{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T04:10:18Z","timestamp":1790827818183,"version":"4.1.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T00:00:00Z","timestamp":1549929600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"},{"start":{"date-parts":[[2019,2,12]],"date-time":"2019-02-12T00:00:00Z","timestamp":1549929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2019,3]]},"abstract":"<jats:p>Kupffer cell and macrophage (M\u00d8) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of M\u00d8, T cells, and expression of C\u2010C chemokine receptor type 2 (<jats:italic toggle=\"yes\">Ccr2<\/jats:italic>) and C\u2010C chemokine receptor type 5 (<jats:italic toggle=\"yes\">Ccr5<\/jats:italic>) in the livers of patients with ALD, and increased circulating chemokines, C\u2010C chemokine ligand types 2 (CCL2), and C\u2010C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2\/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as \u201cprevention\u201d throughout the alcohol feeding or as \u201ctreatment\u201d started after the development of ALD. Alcohol\u2010induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen\u20101) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol\u2010related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)\u2010\u03b1, interleukin (IL)\u20101\u03b2, IL\u20106, and CCL2. CVC administration regimens prevented the increase in infiltrating M\u00d8 (F4\/80<jats:sup>lo <\/jats:sup>CD11b<jats:sup>hi<\/jats:sup>) and reduced proinflammatory Ly6C<jats:sup>hi<\/jats:sup> M\u00d8 in livers of alcohol\u2010fed mice. CVC increased liver T\u2010cell numbers and attenuated <jats:italic toggle=\"yes\">Il\u20102<\/jats:italic> expression without an effect on CD69<jats:sup>+<\/jats:sup> or CD25<jats:sup>+<\/jats:sup> T\u2010cell expression. <jats:italic toggle=\"yes\">In vitro<\/jats:italic>, CVC inhibited CCL2\u2010induced increases in hepatocyte fatty acid synthase (<jats:italic toggle=\"yes\">Fasn<\/jats:italic>) and adipose differentiation\u2010related protein <jats:italic toggle=\"yes\">(Adrp<\/jats:italic>)<jats:italic toggle=\"yes\">,<\/jats:italic> whereas it augmented acyl\u2010coenzyme A oxidase 1 (<jats:italic toggle=\"yes\">Acox\u20101<\/jats:italic>), proliferator\u2010activated receptor gamma co\u2010activator alpha (<jats:italic toggle=\"yes\">Pgc1\u03b1<\/jats:italic>) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide\u2010induced liver injury (TNF\u2010\u03b1, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP\u2010ribose polymerase [PARP] and caspase\u20103 [CASP\u20103] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. <jats:italic toggle=\"yes\">Conclusion:<\/jats:italic> Together, our data demonstrate preclinical evidence for CCR2\/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol\u2010induced steatohepatitis and liver damage.<\/jats:p>","DOI":"10.1002\/hep.30249","type":"journal-article","created":{"date-parts":[[2018,9,4]],"date-time":"2018-09-04T14:22:03Z","timestamp":1536070923000},"page":"1105-1121","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":197,"title":["Pharmacological Inhibition of CCR2\/5 Signaling Prevents and Reverses Alcohol\u2010Induced Liver Damage, Steatosis, and Inflammation in 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