TY - JOUR
T1 - IRAKM-Mincle axis links cell death to inflammation
T2 - Pathophysiological implications for chronic alcoholic liver disease
AU - Zhou, Hao
AU - Yu, Minjia
AU - Zhao, Junjie
AU - Martin, Bradley N.
AU - Roychowdhury, Sanjoy
AU - McMullen, Megan R.
AU - Wang, Emily
AU - Fox, Paul L.
AU - Yamasaki, Sho
AU - Nagy, Laura E.
AU - Li, Xiaoxia
N1 - Funding Information:
We thank Dr. Richard A. Flavell (Department of Immunobiology, Yale University School of Medicine, New Haven, CT) for providing the IRAKM-deficient mice. We thank Dr. Christine A. Wells (Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Australia) for providing anti-Mincle antibody for immune fluorescence staining.
Publisher Copyright:
© 2016 by the American Association for the Study of Liver Diseases
PY - 2016/12/1
Y1 - 2016/12/1
N2 - 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).
AB - 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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U2 - 10.1002/hep.28811
DO - 10.1002/hep.28811
M3 - Article
C2 - 27628766
AN - SCOPUS:84995755382
VL - 64
SP - 1978
EP - 1993
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 6
ER -