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IRAKM‐Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease
Author(s) -
Zhou Hao,
Yu Minjia,
Zhao Junjie,
Martin Bradley N.,
Roychowdhury Sanjoy,
McMullen Megan R.,
Wang Emily,
Fox Paul L.,
Yamasaki Sho,
Nagy Laura E.,
Li Xiaoxia
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28811
Subject(s) - inflammasome , liver injury , alcoholic liver disease , inflammation , pathogenesis , immunology , lipopolysaccharide , innate immune system , receptor , medicine , biology , pharmacology , immune system , cirrhosis
Lipopolysaccharide (LPS)‐mediated activation of Toll‐like receptors (TLRs) in hepatic macrophages and injury to hepatocytes are major contributors to the pathogenesis of alcoholic liver disease. However, the mechanisms by which TLR‐dependent inflammatory responses and alcohol‐induced hepatocellular damage coordinately lead to alcoholic liver disease are not completely understood. In this study, we found that mice deficient in interleukin‐1 receptor‐associated kinase M (IRAKM), a proximal TLR pathway molecule typically associated with inhibition of TLR signaling, were actually protected from chronic ethanol‐induced liver injury. In bone marrow‐derived macrophages challenged with low concentrations of LPS, which reflect the relevant pathophysiological levels of LPS in both alcoholic patients and ethanol‐fed mice, the IRAKM Myddosome was preferentially formed. Further, the IRAKM Myddosome mediated the up‐regulation of Mincle, a sensor for cell death. Mincle‐deficient mice were also protected from ethanol‐induced liver injury. The endogenous Mincle ligand spliceosome‐associated protein 130 (SAP130) is a danger signal released by damaged cells; culture of hepatocytes with ethanol increased the release of SAP130. Ex vivo studies in bone marrow‐derived macrophages suggested that SAP130 and LPS synergistically activated inflammatory responses, including inflammasome activation. Conclusion : This study reveals a novel IRAKM‐Mincle axis that contributes to the pathogenesis of ethanol‐induced liver injury. (H epatology 2016;64:1978‐1993).