Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (43), p.17558-17563
• Main Authors: Alhouayek, Mireille, Masquelier, Julien, Cani, Patrice D., Lambert, Didier M., Muccioli, Giulio G.
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - chemistry; Anti-Inflammatory Agents - pharmacology; Antiinflammatories; Arachidonic Acids - metabolism; Arachidonic Acids - pharmacology; Biological Sciences; Biphenyl Compounds - pharmacology; Cannabinoid receptors; Carbamates - pharmacology; Cell Line; Cell lines; Cells, Cultured; Cyclooxygenase 2 - genetics; Cyclooxygenase 2 - metabolism; Endocannabinoids; Endocannabinoids - metabolism; Endocannabinoids - pharmacology; Enzyme Inhibitors - pharmacology; Enzyme-Linked Immunosorbent Assay; Enzymes; Esters - chemistry; Female; Gene Expression - drug effects; Glycerides - metabolism; Glycerides - pharmacology; Glycerol - chemistry; Inflammation; Inflammation - chemically induced; Inflammation - metabolism; Inflammation - prevention & control; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Intramolecular Oxidoreductases - genetics; Intramolecular Oxidoreductases - metabolism; Lipids; Lipocalins - genetics; Lipocalins - metabolism; Lipopolysaccharides - toxicity; Macrophage activation; Macrophage Activation - drug effects; Macrophages; Macrophages - drug effects; Macrophages - metabolism; Male; Messenger RNA; Metabolites; Mice; Mice, Inbred C57BL; Monoacylglycerol Lipases - antagonists & inhibitors; Monoacylglycerol Lipases - genetics; Monoacylglycerol Lipases - metabolism; Prostaglandin D2 - chemistry; Prostaglandin D2 - metabolism; Prostaglandin D2 - pharmacology; Receptors; Reverse Transcriptase Polymerase Chain Reaction; Rodents; Side effects
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1314017110

Proinflammatory macrophages are key mediators in several pathologies; thus, controlling their activation is necessary. The endocannabinoid system is implicated in various inflammatory processes. Here we show that in macrophages, the newly characterized enzyme α/β-hydrolase domain 6 (ABHD6) controls 2-arachidonoylglycerol (2-AG) levels and thus its pharmacological effects. Furthermore, we characterize a unique pathway mediating the effects of 2-AG through its oxygenation by cyclooxygenase-2 to give rise to the anti-inflammatory prostaglandin D ₂-glycerol ester (PGD ₂-G). Pharmacological blockade of cyclooxygenase-2 or of prostaglandin D synthase prevented the effects of increasing 2-AG levels by ABHD6 inhibition in vitro, as well as the 2-AG–induced increase in PGD ₂-G levels. Together, our data demonstrate the physiological relevance of the interaction between the endocannabinoid and prostanoid systems. Moreover, we show that ABHD6 inhibition in vivo allows for fine-tuning of 2-AG levels in mice, therefore reducing lipopolysaccharide-induced inflammation, without the characteristic central side effects of strong increases in 2-AG levels obtained following monoacylglycerol lipase inhibition. In addition, administration of PGD ₂-G reduces lipopolysaccharide-induced inflammation in mice, thus confirming the biological relevance of this 2-AG metabolite. This points to ABHD6 as an interesting therapeutic target that should be relevant in treating inflammation-related conditions, and proposes PGD ₂-G as a bioactive lipid with potential anti-inflammatory properties in vivo.