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Original article
Inhibition of monoacylglycerol lipase, an anti-inflammatory and antifibrogenic strategy in the liver
  1. Aida Habib1,2,3,
  2. Dina Chokr1,2,4,
  3. JingHong Wan1,2,
  4. Pushpa Hegde1,2,
  5. Morgane Mabire1,2,
  6. Matthieu Siebert1,2,
  7. Lara Ribeiro-Parenti1,2,5,
  8. Maude Le Gall1,2,
  9. Philippe Lettéron1,2,
  10. Nathalie Pilard1,2,
  11. Abdellah Mansouri1,2,
  12. Arthur Brouillet6,
  13. Matteo Tardelli7,
  14. Emmanuel Weiss1,2,
  15. Pauline Le Faouder8,
  16. Hervé Guillou9,
  17. Benjamin F Cravatt10,
  18. Richard Moreau1,2,
  19. Michael Trauner7,
  20. Sophie Lotersztajn1,2
  1. 1INSERM-UMR1149, Centre de Recherche sur l’Inflammation, Paris, France
  2. 2Sorbonne Paris Cité, Laboratoire d’Excellence Inflamex, Faculté de Médecine, Site Xavier Bichat, Université Paris Diderot, Paris, France
  3. 3Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
  4. 4Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
  5. 5Département de Chirurgie générale et digestive, Hôpital Bichat-Claude Bernard, Paris, France
  6. 6INSERM U 955, Eq 18, Hopital Henri Mondor, Creteil, France
  7. 7Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
  8. 8Inserm U1048, MetaToul-Lipidomic Core Facility, MetaboHUB, Toulouse, France
  9. 9Toxalim (Research Centre in Food Toxicology), Université de Toulouse, INRA, ENVT, INP-Purpan, Université Paul Sabatier, Toulouse, France
  10. 10The Skaggs Institute for Chemical Biology and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California, USA
  1. 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; sophie.lotersztajn{at}inserm.fr

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.

  • liver
  • fibrosis
  • inflammation
  • macrophages
  • lipid metabolism

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Footnotes

  • AH and DC contributed equally.

  • Contributors Study concept and design (SL, AH); acquisition of data (DC, AH, JW, PH, MM, NP, AM, AB, HG); surgery and acquisition of data (PL, MS, LRP), LC-MS lipid analysis (PLF, HG); analysis and interpretation of data (SL, AH, DC, JW, MM, AB, MLG, HG, MTa); drafting of the manuscript (AH, DC, MM and SL); critical revision of the manuscript for important intellectual content (DC, AH, JW, PH, EW, RM, MTr, SL); mice and reagents (BFC); statistical analysis (AH, DC, EW); study supervision (SL, AH). SL and MTr provided financial support.

  • Funding This work was supported by grants from INSERM (France), the Université Paris-Diderot, Labex Inflamex (SL), French Lebanese Program CEDRE (SL, AH), Association Française pour l’Etude du Foie (SL), the Fondation pour la Recherche Médicale (FRM grant number DEQ20150331726, SL) and Joint grant from National Research Agency to SL and Austrian Science Funds to MTr (ANR-15-CE14-0031 and I2661).

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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