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<h3>Commentary</h3> <div class='row'> <div class='small-10 medium-7 large-5 small-centered columns'> <ul class='tabs row' data-tab> <li class='tab-title small-6 centered active'> <a href='#articles'>1,874 Articles</a> </li> <li class='tab-title small-6 centered '> <a href='#posts'>0 Posts</a> </li> </ul> </div> </div> <div class='tabs-content'> <div class='content active' id='articles'> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/44?content=articles&page=2">2</a></li> <li><a href="/tags/44?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/44?content=articles&page=187">187</a></li> <li><a href="/tags/44?content=articles&page=188">188</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/44?content=articles&page=2">Next →</a></li></ul></div> </div> </div> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190471">Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190471">Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska</a> <a class='hide-for-small show-more' data-reveal-id='article45891-more' href='#'> <div class='article-authors'> Tzu-Yi Chia, … , Nishanth S. Sadagopan, Jason Miska </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e190471. <a href="https://doi.org/10.1172/JCI190471">https://doi.org/10.1172/JCI190471</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190471">Text</a> | <a href="/articles/view/190471/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190471' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190471/figure/1' ref='group' title='TRAF3 has a regulatory role in GBM via PUFA metabolism and its hypermethylation. (A) In the context of GBM, promoter hypermethylation suppresses TRAF3 expression. The absence of TRAF3 permits ECH1-mediated metabolism of PUFAs and efficient FAO. (B) Zeng et al. showed that TRAF3 overexpression resulted in the ubiquitination (Ub) of ECH1, which impeded FAO, promoted lipid peroxidation, and induced ferroptosis. Furthermore, ECH1 depletion via shRNA induced mitochondrial damage and inhibited tumorigenesis. These findings underscore the therapeutic potential of targeting hypermethylation and the TRAF3/ECH1 axis to suppress tumor growth and enhance sensitivity to immunotherapy.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190471/small/JCI190471.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45891-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190471">Lipid peroxidation and immune activation: TRAF3’s double-edged strategy against glioblastoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190471">Text</a></li> <li><a class="button tiny" href="/articles/view/190471/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Glioblastoma (GBM), the most aggressive type of primary brain tumor, continues to defy therapeutic advances with its metabolic adaptability and resistance to treatment. In this issue of the JCI, Zeng et al. delve into a pivotal mechanism underpinning this adaptability. They identified an important role for TNF receptor–associated factor 3 (TRAF3) in regulating lipid metabolism through its interaction with enoyl-CoA hydratase 1 (ECH1). These findings elucidate a unique signaling axis that shields GBM cells from lipid peroxidation and antitumor immunity, advancing therapeutic strategies for GBM that may also carry over to other cancers with similar metabolic vulnerabilities.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Tzu-Yi Chia, Nishanth S. Sadagopan, Jason Miska</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191422">Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191422">Qun Chen, … , Michael S. Bronze, Min Li</a> <a class='hide-for-small show-more' data-reveal-id='article45902-more' href='#'> <div class='article-authors'> Qun Chen, … , Michael S. Bronze, Min Li </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191422. <a href="https://doi.org/10.1172/JCI191422">https://doi.org/10.1172/JCI191422</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191422">Text</a> | <a href="/articles/view/191422/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191422' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191422/figure/1' ref='group' title='Lactate-induced ENSA-K63 lactylation drives the formation of an immunosuppressive microenvironment in PDAC. In PDAC cells, lactate, generated by LDH during glycolysis, induces ENSA-K63 lactylation (la), which inhibits PP2A activity and sustains SRC phosphorylation. This activation triggers STAT3 phosphorylation, driving the transcriptional upregulation of CCL2. CCL2 recruits macrophages via CCR2. Separately, extracellular lactate secreted by tumor cells through MCTs is taken up by macrophages, further reprogramming them through the ENSA/SRC/STAT3/CCL2 axis and amplifying the expression of genes encoding immunosuppressive factors (including CCL2, ARG1, S100A9, and IL10). These processes establish an immunosuppressive microenvironment and promote resistance to T cell–mediated antitumor immunity and PD-1–mediated immunotherapy.