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Myeloid‐MyD88 Contributes to Ethanol‐Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation
Author(s) -
Zhou Hao,
Yu Minja,
Roychowdhury Sanjoy,
SanzGarcia Carlos,
Pollard Katherine A.,
McMullen Megan R.,
Liu Xiuli,
Li Xiaoxia,
Nagy Laura E.
Publication year - 2017
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.13345
Subject(s) - trif , inflammation , liver injury , inflammasome , myeloid , signal transducing adaptor protein , toll like receptor , receptor , knockout mouse , signal transduction , innate immune system , chemistry , medicine , endocrinology , immunology , cancer research , biology , microbiology and biotechnology
Background Toll‐like receptor 4 ( TLR 4) is critical for ethanol (EtOH)‐induced liver injury. TLR 4 signaling is mediated by 2 proximal adaptor molecules: myeloid differentiation primary response protein (MyD88) and TLR ‐domain‐containing adaptor‐inducing interferon‐β ( TRIF ). Studies utilizing global knockouts of MyD88 and TRIF identified a predominant role for TRIF signaling in the progression of EtOH‐induced liver injury. In contrast, IL ‐1 receptor, which signals solely via the MyD88 pathway, is also known to mediate EtOH‐induced liver injury. We postulated that a cell‐specific role for MyD88 in myeloid cells might explain these apparently discrepant roles of MyD88. Here we made use of myeloid‐specific MyD88‐deficient (MyD88 LysM‐ KO ) mice generated by crossing LysM‐ CRE mice with MyD88 fl/fl mice to test this hypothesis. Methods MyD88 LysM‐ KO and littermate controls were fed a Lieber–DeCarli EtOH‐containing diet or pair‐fed control diets for 25 days. Results Littermate control, but not MyD88 LysM‐ KO , mice developed early stages of EtOH‐induced liver injury including elevated plasma alanine aminotransferase and increased hepatic triglycerides. Lobular inflammation and expression of pro‐inflammatory cytokines/chemokines was increased in control but not MyD88 LysM‐ KO . Further, EtOH‐induced inflammasome activation, indicated by the presence of cleaved caspase‐1 and mature IL ‐1β protein, was also ameliorated in livers of MyD88 LysM‐ KO mice. In contrast, chronic EtOH‐induced apoptosis, assessed via TUNEL staining, was independent of myeloid‐MyD88 expression. Conclusions Collectively, these data demonstrate a cell‐specific role for MyD88 in the development of chronic EtOH‐induced liver injury. While MyD88 LysM‐ KO still exhibited hepatocellular apoptosis in response to chronic EtOH, the absence of MyD88 on myeloid cells prevented the development of hepatic steatosis and inflammation.