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Sci Rep. 2016 Jun 27;6:28806. doi: 10.1038/srep28806.

The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.

Author information

1
INSERM U955, Institut Mondor de Recherche Biomédicale, Créteil, F-94000 France.
2
Université Paris-Est, Faculté de Médecine, UMR-S955, Créteil, F-94000 France.
3
INSERM U1149, Center for Research on Inflammation, Paris, F-75018, France.
4
Université Paris Diderot, Sorbonne Paris Cité, Laboratoire d'Excellence Inflammex, Faculté de Médecine, Site Xavier Bichat, Paris, F-75018, France.

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.

PMID:
27346657
PMCID:
PMC4921859
DOI:
10.1038/srep28806
[Indexed for MEDLINE]
Free PMC Article

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