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191422/small/JCI191422.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45902-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191422">Targeting lactylation and the STAT3/CCL2 axis to overcome immunotherapy resistance in pancreatic ductal adenocarcinoma</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191422">Text</a></li> <li><a class="button tiny" href="/articles/view/191422/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Metabolic reprogramming in pancreatic ductal adenocarcinoma (PDAC) fosters an immunosuppressive tumor microenvironment (TME) characterized by elevated lactate levels, which contribute to immune evasion and therapeutic resistance. In this issue of the JCI, Sun, Zhang, and colleagues identified nonhistone ENSA-K63 lactylation as a critical regulator that inactivates PP2A, activates STAT3/CCL2 signaling, recruits tumor-associated macrophages (TAMs), and suppresses cytotoxic T cell activity. Targeting ENSA-K63 lactylation or CCL2/CCR2 signaling reprograms the TME and enhances the efficacy of immune checkpoint blockade (ICB) in PDAC preclinical models. This work provides critical insights into the metabolic-immune crosstalk in PDAC and highlights promising therapeutic strategies for overcoming immune resistance and improving patient outcomes.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Qun Chen, Hao Yuan, Michael S. Bronze, Min Li</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191423">Insights into protection against <i>Mycobacterium tuberculosis</i> infection: time to officially confirm another phenotype?</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191423">Todia P. Setiabudiawan, … , Andrew R. DiNardo, Reinout van Crevel</a> <a class='hide-for-small show-more' data-reveal-id='article45908-more' href='#'> <div class='article-authors'> Todia P. Setiabudiawan, … , Andrew R. DiNardo, Reinout van Crevel </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191423. <a href="https://doi.org/10.1172/JCI191423">https://doi.org/10.1172/JCI191423</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191423">Text</a> | <a href="/articles/view/191423/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191423' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191423/figure/1' ref='group' title='Different stages after exposure to Mtb. The TB resister phenotype is characterized by persistently negative IGRA/TST despite years-long exposure whereas early clearance reflects repeatedly negative IGRA results over a short period (e.g., 3 months) in the context of a well-defined exposure of TB household contacts to an index patient with a known Mtb isolate.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191423/small/JCI191423.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45908-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191423">Insights into protection against <i>Mycobacterium tuberculosis</i> infection: time to officially confirm another phenotype?</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191423">Text</a></li> <li><a class="button tiny" href="/articles/view/191423/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Immune correlates of protection against infection with Mycobacterium tuberculosis (Mtb) remain elusive. In this issue of the JCI, Dallmann-Sauer and authors demonstrate that lack of tuberculin skin test (TST) and interferon γ release assay (IGRA) conversion among people with HIV despite years-long Mtb exposure is associated with alveolar lymphocytosis, including specific poly-cytotoxic T cells, and M1-type alveolar macrophages with a stronger ex vivo response to the pathogen. Studies in these rare individuals, termed “TB resisters” and in tuberculosis household contacts who are repeatedly IGRA negative in the months after a specific exposure event (known as “early clearers”) help elucidate manipulatable mechanisms to boost protection against Mtb infection.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Todia P. Setiabudiawan, Philip C. Hill, Andrew R. DiNardo, Reinout van Crevel</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191094">ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191094">Sophie O’Keefe, Qiwei Wang</a> <a class='hide-for-small show-more' data-reveal-id='article45912-more' href='#'> <div class='article-authors'> Sophie O’Keefe, Qiwei Wang </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191094. <a href="https://doi.org/10.1172/JCI191094">https://doi.org/10.1172/JCI191094</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191094">Text</a> | <a href="/articles/view/191094/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191094' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191094/figure/1' ref='group' title='Acetyl-CoA acetyltransferase 1 functions as a metabolic regulator of tertiary lymphoid structures in non–small cell lung cancer. Tumor cell–intrinsic Acetyl-CoA acetyltransferase 1 (ACAT1) interacts with succinyl-CoA, driving hypersuccinylation at lysines (Ksucc) of mitochondrial proteins, which enhances intratumoral reactive oxygen species (ROS). This oxidative stress suppresses B cells, thereby inhibiting the formation of tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). NSCLC, non–small cell lung cancer; DC, dendritic cell.