Eri Ishikawa, Hidetaka Kosako, Daisuke Motooka, Mai Imasaka, Hiroshi Watarai, Masaki Ohmuraya, Sho Yamasaki
{"title":"Invariant TCR-triggered protein kinase D activation mediates NKT cell development.","authors":"Eri Ishikawa, Hidetaka Kosako, Daisuke Motooka, Mai Imasaka, Hiroshi Watarai, Masaki Ohmuraya, Sho Yamasaki","doi":"10.1084/jem.20250541","DOIUrl":"https://doi.org/10.1084/jem.20250541","url":null,"abstract":"<p><p>Development of invariant natural killer T (iNKT) cells in the thymus requires cell-cell interaction through invariant TCR (iTCR) and CD1d, which induces expression of the transcription factor, promyelocytic leukemia zinc finger (PLZF). However, the signaling pathway linking iTCR and PLZF remains unclear. Here, we report that a serine/threonine kinase, protein kinase D (PKD), plays a pivotal role in iNKT cell development. In T cell-specific PKD-deficient (Prkd2/3∆CD4) mice, PLZF induction and iNKT cell generation were severely impaired, which were rescued by introduction of a PLZF transgene. We identified the transcription factor Ikaros as a substrate of PKD upon iTCR stimulation. Knock-in mice carrying a phosphorylation-defective mutant Ikaros (Ikzf1S267/275A) exhibited an impairment of iNKT cell development, whereas conventional T cells were normal. In iNKT cells, Ikaros binds to the upstream region of the PLZF gene to induce its transcription. Mutant mice lacking the Ikaros-binding site (Zbtb16∆IBS) generated fewer iNKT cells than WT mice. These results suggest that PKD links iTCRs to PLZF induction through Ikaros, thereby mediating iNKT cell development.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080869","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"RIPK1 autophosphorylation at S161 mediates cell death and inflammation.","authors":"Lioba Koerner, Xiaoming Li, Eveline Silnov, Lucie Laurien, Manolis Pasparakis","doi":"10.1084/jem.20250279","DOIUrl":"10.1084/jem.20250279","url":null,"abstract":"<p><p>RIPK1 regulates cell death and inflammation and has been implicated in the pathogenesis of inflammatory diseases. RIPK1 autophosphorylation promotes cell death induction; however, the underlying mechanisms and the role of specific autophosphorylation sites remain elusive. Using knock-in mouse models, here we show that S161 autophosphorylation has a critical physiological function in RIPK1-mediated cell death and inflammation. S161N substitution partially suppressed RIPK1-mediated catalytic activity and cell death induction but was sufficient to prevent skin inflammation induced by keratinocyte necroptosis or apoptosis in relevant mouse models. Combined S161N and S166A mutations synergized to prevent RIPK1-mediated cell death more efficiently than the single site mutations, revealing functional redundancy. Moreover, phosphomimetic S161E mutation could overcome the necroptosis-inhibitory effect of S166A mutation, revealing that S161 phosphorylation is sufficient for necroptosis induction. Collectively, a functional interplay of S161 and S166 phosphorylation events regulates RIPK1-dependent cell death and inflammation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 12","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12462663/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145137614","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Henry Yi Cheng, Jiachen Chu, Nathachit Limjunyawong, Jianan Chen, Yingzhi Ye, Kevin Hong Chen, Nicholas Koylass, Shuying Sun, Xinzhong Dong, Zhaozhu Qiu
{"title":"Proton-activated chloride channel governs phagosome-mediated antibacterial immunity in peritoneal macrophages.","authors":"Henry Yi Cheng, Jiachen Chu, Nathachit Limjunyawong, Jianan Chen, Yingzhi Ye, Kevin Hong Chen, Nicholas Koylass, Shuying Sun, Xinzhong Dong, Zhaozhu Qiu","doi":"10.1084/jem.20250312","DOIUrl":"https://doi.org/10.1084/jem.20250312","url":null,"abstract":"<p><p>The success of phagosome degradation relies on the ability of phagocytes to regulate the maturation of phagosomes. However, its underlying molecular mechanisms remain poorly understood. Here, we identify the proton-activated chloride (PAC) channel as a key negative regulator of phagosome maturation. PAC deletion enhanced phagosomal acidification and protease activities, leading to augmented bacterial killing in large peritoneal macrophages (LPMs) upon Escherichia coli infection in mice. Surprisingly, phagosome degradation also stimulated STING-IRF3-IFN responses and inflammasome activation in LPMs, both of which are enhanced upon PAC deletion. The increased inflammasome activation induced the release of cleaved gasdermin D, which localized to the surface of bacteria in the peritoneum and further contributed to their killing. Finally, enhanced bacterial clearance by PAC-deficient LPMs reduced proinflammatory immune cell infiltration and peritoneal inflammation, resulting in improved survival in mice. Our study thus provides new insights into the molecular mechanism of phagosome maturation and the dynamics of host defense response following phagosome-mediated bacterial degradation in peritoneal macrophages.