RRC ID 39512
Author Denaës T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, Teixeira-Clerc F.
Title The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.
Journal Sci Rep
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.
Volume 6
Pages 28806
Published 2016-6-27
DOI 10.1038/srep28806
PII srep28806
PMID 27346657
PMC PMC4921859
MeSH Alleles Animals Anti-Inflammatory Agents / chemistry Autophagy* Autophagy-Related Protein 5 / genetics Cell Lineage Ethanol / chemistry Fatty Liver / metabolism Heme Oxygenase-1 / metabolism Hepatitis, Alcoholic / metabolism Inflammation Lipopolysaccharides / chemistry Liver / metabolism Liver Diseases, Alcoholic / metabolism* Liver Diseases, Alcoholic / pathology Liver Diseases, Alcoholic / prevention & control Macrophages / metabolism* Male Membrane Proteins / metabolism Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Knockout Phenotype RAW 264.7 Cells Receptor, Cannabinoid, CB2 / agonists Receptor, Cannabinoid, CB2 / genetics* Receptor, Cannabinoid, CB2 / metabolism*
IF 3.998
Times Cited 32
Mice RBRC00806