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191094/small/JCI191094.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45912-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191094">ACAT1 regulates tertiary lymphoid structures: A target for enhancing immunotherapy in non–small cell lung cancer</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191094">Text</a></li> <li><a class="button tiny" href="/articles/view/191094/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Non–small cell lung cancer (NSCLC), the most common type of lung cancer, remains a leading cause of cancer-related mortality worldwide. Immune checkpoint inhibitors (ICIs) have emerged as a promising therapy for NSCLC but only benefit a subset of patients. In this issue of the JCI, Jiao et al. revealed that acetyl-CoA acetyltransferase 1 (ACAT1) limited the efficacy of ICIs in NSCLC by impeding tertiary lymphoid structures (TLS) in the tumor microenvironment (TME). Targeting ACAT1 in tumor cells reduced mitochondrial hypersuccinylation and oxidative stress, enhancing TLS abundance and improving the efficacy of ICIs in preclinical murine models of NSCLC.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Sophie O’Keefe, Qiwei Wang</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/191355"><i>HoxBlinc</i>: a key driver of chromatin dynamics in NUP98 fusion–driven leukemia</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/191355">Jian Xu, Wei Du</a> <a class='hide-for-small show-more' data-reveal-id='article45915-more' href='#'> <div class='article-authors'> Jian Xu, Wei Du </div> </a> <span class='article-published-at'> Published April 1, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/7">135(7)</a>:e191355. <a href="https://doi.org/10.1172/JCI191355">https://doi.org/10.1172/JCI191355</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/191355">Text</a> | <a href="/articles/view/191355/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI191355' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/191355/figure/1' ref='group' title='HoxBlinc modulates oncogenic transcription and leukemogenesis in NUP98 fusion–driven leukemia. (A) NUP98 fusion induces aberrant activation of HoxBlinc, causing a reorganization of TADs that alters chromatin interactions. HoxBlinc facilitates chromatin accessibility of MLL1 at promoter regions, ultimately enhancing the expression of HOX and other oncogenic genes. (B) Loss of HoxBlinc reduces MLL1 recruitment and decreases leukemic gene transcription.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/191000/191355/small/JCI191355.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45915-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/191355"><i>HoxBlinc</i>: a key driver of chromatin dynamics in NUP98 fusion–driven leukemia</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/191355">Text</a></li> <li><a class="button tiny" href="/articles/view/191355/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Nucleoporin 98 (NUP98) fusion oncogenes are known to promote aggressive pediatric leukemia by disrupting chromatin structure and modulating the expression of homeobox (HOX) genes, yet the precise molecular events are unclear. In this issue of the JCI, K. Hamamoto et al. explore the mechanistic underpinnings of NUP98 fusion–driven pediatric leukemia, with a focus on aberrant activation of the Hoxb-associated long, noncoding RNA (lncRNA) HoxBlinc. The authors provide compelling evidence that HoxBlinc plays a central role in the oncogenic transformation associated with NUP98 fusion protein. The study underscores a CTCF-independent role of HoxBlinc in the regulation of topologically associated domains (TADs) and chromatin accessibility, which has not been fully appreciated in previous research on the NUP98 fusion oncogenes. The discovery of HoxBlinc lncRNA as a downstream regulator of NUP98 fusion oncoproteins offers a potential target for therapeutic intervention in pediatric leukemia.