1. Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver.
- Author
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Habib A, Chokr D, Wan J, Hegde P, Mabire M, Siebert M, Ribeiro-Parenti L, Le Gall M, Lettéron P, Pilard N, Mansouri A, Brouillet A, Tardelli M, Weiss E, Le Faouder P, Guillou H, Cravatt BF, Moreau R, Trauner M, and Lotersztajn S
- Subjects
- Animals, Anti-Inflammatory Agents pharmacology, Autophagy drug effects, Carbamates pharmacology, Carbamates therapeutic use, Carbon Tetrachloride, Cell Count, Cells, Cultured, Cytokines metabolism, Disease Progression, Drug Evaluation, Preclinical methods, Hydrolases metabolism, Inflammation Mediators antagonists & inhibitors, Inflammation Mediators metabolism, Liver Cirrhosis, Experimental chemically induced, Liver Cirrhosis, Experimental enzymology, Liver Cirrhosis, Experimental pathology, Macrophages drug effects, Macrophages metabolism, Macrophages physiology, Male, Mice, Inbred C57BL, Mice, Knockout, Molecular Targeted Therapy methods, Monoacylglycerol Lipases physiology, Receptor, Cannabinoid, CB2 metabolism, Succinimides pharmacology, Succinimides therapeutic use, Anti-Inflammatory Agents therapeutic use, Liver enzymology, Liver Cirrhosis, Experimental drug therapy, Monoacylglycerol Lipases antagonists & inhibitors
- Abstract
Objective: Sustained inflammation originating from macrophages is a driving force of fibrosis progression and resolution. Monoacylglycerol lipase (MAGL) is the rate-limiting enzyme in the degradation of monoacylglycerols. It is a proinflammatory enzyme that metabolises 2-arachidonoylglycerol, an endocannabinoid receptor ligand, into arachidonic acid. Here, we investigated the impact of MAGL on inflammation and fibrosis during chronic liver injury., Design: C57BL/6J mice and mice with global invalidation of MAGL (MAGL
-/- ), or myeloid-specific deletion of either MAGL (MAGLMye-/- ), ATG5 (ATGMye-/- ) or CB2 (CB2Mye-/- ), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl4 ) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells., Results: MAGL-/- or MAGLMye-/- mice exposed to CCl4 or subjected to BDL were more resistant to inflammation and fibrosis than wild-type counterparts. Therapeutic intervention with MJN110, an MAGL inhibitor, reduced hepatic macrophage number and inflammatory gene expression and slowed down fibrosis progression. MAGL inhibitors also accelerated fibrosis regression and increased Ly-6Clow macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGLMye-/- BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGLMye-/- mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2Mye-/- mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5Mye-/- BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited., Conclusion: MAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2019
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