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.
Gut. 2019 Mar;68(3):522-532. doi: 10.1136/gutjnl-2018-316137. Epub 2018 Oct 9.
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.
C57BL/6J mice and mice with global invalidation of MAGL (MAGL ), or myeloid-specific deletion of either MAGL (MAGL), ATG5 (ATG) or CB2 (CB2), were used. Fibrosis was induced by repeated carbon tetrachloride (CCl) injections or bile duct ligation (BDL). Studies were performed on peritoneal or bone marrow-derived macrophages and Kupffer cells.
MAGL or MAGL mice exposed to CCl 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-6C macrophage number. Antifibrogenic effects exclusively relied on MAGL inhibition in macrophages, since MJN110 treatment of MAGL BDL mice did not further decrease liver fibrosis. Cultured macrophages exposed to MJN110 or from MAGL mice displayed reduced cytokine secretion. These effects were independent of the cannabinoid receptor 2, as they were preserved in CB2 mice. They relied on macrophage autophagy, since anti-inflammatory and antifibrogenic effects of MJN110 were lost in ATG5 BDL mice, and were associated with increased autophagic flux and autophagosome biosynthesis in macrophages when MAGL was pharmacologically or genetically inhibited.
MAGL is an immunometabolic target in the liver. MAGL inhibitors may show promising antifibrogenic effects during chronic liver injury.
源于巨噬细胞的持续炎症是纤维化进展和消退的驱动力。单酰基甘油脂肪酶（MAGL）是降解单酰基甘油的限速酶。它是一种促炎酶，可将内源性大麻素受体配体 2-花生四烯酸甘油代谢为花生四烯酸。在这里，我们研究了 MAGL 在慢性肝损伤过程中对炎症和纤维化的影响。
使用 C57BL/6J 小鼠和全身性敲除 MAGL（MAGL ）的小鼠，或髓样细胞特异性敲除 MAGL（MAGL）、ATG5（ATG）或 CB2（CB2）的小鼠。通过重复四氯化碳（CCl）注射或胆管结扎（BDL）诱导纤维化。在腹膜或骨髓来源的巨噬细胞和枯否细胞上进行研究。
暴露于 CCl 或接受 BDL 的 MAGL 或 MAGL 小鼠比野生型小鼠对炎症和纤维化更具抵抗力。MAGL 抑制剂 MJN110 的治疗干预降低了肝巨噬细胞数量和炎症基因表达，并减缓了纤维化进展。MAGL 抑制剂还加速了纤维化的消退并增加了 Ly-6C 巨噬细胞的数量。抗纤维化作用仅依赖于巨噬细胞中的 MAGL 抑制，因为 MJN110 治疗 MAGL BDL 小鼠并未进一步降低肝纤维化。暴露于 MJN110 或来自 MAGL 小鼠的培养巨噬细胞显示出减少的细胞因子分泌。这些作用独立于大麻素受体 2，因为它们在 CB2 小鼠中得以保留。它们依赖于巨噬细胞自噬，因为 MJN110 的抗炎和抗纤维化作用在 ATG5 BDL 小鼠中丧失，并且与 MAGL 被药理学或基因抑制时巨噬细胞中自噬流和自噬体生物合成的增加相关。
MAGL 是肝脏中的一种免疫代谢靶点。MAGL 抑制剂在慢性肝损伤期间可能显示出有希望的抗纤维化作用。
