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Hepatology
Original article
Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver
Aida Habib1,2,3, Dina Chokr1,2,4, JingHong Wan1,2, Pushpa Hegde1,2, Morgane Mabire1,2, Matthieu Siebert1,2, Lara Ribeiro-Parenti1,2,5, Maude Le Gall1,2, Philippe Lettéron1,2, Nathalie Pilard1,2, Abdellah Mansouri1,2, Arthur Brouillet6, Matteo Tardelli7, Emmanuel Weiss1,2, Pauline Le Faouder8, Hervé Guillou9, Benjamin F Cravatt10, Richard Moreau1,2, Michael Trauner7, Sophie Lotersztajn1,2
Author affiliations
INSERM-UMR1149, Centre de Recherche sur l’Inflammation, Paris, France
Sorbonne Paris Cité, Laboratoire d’Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
Département de Chirurgie générale et digestive, Hôpital Bichat-Claude Bernard, Paris, France
INSERM U 955, Eq 18, Hopital Henri Mondor, Creteil, France
Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
Inserm U1048, MetaToul-Lipidomic Core Facility, MetaboHUB, Toulouse, France
Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, Université Paul Sabatier, Toulouse, France
The Skaggs Institute for Chemical Biology and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
Correspondence to Dr Sophie Lotersztajn, Centre de Recherche sur l’Inflammation, INSERM UMR 1149- Université Paris Diderot, Faculté de Médecine Xavier Bichat, Paris 75018, France; [email protected]
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.
http://dx.doi.org/10.1136/gutjnl-2018-316137
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发表于 2018-12-30 10:53