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12373265/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes, Maitriyee Mahanta, Matthew Banicki, Mary Cochran, Samantha Cowdin, Kristen Fortney, George Hartman, Robert E Hughes, Rusty Montgomery, Claudia P Portillo, Paul Rubin, Taiz Salazar, Yan Wang, Shijun Yan, Barry A Morgan, Assem Duisembekova, Romane Riou, Michael Marleaux, Inga V Hochheiser, Hannes Buthmann, Dominic Ferber, Jane Torp, Wei Wang, Melanie Cranston, Chloe M McKee, Thea J Mawhinney, Emma C McKay, Fehime K Eroglu, Jasmin Kümmerle-Deschner, Alexander N R Weber, Bénédicte F Py, Matthias Geyer, Rebecca C Coll
{"title":"Discovery of potent and selective inhibitors of human NLRP3 with a novel mechanism of action.","authors":"Kevin Wilhelmsen, Aditi Deshpande, Sarah Tronnes, Maitriyee Mahanta, Matthew Banicki, Mary Cochran, Samantha Cowdin, Kristen Fortney, George Hartman, Robert E Hughes, Rusty Montgomery, Claudia P Portillo, Paul Rubin, Taiz Salazar, Yan Wang, Shijun Yan, Barry A Morgan, Assem Duisembekova, Romane Riou, Michael Marleaux, Inga V Hochheiser, Hannes Buthmann, Dominic Ferber, Jane Torp, Wei Wang, Melanie Cranston, Chloe M McKee, Thea J Mawhinney, Emma C McKay, Fehime K Eroglu, Jasmin Kümmerle-Deschner, Alexander N R Weber, Bénédicte F Py, Matthias Geyer, Rebecca C Coll","doi":"10.1084/jem.20242403","DOIUrl":"10.1084/jem.20242403","url":null,"abstract":"<p><p>The NLRP3 inflammasome is an intracellular protein complex that causes inflammation via the release of IL-1β and pyroptosis. NLRP3 activation is associated with many age-related inflammatory diseases, and NLRP3 inhibition is a promising therapeutic strategy. We previously performed a DNA-encoded library screen to identify novel NLRP3-binding molecules. Herein we describe the characterization of BAL-0028 as a potent and specific inhibitor of NLRP3 signaling. Notably, BAL-0028 is a poor inhibitor of mouse NLRP3 but inhibits human and primate NLRP3 with nanomolar potency. Using cellular and biochemical analyses, we demonstrate that BAL-0028 binds to the NLRP3 NACHT domain at a site that is distinct from the MCC950-binding pocket. Using humanized NLRP3 mice, we show that a derivative of BAL-0028, BAL-0598, inhibits NLRP3 activation in vivo in a peritonitis model. Finally, we demonstrate that both BAL-0028 and BAL-0598 inhibit select hyperactive NLRP3 mutations associated with autoinflammatory diseases more potently than MCC950. BAL-0028 and BAL-0598 thus represent a new modality for NLRP3 inhibition in inflammatory diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12404154/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956574","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Akriti Gupta, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Yasmine Belkaid, Michael G Constantinides, Anthony J St Leger, Rachel R Caspi
{"title":"TLR2 supports γδ T cell IL-17A response to ocular surface commensals by metabolic reprogramming.","authors":"Wenjie Zhu, Xiaoyan Xu, Vijayaraj Nagarajan, Jing Guo, Akriti Gupta, Zixuan Peng, Amy Zhang, Jie Liu, Mary J Mattapallil, Yingyos Jittayasothorn, Reiko Horai, Yasmine Belkaid, Michael G Constantinides, Anthony J St Leger, Rachel R Caspi","doi":"10.1084/jem.20251046","DOIUrl":"10.1084/jem.20251046","url":null,"abstract":"<p><p>The ocular surface is a mucosal barrier tissue colonized by commensal microbes, which tune local immunity by eliciting IL-17 from conjunctival γδ T cells to prevent pathogenic infection. The commensal Corynebacterium mastitidis (C. mast) elicits protective IL-17 responses from conjunctival Vγ4 T cells through a combination of γδ TCR ligation and IL-1 signaling. Here, we identify Vγ6 T cells as a major C. mast-responsive subset in the conjunctiva and uncover its unique activation requirements. We demonstrate that Vγ6 cells require both extrinsic (via dendritic cells) and intrinsic TLR2 stimulation for optimal IL-17A response. Mechanistically, intrinsic TLR2 signaling was associated with epigenetic changes and enhanced expression of genes involved in fatty acid oxidation to support Il17a transcription. We identify a key transcription factor, IκBζ, which is upregulated by TLR2 stimulation and is essential for this program. Our study highlights the importance of intrinsic TLR2 signaling in driving metabolic reprogramming and production of IL-17A in microbiome-specific mucosal γδ T cells.