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

• Published in: Alcoholism, clinical and experimental research clinical and experimental research, 2017-04, Vol.41 (4), p.719-726
• Main Authors: Zhou, Hao, Yu, Minja, Roychowdhury, Sanjoy, Sanz‐Garcia, Carlos, Pollard, Katherine A., McMullen, Megan R., Liu, Xiuli, Li, Xiaoxia, Nagy, Laura E.
• Format: Article
• Language: English
• Subjects: Alcoholic Liver Disease; Animals; Cell Death - physiology; Ethanol - administration & dosage; Ethanol - toxicity; Female; Hepatic Macrophages; Hepatitis - metabolism; Hepatitis - pathology; Hepatocytes - drug effects; Hepatocytes - metabolism; Hepatocytes - pathology; Liver Diseases, Alcoholic - metabolism; Liver Diseases, Alcoholic - pathology; Mice; Mice, Knockout; MyD88; Myeloid Differentiation Factor 88 - deficiency; Random Allocation; TLR4
• ISSN: 0145-6008; 1530-0277
• DOI: 10.1111/acer.13345

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 (MyD88LysM‐KO) mice generated by crossing LysM‐CRE mice with MyD88fl/fl mice to test this hypothesis. Methods MyD88LysM‐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 MyD88LysM‐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 MyD88LysM‐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 MyD88LysM‐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 MyD88LysM‐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. Absence of MyD88 in myeloid cells dampens ethanol‐induced hepatic inflammatory responses. Ethanol‐induced expression of IL‐1β and MCP1 mRNA, as well as TNFα protein, was reduced in livers of MyD88LySM‐KO mice. Myeloid‐MyD88‐deficiency also protected against ethanol‐induced expression of MINCLE, a sensor for cell death, and phosphorylation of its downstream target SYK. MyD88LySM‐KO mice were protected against oxidative stress, but not hepatocyte apoptosis. Taken together, these data demonstrate a cell specific role for MyD88 in the development of chronic ethanol‐induced liver injury.