aria-labelledby="Bib1" data-title="References"><div class="c-article-section" id="Bib1-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Bib1">References</h2><div class="c-article-section__content" id="Bib1-content"><div data-container-section="references"><ol class="c-article-references" data-track-component="outbound reference" data-track-context="references section"><li class="c-article-references__item js-c-reading-companion-references-item" data-counter="1."><p class="c-article-references__text" id="ref-CR1">Akassoglou K, Kombrinck KW, Degen JL, Strickland S (2000) Tissue plasminogen activator-mediated fibrinolysis protects against axonal degeneration and demyelination after sciatic nerve injury. 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Lee (Clinical Physiology/Nutritional Medicine, Charité Berlin) for excellent technical assistance. Schematic illustrations were created with BioRender.com.</p></div></div></section><section data-title="Funding"><div class="c-article-section" id="Fun-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="Fun">Funding</h2><div class="c-article-section__content" id="Fun-content"><p>Open Access funding enabled and organized by Projekt DEAL. This study was supported by the German Research Foundation Clinical Research Group ResolvePAIN KFO5001 – 42650386, Ri 817/15–1 – 433191715 and SFB 1039/Z01 as well as Evangelisches Studienwerk Villigst and DAAD. PVM received support from the Craig H Neilsen Foundation and the Department of Neurosurgery from the UK.</p></div></div></section><section aria-labelledby="author-information" data-title="Author information"><div class="c-article-section" id="author-information-section"><h2 class="c-article-section__title js-section-title js-c-reading-companion-sections-item" id="author-information">Author information</h2><div class="c-article-section__content" id="author-information-content"><h3 class="c-article__sub-heading" id="affiliations">Authors and Affiliations</h3><ol class="c-article-author-affiliation__list"><li id="Aff1"><p class="c-article-author-affiliation__address">Centre for Interdisciplinary Pain Medicine, Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany</p><p class="c-article-author-affiliation__authors-list">Beate Hartmannsberger, Adel Ben-Kraiem, Sofia Kramer, Carolina Guidolin, Ida Kazerani, Alexander Brack & Heike L. Rittner</p></li><li id="Aff2"><p class="c-article-author-affiliation__address">Helmholtz Institute for Metabolic, Obesity and Vascular Research, Diet-Induced Metabolic Alterations Group, Leipzig, Germany</p><p class="c-article-author-affiliation__authors-list">Adel Ben-Kraiem</p></li><li id="Aff3"><p class="c-article-author-affiliation__address">Department of Neurology, University Hospital Würzburg, Würzburg, Germany</p><p class="c-article-author-affiliation__authors-list">Kathrin Doppler & Claudia Sommer</p></li><li id="Aff4"><p class="c-article-author-affiliation__address">Goethe University, Frankfurt, Faculty of Medicine, Institute of Clinical Pharmacology, Frankfurt Am Main, Germany</p><p class="c-article-author-affiliation__authors-list">Dominique Thomas, Robert Gurke & Marco Sisignano</p></li><li id="Aff5"><p class="c-article-author-affiliation__address">Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, and Fraunhofer Cluster of Excellence of Immune Mediate Diseases CIMD, Frankfurt Am Main, Germany</p><p class="c-article-author-affiliation__authors-list">Dominique Thomas, Robert Gurke & Marco Sisignano</p></li><li id="Aff6"><p class="c-article-author-affiliation__address">George W. Woodruff School of Mechanical Engineering, Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, USA</p><p class="c-article-author-affiliation__authors-list">Pranav P. Kalelkar & Andrés J. García</p></li><li id="Aff7"><p class="c-article-author-affiliation__address">Department of Neurosurgery, College of Medicine, University of Kentucky, Lexington, KY, USA</p><p class="c-article-author-affiliation__authors-list">Paula V. Monje</p></li><li id="Aff8"><p class="c-article-author-affiliation__address">Department of Applied Sciences and Health, Coburg University of Applied Sciences and Art, Coburg, Germany</p><p class="c-article-author-affiliation__authors-list">Michael Sammeth</p></li><li id="Aff9"><p class="c-article-author-affiliation__address">Department of Anaesthesiology, Intensive Care, Emergency and Pain Medicine, University Hospital Würzburg, Würzburg, Germany</p><p class="c-article-author-affiliation__authors-list">Michael Sammeth</p></li><li id="Aff10"><p class="c-article-author-affiliation__address">Department of Pathology, University of Michigan, Ann Arbor, MI, USA</p><p class="c-article-author-affiliation__authors-list">Asma Nusrat</p></li><li id="Aff11"><p class="c-article-author-affiliation__address">Charité-Universitätsmedizin Berlin, Clinical Physiology/Nutritional Medicine, Berlin, Germany</p><p class="c-article-author-affiliation__authors-list">Susanne M. Krug</p></li></ol><div class="u-js-hide u-hide-print" data-test="author-info"><span class="c-article__sub-heading">Authors</span><ol class="c-article-authors-search u-list-reset"><li id="auth-Beate-Hartmannsberger-Aff1"><span class="c-article-authors-search__title u-h3 js-search-name">Beate Hartmannsberger</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Beate%20Hartmannsberger" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Beate%20Hartmannsberger" data-track="click" data-track-action="author link - 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Rittner</span><div class="c-article-authors-search__list"><div class="c-article-authors-search__item c-article-authors-search__list-item--left"><a href="/search?dc.creator=Heike%20L.