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033466","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Specific loading of oncolytic VSV on CAR enhances CAR-T cell signaling and antitumor activity.","authors":"Fan Xing, Xuemei Wang, Zeying Li, Liangying Zheng, Zuda Huang, Jieqing Guo, Zhihui Xi, Huolun Feng, Baijin Xia, Yingtong Lin, Fei Yu, Jie Chen, Hui Zhang","doi":"10.1084/jem.20241851","DOIUrl":"10.1084/jem.20241851","url":null,"abstract":"<p><p>Oncolytic viruses (OVs) have been shown to increase the efficacy of chimeric antigen receptor (CAR) T cells in treating solid tumors. However, their combined effect has been limited by the unbalanced distribution of two agents in tumor tissue and viral infection-mediated CAR-T cell exhaustion. Here, we designed a CAR moiety by inserting the CR2 and CR3 domains (CR2/3-CAR) of low-density lipoprotein receptor, which is the viral receptor of oncolytic vesicular stomatitis virus (VSV) mutant (VSVΔ51), enabling specific loading of VSVΔ51 onto CAR-T cells. The anchored VSVΔ51 could be released from CAR-T cells and efficiently delivered to tumor tissue. Further investigation revealed that the cross-connection between viral envelope proteins and CR2/3-CAR moieties facilitated forming antigen-free CAR clusters and antigen-induced CAR synapse, triggered CAR signaling transduction, and directly pre-activated the CAR-T cells. Consequently, this approach potently enhanced the proliferation, metabolic fitness, and immunological activities of CAR-T cells, and subsequently enhanced the OV/CAR-T synergetic cytotoxicity, revealing an effective strategy for treating solid tumors.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145040227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jinjin Xu, Lingjia Kong, Elizabeth A Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A Oliver, Tyler T Dao, Angela R Shih, Mark J Daly, Alex K Shalek, Clary B Clish, Daniel B Graham, Jacques Deguine, Ramnik J Xavier
{"title":"Autoimmune disease risk gene ANKRD55 promotes TH17 effector function through metabolic modulation.","authors":"Jinjin Xu, Lingjia Kong, Elizabeth A Creasey, Sneha Rath, Lei Deng, Julian Avila-Pacheco, Chenhao Li, Blayne A Oliver, Tyler T Dao, Angela R Shih, Mark J Daly, Alex K Shalek, Clary B Clish, Daniel B Graham, Jacques Deguine, Ramnik J Xavier","doi":"10.1084/jem.20250185","DOIUrl":"https://doi.org/10.1084/jem.20250185","url":null,"abstract":"<p><p>Genome-wide association studies (GWAS) have linked the locus encoding ankyrin repeat domain 55 (ANKRD55) with numerous autoimmune diseases; however, its biological function and role in inflammation are unclear. Here, we demonstrate that Ankrd55-deficient mice are protected from T cell-mediated colitis but are more susceptible to Citrobacter rodentium infection. Mechanistically, Ankrd55 deletion impairs CD4+ T cell proliferation and reduces effector cytokine production in T helper 17 (TH17) cells in a cell-intrinsic manner. ANKRD55 is associated with mitochondria, and its loss is associated with impaired mitochondrial respiration and activation of the LKB1 pathway. Consistently, IL-17 production can be rescued by the deletion of LKB1 in Ankrd55-deficient T cells. Altogether, our study implicates the protein ANKRD55 as a functional modulator of T cell metabolism that directly impacts TH17 responses, highlighting it as a potential target across multiple autoimmune diseases.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145033454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Integrated screens identify AURKB dependency in advanced gastrointestinal stromal tumors.","authors":"Yumei Cheng, Haoqi Lan, Xiaojing Lu, Chunling Zeng, Yue Dong, Yanying Shen, Yuxiang Luo, Yangjie Xiong, Xiaofang Wang, Jianzhi Cui, Lechun Hou, Xiaona Jia, Hui Cao, Simin Wang, Ming Wang, Yuexiang Wang","doi":"10.1084/jem.20250256","DOIUrl":"https://doi.org/10.1084/jem.20250256","url":null,"abstract":"<p><p>The only approved systemic treatments for gastrointestinal stromal tumors (GISTs) are KIT/PDGFRA-directed tyrosine kinase inhibitors (TKIs), which eventually lead to the development of secondary polyclonal resistance mutations. Complementary treatment strategies are urgently needed. Using transcriptomic profiling, CRISPR screens, and chemical screens, we identify aurora kinase B (AURKB) as a previously less recognized therapeutic vulnerability to advanced GISTs. AURKB is frequently overexpressed in high-risk and metastatic GISTs