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. (Hepatology 2016;64:1978-1993).
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