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Jian Xu, Wei Du</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190955">Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190955">Selket Delafontaine, Isabelle Meyts</a> <a class='hide-for-small show-more' data-reveal-id='article45847-more' href='#'> <div class='article-authors'> Selket Delafontaine, Isabelle Meyts </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190955. <a href="https://doi.org/10.1172/JCI190955">https://doi.org/10.1172/JCI190955</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190955">Text</a> | <a href="/articles/view/190955/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190955' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190955/figure/1' ref='group' title='Autosomal recessive OSM deficiency causes an isolated phenotype of IBMFS through an alteration of the BMM. OSM is a pleiotropic cytokine, secreted by activated immune cells such as T cells, monocytes, macrophages, and neutrophils. Upon binding to its receptors, composed of gp130 and LIFR and/or gp130 and OSMRb, which are widely expressed in hematopoietic and nonhematopoietic tissue, OSM activates the JAK/STAT, the RAS/MAPK, and the PI3K/AKT signaling pathways. Garrigue, Kermasson, and colleagues (1) demonstrated how a homozygous LoF mutation, found in three children from a consanguineous family, leads to the production of a neopeptide, impeding the interaction with both OSM receptors on HSPCs, which ultimately underlies an IBMFS characterized by profound anemia, neutropenia, and thrombocytopenia. This discovery demonstrates that genetic causes of IBMFS extend beyond HSPC intrinsic defects, as alterations of the BMM and inflammatory cytokines can play a pathogenic role in the development of IBMFS.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190955/small/JCI190955.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45847-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190955">Oncostatin M silence and neopeptide: the value of exploring patients with rare inherited bone marrow failure</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190955">Text</a></li> <li><a class="button tiny" href="/articles/view/190955/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Inherited bone marrow failure syndromes (IBMFSs) encompass a diverse group of hematological disorders characterized by a progressive single-lineage cytopenia or pancytopenia. Despite their heterogeneity, these syndromes often result from genetic errors affecting key biological mechanisms, including telomere maintenance, DNA repair and chromosomal stability, and ribosome assembly, generally leading to accelerated apoptosis of hematopoietic cells. Nevertheless, a genetic diagnosis remains elusive in more than half of the cases. The increased risk of myelodysplastic syndrome (MDS), acute leukemia, and solid tumors associated with IBMFS frequently prompts early hematopoietic stem cell transplantation (HSCT). In this issue of the JCI, Garrigue, Kermasson, and colleagues identified a homozygous variant in Oncostatin M (OSM) in 3 children from a consanguineous family presenting with IBMFS characterized by profound anemia, thrombocytopenia, and neutropenia. The findings suggest that the loss-of-function OSM variant affected hematopoietic stem cell function through changes to the bone marrow microenvironment (BMM).</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Selket Delafontaine, Isabelle Meyts</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190957">Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190957">Edda Spiekerkoetter</a> <a class='hide-for-small show-more' data-reveal-id='article45854-more' href='#'> <div class='article-authors'> Edda Spiekerkoetter </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190957. <a href="https://doi.org/10.1172/JCI190957">https://doi.org/10.1172/JCI190957</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190957">Text</a> | <a href="/articles/view/190957/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190957' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45854-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190957">Macrophages: key conductors behind perivascular inflammation and vascular remodeling in hypoxia-induced pulmonary hypertension</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190957">Text</a></li> <li><a class="button tiny" href="/articles/view/190957/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Pulmonary hypertension (PH) encompasses a heterogenous group of disorders with the common feature of increased pulmonary arterial pressures. Patients with PH associated with lung disease and/or hypoxia undergo immune-mediated vascular remodeling that includes thickening of the muscular layer surrounding arteries and arterioles. In this issue of the JCI, Kumar and colleagues examined the role of interstitial macrophages in a model of high-altitude PH. Resident interstitial macrophages increased, proliferated, and expressed CCL2, a monocyte chemoattractant ligand. There was also a rise in CCR2+ macrophages expressing thrombospondin-1, which is known to activate vascular remodeling through TGF-β. Blocking monocyte recruitment partially reduced hypoxic PH, and corticosteroid treatment effectively reduced CCL2 expression and CCR2+ monocyte recruitment. Further, plasma samples collected from individuals ascending from low to high altitudes showed increased thrombospondin-1 and TGF-β levels, which were reduced with dexamethasone. These findings reveal interstitial macrophage populations as potential therapeutic targets in hypoxic PH.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Edda Spiekerkoetter</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/190230">Sensing mycobacteria through unconventional pathways</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/190230">Catarina F. Almeida, Jennifer A. Juno</a> <a class='hide-for-small show-more' data-reveal-id='article45861-more' href='#'> <div class='article-authors'> Catarina F. Almeida, Jennifer A. Juno </div> </a> <span class='article-published-at'> Published March 17, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/6">135(6)</a>:e190230. <a href="https://doi.org/10.1172/JCI190230">https://doi.org/10.1172/JCI190230</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/190230">Text</a> | <a href="/articles/view/190230/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI190230' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/190230/figure/1' ref='group' title='Mycobacterial lipids play a dual role in stimulating the immune system. The mycobacterial cell wall contains numerous MAs with immunostimulatory activity. Mycolate lipids such as TMM, TDM, and diacyltrehalose (DAT) bind to the C-type lectin receptor Mincle on myeloid cells, stimulating downstream inflammatory processes. Others such as LAM and PIM bind TLR2, which triggers GM-CSF secretion and CD1 upregulation on antigen-presenting cells, including myeloid cells, monocytes, and macrophages. These and other lipid-based molecules, such as MA or its ester derivatives GMM, DAT, and SGL, can also be captured by CD1b and presented to unconventional T cells that recognize such CD1b-lipid complexes via their TCR. The CD1b-TMM–specific T cell populations revealed by Sakai and colleagues (3) expand upon M. tuberculosis infection and exhibited conserved features shared across different individuals. Some of these characteristics are also common among other CD1b-restricted T cell subsets, including expression of the CD4 coreceptor and cytotoxicity-associated effector molecules, such as IFN, TNF, granzyme B (GzmB), and perforin. They also share a previously described TRBV4-1 usage for CD1b-restricted cells (albeit with long and flexible CDR3β loops to accommodate a complex lipid headgroup that protrudes from CD1b) and positively charged amino acids comprising the CDR3α (similar to CD1b-GMM–reactive cells), which define the TCR specificity for CD1b-TMM.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/190000/190230/small/JCI190230.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45861-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/190230">Sensing mycobacteria through unconventional pathways</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/190230">Text</a></li> <li><a class="button tiny" href="/articles/view/190230/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Approximately one-quarter of the global population is estimated to be infected with Mycobacterium tuberculosis. New developments in vaccine design and therapeutics are urgently needed, particularly in the face of multidrug-resistant tuberculosis (TB). In this issue of the JCI, Sakai and colleagues used a multidisciplinary approach to determine that trehalose-6-monomycolate (TMM), a mycobacterial cell wall lipid, serves as a T cell antigen presented by CD1b. CD1b-TMM–specific T cells were characterized by conserved T cell receptor features and were present at elevated frequencies in individuals with active TB disease. These findings highlight the dual role of TMM in stimulating both innate and adaptive immunity and broaden our understanding of CD1-mediated lipid recognition by unconventional T cells.