title: IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease.
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.
  
  
  
  This study reveals a novel IRAKM-Mincle axis that contributes to the pathogenesis of ethanol-induced liver injury. (Hepatology 2016;64:1978-1993).
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Minjia
authors.initials: M
authors.lastname: Yu
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Junjie
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Bradley N
authors.initials: BN
authors.lastname: Martin
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Sanjoy
authors.initials: S
authors.lastname: Roychowdhury
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH.
authors.forename: Megan R
authors.initials: MR
authors.lastname: McMullen
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Emily
authors.initials: E
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine, Lerner Research Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Paul L
authors.initials: PL
authors.lastname: Fox
authors.affiliation: Division of Molecular Immunology, Research Center for Infectious Diseases, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Yamasaki
authors.affiliation: Center for Liver Disease Research, Department of Pathobiology, Cleveland Clinic, Cleveland, OH.|Department of Gastroenterology, Cleveland Clinic, Cleveland, OH.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
authors.affiliation: Department of Immunology, Cleveland Clinic, Cleveland, OH.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002908:Chronic Disease; D005260:Female; D007249:Inflammation / Q000209:etiology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000502:physiology*; D037181:Lectins, C-Type / Q000502:physiology*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008108:Liver Diseases, Alcoholic / Q000503:physiopathology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D016328:NF-kappa B / Q000502:physiology
chemical_list: C113583:Clecsf8 protein, mouse; D037181:Lectins, C-Type; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D016328:NF-kappa B; D053592:Interleukin-1 Receptor-Associated Kinases; C507772:Irak3 protein, mouse