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

Hao Zhou, Minjia Yu, Junjie Zhao, Bradley N. Martin, Sanjoy Roychowdhury, Megan R. McMullen, Emily Wang, Paul L. Fox, Sho Yamasaki, Laura E. Nagy, Xiaoxia Li

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    22 Citations (Scopus)

    Abstract

    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).

    Original languageEnglish
    Pages (from-to)1978-1993
    Number of pages16
    JournalHepatology
    Volume64
    Issue number6
    DOIs
    Publication statusPublished - Dec 1 2016

    All Science Journal Classification (ASJC) codes

    • Hepatology

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  • Cite this

    Zhou, H., Yu, M., Zhao, J., Martin, B. N., Roychowdhury, S., McMullen, M. R., Wang, E., Fox, P. L., Yamasaki, S., Nagy, L. E., & Li, X. (2016). IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology, 64(6), 1978-1993. https://doi.org/10.1002/hep.28811