{"title":"MYOCD and SRF-mediated MLCK transcription prevents polymorphonuclear neutrophils from ferroptosis in sepsis-related acute lung injury.","authors":"Danfeng Pan, Qiu Wu, Chunfeng Zhang, Tao Qin, Tian Jiang, Ximei Wu, Fugen Wu","doi":"10.1007/s12026-024-09529-x","DOIUrl":null,"url":null,"abstract":"<p><p>Persistent activation of polymorphonuclear neutrophils (PMNs) plays a crucial role in the development of sepsis-related acute lung injury (ALI). This study investigated key molecular mechanisms involved in the hyperactivation of PMNs during ALI. A mouse model of sepsis-related ALI was generated by lipopolysaccharide (LPS) injection. RNA sequencing identified myosin light chain kinase (MLCK) as the most significant differentially expressed gene (DEG) between PMNs isolated from model and control mice. Myocardin (MYOCD) and serum response factor (SRF) were two of the DEGs that could promote transcription of MLCK by binding to its promoter. Either knockdown of MLCK, MYOCD, or SRF ameliorated dysfunction and edema in the lungs of LPS-treated mice. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the DEGs are enriched in a ferroptosis-related signaling pathway. The MLCK, MYOCD, or SRF knockdown increased contents of ROS, MDA, ferritin, and ferrous iron, and reduced levels of GSH and GPX4 in the PMNs. However, the MLCK overexpression restored ferroptosis resistance and activity of the PMNs, resulting in increased lung injury. Collectively, this study demonstrates that MYOCD and SRF-mediated MLCK upregulation is correlated with ferroptosis resistance and hyperactivation of PMNs in sepsis-related ALI.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":" ","pages":"1299-1312"},"PeriodicalIF":3.3000,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Immunologic Research","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1007/s12026-024-09529-x","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/8/28 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"IMMUNOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Persistent activation of polymorphonuclear neutrophils (PMNs) plays a crucial role in the development of sepsis-related acute lung injury (ALI). This study investigated key molecular mechanisms involved in the hyperactivation of PMNs during ALI. A mouse model of sepsis-related ALI was generated by lipopolysaccharide (LPS) injection. RNA sequencing identified myosin light chain kinase (MLCK) as the most significant differentially expressed gene (DEG) between PMNs isolated from model and control mice. Myocardin (MYOCD) and serum response factor (SRF) were two of the DEGs that could promote transcription of MLCK by binding to its promoter. Either knockdown of MLCK, MYOCD, or SRF ameliorated dysfunction and edema in the lungs of LPS-treated mice. Kyoto Encyclopedia of Genes and Genomes enrichment analysis suggested that the DEGs are enriched in a ferroptosis-related signaling pathway. The MLCK, MYOCD, or SRF knockdown increased contents of ROS, MDA, ferritin, and ferrous iron, and reduced levels of GSH and GPX4 in the PMNs. However, the MLCK overexpression restored ferroptosis resistance and activity of the PMNs, resulting in increased lung injury. Collectively, this study demonstrates that MYOCD and SRF-mediated MLCK upregulation is correlated with ferroptosis resistance and hyperactivation of PMNs in sepsis-related ALI.
期刊介绍:
IMMUNOLOGIC RESEARCH represents a unique medium for the presentation, interpretation, and clarification of complex scientific data. Information is presented in the form of interpretive synthesis reviews, original research articles, symposia, editorials, and theoretical essays. The scope of coverage extends to cellular immunology, immunogenetics, molecular and structural immunology, immunoregulation and autoimmunity, immunopathology, tumor immunology, host defense and microbial immunity, including viral immunology, immunohematology, mucosal immunity, complement, transplantation immunology, clinical immunology, neuroimmunology, immunoendocrinology, immunotoxicology, translational immunology, and history of immunology.