Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation

Background: Toll-like receptor 4 (TLR4) is critical for ethanol (EtOH)-induced liver injury. TLR4 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.