BackgroundToll‐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.MethodsMyD88^LysM‐KO and littermate controls were fed a Lieber–DeCarli EtOH‐containing diet or pair‐fed control diets for 25 days.ResultsLittermate 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.ConclusionsCollectively, 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.