Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice

Abstract

Activation of Kupffer cells plays a central role in the pathogenesis of alcoholic liver disease. Because cannabinoid CB2 receptors (CB2) display potent anti-inflammatory properties, we investigated their role in the pathogenesis of alcoholic liver disease, focusing on the impact of CB2 on Kupffer cell polarization and the consequences on liver steatosis. Wildtype (WT) mice fed an alcohol diet showed an induction of hepatic classical (M1) and alternative (M2) markers. Cotreatment of alcohol-fed mice with the CB2 agonist, JWH-133, decreased hepatic M1 gene expression without affecting the M2 profile. In keeping with this, genetic ablation of CB2 enhanced hepatic induction of M1 gene signature and blunted the induction of M2 markers. CB2 also modulated alcohol-induced fatty liver, as shown by the reduction of hepatocyte steatosis in JWH-133-treated mice and its enhancement in CB22/2 animals. Studies in isolated Kupffer cells and cultured macrophages further demonstrated that CB2 inhibits M1 polarization and favors the transition to an M2 phenotype. In addition, conditioned-medium experiments showed that preventing M1 polarization in CB2-activated macrophages protects from lipid accumulation in hepatocytes. Heme oxygenase-1 (HO-1) mediated the anti-inflammatory effects of CB2 receptors. Indeed, alcohol-fed mice treated with JWH-133 showed increased hepatic expression of macrophage HO-1, as compared to vehicle-treated counterparts. In keeping with this, JWH-133 induced HO-1 expression in cultured macrophages, and the HO-1 inhibitor, zinc protoporphyrin, blunted the inhibitory effect of JWH-133 on lipopolysaccharideinduced nuclear factor-kappa B activation and M1 polarization. Altogether, these findings demonstrate that CB2 receptors display beneficial effects on alcohol-induced inflammation by regulating M1/M2 balance in Kupffer cells, thereby reducing hepatocyte steatosis via paracrine interactions between Kupffer cells and hepatocytes. These data identify CB2 agonists as potential therapeutic agents for the management of alcoholic liver disease.

Microsatellite polymorphism in the heme oxygenase-1 gene promoter is not associated with alcoholic liver disease severity

“…1 Clinical studies have further suggested that the presence of the short (GT)n repeat variant is associated with a reduced risk of cardiovascular or pulmonary disease, among others, whereas conversely, there is an increased risk in patients with the long (GT)n repeat variant. Interestingly, we previously reported that HO-1 is antifibrogenic 2,3 and that induction of HO-1 protects against alcohol-induced liver injury. 4 These data raised the interesting hypothesis that the long (GT)n repeat variant in HO-1 promoter could be associated with the presence and severity of ALD.…”

“…Induction of heme oxygenase-1 (HO-1) was shown to prevent liver fibrosis 1 and ethanol-induced liver damage in mice. 2,3 A functional microsatellite (GT) n repeat variant in the HO-1 promoter region is tightly correlated with inducibility of HO-1 protein expression, i.e., short (<26) (GT) n repeat carriers present increased HO-1-expression-derived antiinflammatory and cytoprotective effects. 4 As opposed to cardiac or pulmonary disease, HO-1 gene polymorphisms in human liver disease have been largely unexplored.…”

Cannabinoid Receptor Type I Modulates Alcohol-Induced Liver Fibrosis

“…A recent study suggested that an antiinflammatory effect of CB1 antagonist SR141716 also may contribute to the favorable effects of CB1 receptor antagonists in the treatment of obesity, nonalcoholic fatty liver disease and closely related features of the metabolic syndrome (41). However, published data in this regard remain contradictory, and only one study addressed the mechanisms of how the ECS intercepts with inflammatory processes (23). In our study, we observed moderately reduced portal inflammation and a lack of COX-2 upregulation in CB1 -/-mice following alcohol exposure, while TNFα and iNOS were not different between CB1 -/-and WT mice, suggesting that the absence of CB1 has little impact on well-established triggers of hepatic inflammation.…”

“…Endocannabinoids exert numerous and sometimes opposite effects on liver target cells which could be CB receptor-dependent or independent, and are involved in control of cell survival and apoptosis (18). Thus, AEA induced cell necrosis via several mechanisms, whereas 2-AG induced apoptosis in HSC (10,19,20 (23). However, the extent of and effects on fibrosis by CB1 antagonism in the study by Trebicka et al were small, albeit significant, which could be due to the animal model in which mice received alcohol via drinking water.…”

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“…Cannabidiol a plant-derived cannabinoid exhibit anti-fibrotic potential preventing proliferation and induces endoplasmic reticulum stress mediated apoptosis in activated HSC [19]. It has been reported that endocannabinoid receptors CB2 agonist JWH-133 reduces fibrosis through promoting apoptosis in activated HSC, liver regeneration, regulating pro-inflammatory macrophage polarization and down regulation of the profibrogenic cytokine IL17 by Th17 lymphocytes [20][21][22][23]. Upon liver injury CCL5 chemokine strongly expressed to recruit inflammatory cells and HSC.…”