title: Immune responsive gene 1 (IRG1) promotes endotoxin tolerance by increasing A20 expression in macrophages through reactive oxygen species.
abstract: Sepsis-associated immunosuppression (SAIS) is regarded as one of main causes for the death of septic patients at the late stage because of the decreased innate immunity with a more opportunistic infection. LPS-tolerized macrophages, which are re-challenged by LPS after prior exposure to LPS, are regarded as the common model of hypo-responsiveness for SAIS. However, the molecular mechanisms of endotoxin tolerance and SAIS remain to be fully elucidated. In addition, negative regulation of the Toll-like receptor (TLR)-triggered innate inflammatory response needs further investigation. Here we show that expression of immune responsive gene 1 (IRG1) was highly up-regulated in the peripheral blood mononuclear cells of septic patients and in LPS-tolerized mouse macrophages. IRG1 significantly suppressed TLR-triggered production of proinflammatory cytokines TNF-α, IL-6, and IFN-β in LPS-tolerized macrophages, with the elevated expression of reactive oxygen species (ROS) and A20. Moreover, ROS enhanced A20 expression by increasing the H3K4me3 modification of histone on the A20 promoter domain, and supplement of the ROS abrogated the IRG1 knockdown function in breaking endotoxin tolerance by increasing A20 expression. Our results demonstrate that inducible IRG1 promotes endotoxin tolerance by increasing A20 expression through ROS, indicating a new molecular mechanism regulating hypoinflammation of sepsis and endotoxin tolerance.
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433; Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003.
authors.forename: Yingke
authors.initials: Y
authors.lastname: Li
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003.
authors.forename: Chengcai
authors.initials: C
authors.lastname: Wang
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Han
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058.
authors.forename: Jun
authors.initials: J
authors.lastname: Meng
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Liu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
authors.forename: Sheng
authors.initials: S
authors.lastname: Xu
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433.
authors.forename: Nan
authors.initials: N
authors.lastname: Li
authors.affiliation: Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wang
authors.affiliation: Department of Anesthesiology, Changzheng Hospital, Second Military Medical University, Shanghai 200003. Electronic address: shixueyin1128@yahoo.com.cn.
authors.forename: Xueyin
authors.initials: X
authors.lastname: Shi
authors.affiliation: National Key Laboratory of Medical Immunology and Institute of Immunology, Second Military Medical University, Shanghai 200433; Institute of Immunology, Zhejiang University School of Medicine, Hangzhou 310058; National Key Laboratory of Medical Molecular Biology and Department of Immunology, Chinese Academy of Medical Sciences, Beijing 100021, China. Electronic address: caoxt@immunol.org.
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D002262:Carboxy-Lyases; D003546:Cysteine Endopeptidases; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D055785:Gene Knockdown Techniques; D006657:Histones / Q000235:genetics / Q000276:immunology; D006801:Humans; D006836:Hydro-Lyases / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects*; D007113:Immunity, Innate / Q000187:drug effects*; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008070:Lipopolysaccharides / Q000276:immunology / Q000633:toxicity*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology*; D011506:Proteins / Q000235:genetics / Q000276:immunology*; D017382:Reactive Oxygen Species / Q000276:immunology*; D018805:Sepsis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D006657:Histones; C508600:IL6 protein, human; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D009687:Nuclear Proteins; D011506:Proteins; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D044767:Ubiquitin-Protein Ligases; C076529:TNFAIP3 protein, human; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse; C561544:ACOD1 protein, human; D002262:Carboxy-Lyases; D006836:Hydro-Lyases; C487648:Acod1 protein, mouse
keywords: A20; Endotoxin Tolerance; Immune Responsive Gene 1; Inflammation; Innate Immunity; Macrophages; ROS; Reactive Oxygen Species (ROS); Toll-like Receptors (TLR)