RRC ID |
39512
|
著者 |
Denaës T, Lodder J, Chobert MN, Ruiz I, Pawlotsky JM, Lotersztajn S, Teixeira-Clerc F.
|
タイトル |
The Cannabinoid Receptor 2 Protects Against Alcoholic Liver Disease Via a Macrophage Autophagy-Dependent Pathway.
|
ジャーナル |
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.
|
巻・号 |
6
|
ページ |
28806
|
公開日 |
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
|
引用数 |
32
|
WOS 分野
|
CELL BIOLOGY
|
リソース情報 |
実験動物マウス |
RBRC00806 |