Macrophage-derived IL-1α promotes sterile inflammation in a mouse model of acetaminophen hepatotoxicity  

作　　者：Chao Zhang Jin Feng Jun Du Zhiyong Zhuo Shuo Yang Weihong Zhang Weihong Wang Shengyuan Zhang Yoichiro Iwakura Guangxun Meng Yang-Xin Fu Baidong Hou Hong Tang 

机构地区：[1]The Key Laboratory of Infection and Immunity,The Institute of Biophysics,Chinese Academy of Sciences,100101,Beijing,China [2]The Institute of Biotechnology,Shanxi University,030006,Taiyuan,China [3]The Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,200031,Shanghai,China [4]Division of Experimental Animal Immunology,Center for Animal Disease Models,Research Institute for Biomedical Sciences,Tokyo University of Science,278-0022,Chiba,Japan [5]Department of Pathology,The University of Chicago,60637,Chicago,USA,IL

出　　处：《Cellular & Molecular Immunology》2018年第11期973-982,共10页中国免疫学杂志（英文版）

基　　金：This work was supported by grants from the National Science Foundation of China(31030031 and 81220108018);the Ministry of Science and Technology of China(2011CB946104)to HT.

摘　　要：The metabolic intermediate of acetaminophen(APAP)can cause severe hepatocyte necrosis,which triggers aberrant immune activation of liver non-parenchymal cells(NPC).Overzealous hepatic inflammation determines the morbidity and mortality of APAP-induced liver injury(AILI).Interleukin-1 receptor(IL-1R)signaling has been shown to play a critical role in various inflammatory conditions,but its precise role and underlying mechanism in AILI remain debatable.Herein,we show that NLRP3 inflammasome activation of IL-1βis dispensable to AILI,whereas IL-1α,the other ligand of IL-1R1,accounts for hepatic injury by a lethal dose of APAP.Furthermore,Kupffer cells function as a major source of activated IL-1αin the liver,which is activated by damaged hepatocytes through TLR4/MyD88 signaling.Finally,IL-1αis able to chemoattract and activate CD11b^(+)Gr-1^(+) myeloid cells,mostly neutrophils and inflammatory monocytes,to amplify deteriorated inflammation in the lesion.Therefore,this work identifies that MyD88-dependent activation of IL-1αin Kupffer cells plays a central role in the immunopathogenesis of AILI and implicates that IL-1αis a promising therapeutic target for AILI treatment.

关 键 词：ACETAMINOPHEN IL-α Kupffer cells sterile immunity TLR4 

分 类 号：R57[医药卫生—消化系统]