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Catarina F. Almeida, Jennifer A. Juno</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/188251">Bridging the gap: insights into sensorimotor deficits in NMDA receptor antibody encephalitis</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/188251">Puneet Opal, Geoffrey T. Swanson</a> <a class='hide-for-small show-more' data-reveal-id='article45793-more' href='#'> <div class='article-authors'> Puneet Opal, Geoffrey T. Swanson </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e188251. <a href="https://doi.org/10.1172/JCI188251">https://doi.org/10.1172/JCI188251</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/188251">Text</a> | <a href="/articles/view/188251/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI188251' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/188251/figure/1' ref='group' title='Anti-GluN1 antibody exposure at an early stage of cortical development affects brain function into adulthood. Zhou and colleagues produced mAbs against GluN1 after isolating B cells from a patient with NMDAR-AE. Administration of mAb3[GluN1] to mice from postnatal day 3 to 12 resulted in long-lasting sensorimotor effects. Critical developmental events during this period involve interhemispheric connectivity through callosal projections and synaptogenesis. Correspondingly, young mice showed morphological changes, including increased axon branching at terminals, that persisted with age (12).'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/188000/188251/small/JCI188251.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45793-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/188251">Bridging the gap: insights into sensorimotor deficits in NMDA receptor antibody encephalitis</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/188251">Text</a></li> <li><a class="button tiny" href="/articles/view/188251/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>N-methyl-d-aspartate (NMDA) receptor–mediated autoimmune encephalitis (NMDAR-AE) is the most common cause of autoimmune encephalitis, especially in children and young adults. The disorder is caused by antibodies directed against the GluN1 protein, an obligatory constituent of NMDA receptors, which are key signaling molecules in brain development, learning and memory, and executive function. The manuscript by Zhou et al. offers key insights into aberrant development of cortical pathways that may underly persistent sensorimotor deficits associated with this encephalitis in a newly generated mouse model. This study convincingly links transient exposure to a patient-derived anti-GluN1 mAb during a critical developmental period to lasting disruptions in interhemispheric connectivity through callosal projections. These findings provide insight into the impact of a prevalent autoimmune disorder on fundamental aspects of brain development and establish a model system that could be further employed to probe other aspects of NMDAR-AE pathogenesis.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Puneet Opal, Geoffrey T. Swanson</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> <hr> <div class='row'> <div class='small-12 medium-9 columns'> <div class='row'> <div class='small-12 columns'> <h5 class='article-title' style='display: inline-block;'><a href="/articles/view/189519">Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy</a></h5> </div> </div> <div class='row'> <div class='small-12 columns article-metadata'> <a class="show-for-small" href="/articles/view/189519">Gemma L Carvill</a> <a class='hide-for-small show-more' data-reveal-id='article45814-more' href='#'> <div class='article-authors'> Gemma L Carvill </div> </a> <span class='article-published-at'> Published March 3, 2025 </span> <br/>Citation Information: <i>J Clin Invest.</i> 2025;<a id="article_metadata" href="http://www.jci.org/135/5">135(5)</a>:e189519. <a href="https://doi.org/10.1172/JCI189519">https://doi.org/10.1172/JCI189519</a>. <div class='row'> <div class='small-12 columns article-links'> View: <a href="/articles/view/189519">Text</a> | <a href="/articles/view/189519/pdf">PDF</a> </div> </div> <div class='row'> <div class='small-12 columns'> <span class='altmetric-embed' data-badge-popover='bottom' data-badge-type='2' data-doi='10.1172/JCI189519' data-hide-no-mentions='true'></span> </div> </div> </div> </div> </div> <div class='medium-3 hide-for-small columns'> <a href='https://www.jci.org/articles/view/189519/figure/1' ref='group' title='Senescent neurons contribute to drug-resistant epilepsy. Healthy neurons, which are postmitotic from birth, are typically paused in the G0 phase of the cell cycle. Senescent neurons feature a senescence-associated secretory-phenotype (SASP), consisting of inflammatory cytokines and chemokines. They also display DNA damage, decayed nuclear envelopes, and organelle damage, including mitochondria and lysosome degradation. Ge et al. performed patch-seq on neurons from individuals with drug-resistant epilepsy, characterizing neuronal morphological, electrophysiological, and transcriptional profiles. This strategy enriched a subpopulation of pathological cortical pyramidal neurons possessing a senescent phenotype. Neurons with this phenotype expressed markers of cell senescence, including β-galactosidase. They also showed increased expression of cell cycle inhibitors (e.g. P21, P53) typically associated with cell cycle arrest. Notably, a mouse model of chronic epilepsy also induced senescent neurons.'