title: The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.
abstract: Kupffer cells, the resident macrophages of the liver, play a major role in the pathogenesis of alcoholic liver disease. We have previously demonstrated that CB2 receptor protects against alcoholic liver disease by inhibiting alcohol-induced inflammation and steatosis via the regulation of Kupffer cell activation. Here, we explored the mechanism underlying these effects and hypothesized that the anti-inflammatory properties of CB2 receptor in Kupffer cells rely on activation of autophagy. For this purpose, mice invalidated for CB2 receptor (CB2(Mye-/-) mice) or for the autophagy gene ATG5 (ATG5(Mye-/-) mice) in the myeloid lineage, and their littermate wild-type mice were subjected to chronic-plus-binge ethanol feeding. CB2(Mye-/-) mice showed exacerbated alcohol-induced pro-inflammatory gene expression and steatosis. Studies in cultured macrophages demonstrated that CB2 receptor activation by JWH-133 stimulated autophagy via a heme oxygenase-1 dependent pathway. Moreover, JWH-133 reduced the induction of inflammatory genes by lipopolysaccharide in wild-type macrophages, but not in ATG5-deficient cells. The CB2 agonist also protected from alcohol-induced liver inflammation and steatosis in wild-type mice, but not in ATG5(Mye-/-) mice demonstrating that macrophage autophagy mediates the anti-inflammatory and anti-steatogenic effects of CB2 receptor. Altogether these results demonstrate that CB2 receptor activation in macrophages protects from alcohol-induced steatosis by inhibiting hepatic inflammation through an autophagy-dependent pathway.
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Timothé
authors.initials: T
authors.lastname: Denaës
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Jasper
authors.initials: J
authors.lastname: Lodder
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Marie-Noële
authors.initials: MN
authors.lastname: Chobert
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Isaac
authors.initials: I
authors.lastname: Ruiz
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pawlotsky
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.|INSERM U1149, Center for Research on Inflammation, Paris, F-75018, France.|Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflammex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lotersztajn
authors.affiliation: INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.|Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Teixeira-Clerc
mesh_terms: D000483:Alleles; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000737:chemistry; D001343:Autophagy; D000071187:Autophagy-Related Protein 5 / Q000235:genetics; D019070:Cell Lineage; D000431:Ethanol / Q000737:chemistry; D005234:Fatty Liver / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000378:metabolism; D006519:Hepatitis, Alcoholic / Q000378:metabolism; D007249:Inflammation; D008070:Lipopolysaccharides / Q000737:chemistry; D008099:Liver / Q000378:metabolism; D008108:Liver Diseases, Alcoholic / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D000067996:RAW 264.7 Cells; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000235:genetics* / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; C495773:Atg5 protein, mouse; D000071187:Autophagy-Related Protein 5; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D043885:Receptor, Cannabinoid, CB2; D000431:Ethanol; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse