Anne Doye, Paul Chaintreuil, Chantal Lagresle-Peyrou, Ludovic Batistic, Valentine Marion, Patrick Munro, Celine Loubatier, Rayana Chirara, Nataël Sorel, Boris Bessot, Pauline Bronnec, Julie Contenti, Johan Courjon, Valerie Giordanengo, Arnaud Jacquel, Pascal Barbry, Marie Couralet, Nathalie Aladjidi, Alain Fischer, Marina Cavazzana, Coralie Mallebranche, Orane Visvikis, Sven Kracker, Despina Moshous, Els Verhoeyen, Laurent Boyer
{"title":"导致先天性免疫错误的 RAC2 功能增益变异驱动 NLRP3 炎症小体激活。","authors":"Anne Doye, Paul Chaintreuil, Chantal Lagresle-Peyrou, Ludovic Batistic, Valentine Marion, Patrick Munro, Celine Loubatier, Rayana Chirara, Nataël Sorel, Boris Bessot, Pauline Bronnec, Julie Contenti, Johan Courjon, Valerie Giordanengo, Arnaud Jacquel, Pascal Barbry, Marie Couralet, Nathalie Aladjidi, Alain Fischer, Marina Cavazzana, Coralie Mallebranche, Orane Visvikis, Sven Kracker, Despina Moshous, Els Verhoeyen, Laurent Boyer","doi":"10.1084/jem.20231562","DOIUrl":null,"url":null,"abstract":"<p><p>A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 10","pages":""},"PeriodicalIF":12.6000,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363864/pdf/","citationCount":"0","resultStr":"{\"title\":\"RAC2 gain-of-function variants causing inborn error of immunity drive NLRP3 inflammasome activation.\",\"authors\":\"Anne Doye, Paul Chaintreuil, Chantal Lagresle-Peyrou, Ludovic Batistic, Valentine Marion, Patrick Munro, Celine Loubatier, Rayana Chirara, Nataël Sorel, Boris Bessot, Pauline Bronnec, Julie Contenti, Johan Courjon, Valerie Giordanengo, Arnaud Jacquel, Pascal Barbry, Marie Couralet, Nathalie Aladjidi, Alain Fischer, Marina Cavazzana, Coralie Mallebranche, Orane Visvikis, Sven Kracker, Despina Moshous, Els Verhoeyen, Laurent Boyer\",\"doi\":\"10.1084/jem.20231562\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.</p>\",\"PeriodicalId\":15760,\"journal\":{\"name\":\"Journal of Experimental Medicine\",\"volume\":\"221 10\",\"pages\":\"\"},\"PeriodicalIF\":12.6000,\"publicationDate\":\"2024-10-07\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11363864/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Experimental Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1084/jem.20231562\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/8/30 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"IMMUNOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Experimental Medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1084/jem.20231562","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/30 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
A growing number of patients presenting severe combined immunodeficiencies attributed to monoallelic RAC2 variants have been identified. The expression of the RHO GTPase RAC2 is restricted to the hematopoietic lineage. RAC2 variants have been described to cause immunodeficiencies associated with high frequency of infection, leukopenia, and autoinflammatory features. Here, we show that specific RAC2 activating mutations induce the NLRP3 inflammasome activation leading to the secretion of IL-1β and IL-18 from macrophages. This activation depends on the activation state of the RAC2 variant and is mediated by the downstream kinase PAK1. Inhibiting the RAC2-PAK1-NLRP3 inflammasome pathway might be considered as a potential treatment for these patients.
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Since its establishment in 1896, the Journal of Experimental Medicine (JEM) has steadfastly pursued the publication of enduring and exceptional studies in medical biology. In an era where numerous publishing groups are introducing specialized journals, we recognize the importance of offering a distinguished platform for studies that seamlessly integrate various disciplines within the pathogenesis field.
Our unique editorial system, driven by a commitment to exceptional author service, involves two collaborative groups of editors: professional editors with robust scientific backgrounds and full-time practicing scientists. Each paper undergoes evaluation by at least one editor from both groups before external review. Weekly editorial meetings facilitate comprehensive discussions on papers, incorporating external referee comments, and ensure swift decisions without unnecessary demands for extensive revisions.
Encompassing human studies and diverse in vivo experimental models of human disease, our focus within medical biology spans genetics, inflammation, immunity, infectious disease, cancer, vascular biology, metabolic disorders, neuroscience, and stem cell biology. We eagerly welcome reports ranging from atomic-level analyses to clinical interventions that unveil new mechanistic insights.
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