Myeloid-MyD88 Contributes to Ethanol-Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation.
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/flmice to test this hypothesis.



MyD88LysM-KOand littermate controls were fed a Lieber-DeCarli EtOH-containing diet or pair-fed control diets for 25 days.



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-KOmice. In contrast, chronic EtOH-induced apoptosis, assessed via TUNEL staining, was independent of myeloid-MyD88 expression.



Collectively, these data demonstrate a cell-specific role for MyD88 in the development of chronic EtOH-induced liver injury. While MyD88LysM-KOstill exhibited hepatocellular apoptosis in response to chronic EtOH, the absence of MyD88 on myeloid cells prevented the development of hepatic steatosis and inflammation.
Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
Hao
H
Zhou
Department of Immunology, Cleveland Clinic, Cleveland, Ohio.
Minja
M
Yu
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.
Sanjoy
S
Roychowdhury
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio.
Carlos
C
Sanz-Garcia
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio.
Katherine A
KA
Pollard
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio.
Megan R
MR
McMullen
Department of Anatomic Pathology, Cleveland Clinic, Cleveland, Ohio.
Xiuli
X
Liu
Department of Immunology, Cleveland Clinic, Cleveland, Ohio.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.
Xiaoxia
X
Li
Department of Pathobiology, Cleveland Clinic, Cleveland, Ohio.|Department of Molecular Medicine, Case Western Reserve University, Cleveland, Ohio.|Department of Gastroenterology/Hepatology, Cleveland Clinic, Cleveland, Ohio.
Laura E
LE
Nagy
D000818:Animals; D016923:Cell Death / Q000502:physiology; D000431:Ethanol / Q000008:administration & dosage / Q000633:toxicity*; D005260:Female; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency*; D011897:Random Allocation
C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D000431:Ethanol
Alcoholic Liver Disease; Hepatic Macrophages; MyD88; TLR4