%20Rittner" class="c-article-button" data-track="click" data-track-action="author link - publication" data-track-label="link" rel="nofollow">View author publications</a></div><div class="c-article-authors-search__item c-article-authors-search__list-item--right"><p class="search-in-title-js c-article-authors-search__text">You can also search for this author in <span class="c-article-identifiers"><a class="c-article-identifiers__item" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&term=Heike%20L.%20Rittner" data-track="click" data-track-action="author link - pubmed" data-track-label="link" rel="nofollow">PubMed</a><span class="u-hide"> </span><a class="c-article-identifiers__item" href="http://scholar.google.co.uk/scholar?as_q=&num=10&btnG=Search+Scholar&as_epq=&as_oq=&as_eq=&as_occt=any&as_sauthors=%22Heike%20L.%20Rittner%22&as_publication=&as_ylo=&as_yhi=&as_allsubj=all&hl=en" data-track="click" data-track-action="author link - scholar" data-track-label="link" rel="nofollow">Google Scholar</a></span></p></div></div></li></ol></div><h3 class="c-article__sub-heading" id="contributions">Contributions</h3><p>BH and HLR conceptualized this study. HLR and AB secured the research funding. CS and KD provided human nerve samples. AN and PVM provided valuable guidance on experimental setups and protocols. PMV provided data on RNAseq analysis. PPK and AJG produced and provided the nanoparticles. DT, RG, and MaSi performed the LCMSMS. BH, ABK, SK, CG, IK, and SMK performed experiments. BH, MiSa, ABK, SK, CG, and SMK analysed data. BH drafted the original manuscript. HLR critically reviewed the first draft of the manuscript for intellectual content. All authors read, commented on, and approved the final manuscript.</p><h3 class="c-article__sub-heading" id="corresponding-author">Corresponding author</h3><p id="corresponding-author-list">Correspondence to <a id="corresp-c1" href="mailto:rittner_h@ukw.de">Heike L. 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id="citeas">Cite this article</h3><p class="c-bibliographic-information__citation">Hartmannsberger, B., Ben-Kraiem, A., Kramer, S. <i>et al.</i> TAM receptors mediate the Fpr2-driven pain resolution and fibrinolysis after nerve injury. <i>Acta Neuropathol</i> <b>149</b>, 1 (2025). https://doi.org/10.1007/s00401-024-02840-9</p><p class="c-bibliographic-information__download-citation u-hide-print"><a data-test="citation-link" data-track="click" data-track-action="download article citation" data-track-label="link" data-track-external="" rel="nofollow" href="https://citation-needed.springer.com/v2/references/10.1007/s00401-024-02840-9?format=refman&flavour=citation">Download citation<svg width="16" height="16" focusable="false" role="img" aria-hidden="true" class="u-icon"><use xmlns:xlink="http://www.w3.org/1999/xlink" xlink:href="#icon-eds-i-download-medium"></use></svg></a></p><ul class="c-bibliographic-information__list" data-test="publication-history"><li class="c-bibliographic-information__list-item"><p>Received<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2024-08-13">13 August 2024</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Revised<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2024-11-29">29 November 2024</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Accepted<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2024-12-05">05 December 2024</time></span></p></li><li class="c-bibliographic-information__list-item"><p>Published<span class="u-hide">: </span><span class="c-bibliographic-information__value"><time datetime="2024-12-16">16 December 2024</time></span></p></li><li class="c-bibliographic-information__list-item c-bibliographic-information__list-item--full-width"><p><abbr title="Digital Object Identifier">DOI</abbr><span 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href="/search?query=Fibrinogen&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Fibrinogen</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Pain%20resolution&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Pain resolution</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Resolvin%20D1&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Resolvin D1</a></span></li><li class="c-article-subject-list__subject"><span><a href="/search?query=Chronic%20constriction%20injury&facet-discipline="Medicine%20%26%20Public%20Health"" data-track="click" data-track-action="view keyword" data-track-label="link">Chronic constriction injury</a></span></li><li 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