but not in low-/intermediate-risk GISTs across our two patient cohorts, with FOXM1 responsible for AURKB overexpression. Genetic depletion of AURKB inhibits GIST proliferation and growth in vitro and in vivo. Mechanistically, our mass spectrometry-based proteomics screen further reveals that AURKB binds to and stabilizes ATAD2 via the ubiquitin-proteasome system, enhancing chromatin accessibility for DNA damage repair genes. Notably, AURKB inhibitors demonstrate potent efficacy in multiple preclinical GIST cell models and xenograft models at safe doses, overcoming TKI resistance. Our comprehensive approaches define unique AURKB-ATAD2 dependency in GISTs and identify non-receptor tyrosine kinase therapeutic strategies for clinical translation.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955914","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marjon Wouters, Lisa Ehlers, Wout Van Eynde, Meltem Ece Kars, Selket Delafontaine, Verena Kienapfel, Mariia Dzhus, Rik Schrijvers, Petra De Haes, Sofie Struyf, Giorgia Bucciol, Yuval Itan, Alexandre Bolze, Arnout Voet, Anneleen Hombrouck, Leen Moens, Benson Ogunjimi, Isabelle Meyts
{"title":"Dominant negative ADA2 mutations cause ADA2 deficiency in heterozygous carriers.","authors":"Marjon Wouters, Lisa Ehlers, Wout Van Eynde, Meltem Ece Kars, Selket Delafontaine, Verena Kienapfel, Mariia Dzhus, Rik Schrijvers, Petra De Haes, Sofie Struyf, Giorgia Bucciol, Yuval Itan, Alexandre Bolze, Arnout Voet, Anneleen Hombrouck, Leen Moens, Benson Ogunjimi, Isabelle Meyts","doi":"10.1084/jem.20250499","DOIUrl":"10.1084/jem.20250499","url":null,"abstract":"<p><p>Human ADA2 deficiency (DADA2) is an inborn error of immunity with a broad clinical phenotype, which encompasses vasculopathy and hemato-immunological features. Diagnosis is based on the combination of decreased serum ADA2 activity and the identification of biallelic deleterious alleles in the ADA2 gene. DADA2 carriers harbor a single pathogenic variant in ADA2 and are mostly considered healthy and asymptomatic. Here, we report ten patients from seven kindreds presenting with a phenotype indicative of DADA2, in whom only a single pathogenic variant was identified. We investigated the effect of these and additional reported ADA2 missense variants on ADA2 protein expression, secretion, and enzymatic activity. Our studies indicate that p.G47A, p.G47R, p.G47V, p.R169Q, p.E328K, p.H424N, and p.Y453C exert a dominant negative effect on ADA2 enzymatic activity, dimerization, and/or secretion. We conclude that humans with heterozygous dominant negative missense variants in ADA2 are at risk of DADA2.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382605/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955940","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
An Ping, Fan Yang, Lingxiao Lu, Xiaotao Zhang, Jianan Lu, Huaming Li, Yichen Gu, Ziyang Jin, Jianmin Zhang, Ligen Shi
{"title":"Brain-infiltrating ILC2s boost poststroke angiogenic initiation through α-CGRP production.","authors":"An Ping, Fan Yang, Lingxiao Lu, Xiaotao Zhang, Jianan Lu, Huaming Li, Yichen Gu, Ziyang Jin, Jianmin Zhang, Ligen Shi","doi":"10.1084/jem.20241830","DOIUrl":"https://doi.org/10.1084/jem.20241830","url":null,"abstract":"<p><p>Group 2 innate lymphoid cells (ILC2s) regulate immunity and tissue repair but are rarely found in the brain. Whether ILC2s can infiltrate the brain from bloodstream and the underlying mechanisms involved remain unclear. While ILC2s have recently been identified as key immunosuppressive players in neuroinflammation, their role in brain tissue repair remains promising but underexplored. Here, using in vivo and in vitro expansion of ILC2s, we demonstrate that ILC2s can enter the brain parenchyma from the blood circulation early after ischemic stroke in a CXCR1-dependent manner. Once in the brain, ILC2s improve long-term recovery of sensory-motor functions by promoting initiation of angiogenesis, namely angiogenic sprouting. Mechanistically, ILC2s produce α-calcitonin gene-related peptide (α-CGRP) to enhance angiogenic sprouting. ILC2s depleted of α-CGRP infiltrate the brain but fail to initiate angiogenesis. Impaired function of CGRP receptors on cerebrovascular endothelial cells abolishes the angiogenic effect of ILC2s. These findings highlight ILC2s as a promising target for promoting therapeutic angiogenesis in stroke recovery.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 11","pages":""},"PeriodicalIF":10.6,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144956538","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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