> <img src='//dm5migu4zj3pb.cloudfront.net/manuscripts/189000/189519/small/JCI189519.f1.gif'> </a> </div> </div> <div class='reveal-modal xlarge' data-reveal='' id='article45814-more'> <div class='row'> <div class='small-12 columns'> <h4><a href="/articles/view/189519">Zombie neurons in epilepsy: a burgeoning role for senescence in drug-resistant epilepsy</a></h4> </div> <div class='small-12 columns'> <ul class='button-group'> <li><a class="button tiny" href="/articles/view/189519">Text</a></li> <li><a class="button tiny" href="/articles/view/189519/pdf">PDF</a></li> </ul> </div> <div class='small-12 columns'> <h5>Abstract</h5> </div> <div class='small-12 columns'> <p>Cellular senescence is a cell state induced by irreparable cellular damage. The hallmark of senescence is cell cycle exit, yet neurons, which are postmitotic from birth, have also been found to undergo senescence. Neuronal senescence is prevalent in aging as well as in neurodegenerative disease. However, a role for senescence in epilepsy is virtually unexplored. In this issue of the JCI, Ge and authors used resected brain tissue from individuals with drug-resistant epilepsy, a genetic knockout mouse model, and a chemoconvulsant mouse model, to demonstrate a subset of cortical pyramidal senescent neurons that likely contribute to the pathophysiology of epilepsy. These findings highlight senescence as a possible target in precision-therapy approaches for epilepsy and warrant further investigation.</p> </div> <div class='small-12 columns'> <h5>Authors</h5> </div> <div class='small-12 columns'> <p>Gemma L Carvill</p> </div> </div> <a class='close-reveal-modal'>×</a> </div> </div> </div> <div class='row'> <div class='small-12 columns'> <div role="navigation" aria-label="Pagination" class="pagination-centered" previous_label="<--" next_label="-->"><ul class="pagination"><li class="arrow unavailable"><a class="arrow unavailable">← Previous</a></li> <li class="current"><a class="current">1</a></li> <li><a rel="next" href="/tags/44?content=articles&page=2">2</a></li> <li><a href="/tags/44?content=articles&page=3">3</a></li> <li class="unavailable"><a>…</a></li> <li><a href="/tags/44?content=articles&page=187">187</a></li> <li><a href="/tags/44?content=articles&page=188">188</a></li> <li class="arrow"><a class="arrow" rel="next" href="/tags/44?content=articles&page=2">Next →</a></li></ul></div> </div> </div> </div> <div class='content ' id='posts'> <p>No posts were found with this tag.</p> </div> </div> </div> <div class='large-2 medium-3 hide-for-small columns' style='padding: 12px 9px 12px 9px;'> <div style='width:100%; text-align: center;'> <div id='jci-interior-skyscraper-right-col'> <span class='secondary label'>Advertisement</span> <script> try { googletag.cmd.push(function () { googletag.display('jci-interior-skyscraper-right-col'); }); } catch(e){} </script> </div> </div> </div> </div> </div> </div> </div> </div> <div id='footer'> <div class='row panel-padding'> <div class='small-6 columns'> <div id='social-links'> <a onclick="trackOutboundLink('/twitter?ref=footer');" href="/twitter"><img title="Twitter" src="/assets/social/twitter-round-blue-78025a92064e3594e44e4ccf5446aefeafba696cd3c8e4a7be1850c7c9f62aba.png" /></a> <a onclick="trackOutboundLink('/facebook?ref=footer');" href="/facebook"><img title="Facebook" src="/assets/social/facebook-round-blue-2787910d46dcbdbee4bd34030fee044e5a77cfda2221af9191d437b2f5fadeb1.png" /></a> <a href="/rss"><img title="RSS" src="/assets/social/rss-round-color-6f5fa8e93dc066ee4923a36ba6a7cb97d53c5b77de78a2c7b2a721adc603f342.png" /></a> </div> <br> Copyright © 2025 <a href="http://www.the-asci.org">American Society for Clinical Investigation</a> <br> ISSN: 0021-9738 (print), 1558-8238 (online) </div> <div class='small-6 columns'> <div class='row'> <div class='small-12 columns'> <h4 class='notices-signup'>Sign up for email alerts</h4> <form action='https://notices.jci.org/subscribers/new' method='get'> <input name='utm_source' type='hidden' value='jci'> <input name='utm_medium' type='hidden' value='web'> <input name='utm_campaign' type='hidden' value='email_signup'> <input name='utm_content' type='hidden' value='footer'> <div class='row'> <div class='small-12 medium-9 columns'> <input name='email_address' placeholder='Your email address' required type='text'> </div> <div class='small-12 medium-3 columns'> <input class='button tiny orange' type='submit' value='Sign up'> </div> </div> </form> </div> </div> </div> </div> </div> </div> <script src="/assets/application-27f18b5fe3b7302e5b3e3c6d7cf9bb3f54759fad32679209f5aef429b89f3aef.js"></script>  <script src="//s7.addthis.com/js/300/addthis_widget.js#pubid=ra-4d8389db4b0bb592" async="async"></script> <script src="//d1bxh8uas1mnw7.cloudfront.net/assets/embed.js" async="async"></script>  </body> </html>