IRAKM‐Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease

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• 作者：Hao Zhou ; Minjia Yu ; Junjie Zhao ; Bradley N. Martin ; Sanjoy Roychowdhury ; Megan R. McMullen ; Emily Wang ; Paul L. Fox ; Sho Yamasaki ; Laura E. Nagy ; et al
• 刊名：Hepatology
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：64
• 期：6
• 页码：1978-1993
• 全文大小：1.2MB
• ISSN：1527-3350

文摘

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).