{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T16:11:33Z","timestamp":1785859893595,"version":"3.56.0"},"reference-count":28,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2017,3,10]],"date-time":"2017-03-10T00:00:00Z","timestamp":1489104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["1RO1AA023722"],"award-info":[{"award-number":["1RO1AA023722"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P50AA024333"],"award-info":[{"award-number":["P50AA024333"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R21AA020941"],"award-info":[{"award-number":["R21AA020941"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1AA011975"],"award-info":[{"award-number":["RO1AA011975"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["UO1AA021890"],"award-info":[{"award-number":["UO1AA021890"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Alcoholism Clin &amp;amp; Exp Res"],"published-print":{"date-parts":[[2017,4]]},"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Toll\u2010like receptor 4 (<jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4) is critical for ethanol (EtOH)\u2010induced liver injury. <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>4 signaling is mediated by 2 proximal adaptor molecules: myeloid differentiation primary response protein (MyD88) and <jats:styled-content style=\"fixed-case\">TLR<\/jats:styled-content>\u2010domain\u2010containing adaptor\u2010inducing interferon\u2010\u03b2 (<jats:styled-content style=\"fixed-case\">TRIF<\/jats:styled-content>). Studies utilizing global knockouts of MyD88 and <jats:styled-content style=\"fixed-case\">TRIF<\/jats:styled-content> identified a predominant role for <jats:styled-content style=\"fixed-case\">TRIF<\/jats:styled-content> signaling in the progression of EtOH\u2010induced liver injury. In contrast, <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101 receptor, which signals solely via the MyD88 pathway, is also known to mediate EtOH\u2010induced liver injury. We postulated that a cell\u2010specific role for MyD88 in myeloid cells might explain these apparently discrepant roles of MyD88. Here we made use of myeloid\u2010specific MyD88\u2010deficient (MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content>) mice generated by crossing LysM\u2010<jats:styled-content style=\"fixed-case\">CRE<\/jats:styled-content> mice with MyD88<jats:sup>fl\/fl<\/jats:sup> mice to test this hypothesis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content> and littermate controls were fed a Lieber\u2013DeCarli EtOH\u2010containing diet or pair\u2010fed control diets for 25\u00a0days.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Littermate control, but not MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content>, mice developed early stages of EtOH\u2010induced liver injury including elevated plasma alanine aminotransferase and increased hepatic triglycerides. Lobular inflammation and expression of pro\u2010inflammatory cytokines\/chemokines was increased in control but not MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content>. Further, EtOH\u2010induced inflammasome activation, indicated by the presence of cleaved caspase\u20101 and mature <jats:styled-content style=\"fixed-case\">IL<\/jats:styled-content>\u20101\u03b2 protein, was also ameliorated in livers of MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content> mice. In contrast, chronic EtOH\u2010induced apoptosis, assessed via <jats:styled-content style=\"fixed-case\">TUNEL<\/jats:styled-content> staining, was independent of myeloid\u2010MyD88 expression.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Collectively, these data demonstrate a cell\u2010specific role for MyD88 in the development of chronic EtOH\u2010induced liver injury. While MyD88<jats:sup>LysM\u2010<\/jats:sup><jats:styled-content style=\"fixed-case\"><jats:sup>KO<\/jats:sup><\/jats:styled-content> still exhibited hepatocellular apoptosis in response to chronic EtOH, the absence of MyD88 on myeloid cells prevented the development of hepatic steatosis and inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/acer.13345","type":"journal-article","created":{"date-parts":[[2017,2,6]],"date-time":"2017-02-06T14:32:51Z","timestamp":1486391571000},"page":"719-726","source":"Crossref","is-referenced-by-count":9,"title":["Myeloid\u2010MyD88 Contributes to Ethanol\u2010Induced Liver Injury in Mice Linking Hepatocellular Death to Inflammation"],"prefix":"10.1111","volume":"41","author":[{"given":"Hao","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Immunology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minja","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Immunology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjoy","family":"Roychowdhury","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio"},{"name":"Department of Molecular Medicine Case Western Reserve University Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Sanz\u2010Garcia","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katherine A.","family":"Pollard","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Megan R.","family":"McMullen","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuli","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Anatomic Pathology Cleveland Clinic Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoxia","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Immunology Cleveland Clinic Cleveland Ohio"},{"name":"Department of Molecular Medicine Case Western Reserve University Cleveland Ohio"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E.","family":"Nagy","sequence":"additional","affiliation":[{"name":"Department of Pathobiology Cleveland Clinic Cleveland Ohio"},{"name":"Department of Molecular Medicine Case Western Reserve University Cleveland Ohio"},{"name":"Department of Gastroenterology\/Hepatology Cleveland Clinic Cleveland 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