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Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6.
Proc Natl Acad Sci U S A. 2013 Oct 22; 110(43):17558-63.PN

Abstract

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 D2-glycerol ester (PGD2-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 PGD2-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 PGD2-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 PGD2-G as a bioactive lipid with potential anti-inflammatory properties in vivo.

Authors+Show Affiliations

Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, Université catholique de Louvain, B-1200 Brussels, Belgium.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24101490

Citation

Alhouayek, Mireille, et al. "Implication of the Anti-inflammatory Bioactive Lipid Prostaglandin D2-glycerol Ester in the Control of Macrophage Activation and Inflammation By ABHD6." Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 43, 2013, pp. 17558-63.
Alhouayek M, Masquelier J, Cani PD, et al. Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6. Proc Natl Acad Sci U S A. 2013;110(43):17558-63.
Alhouayek, M., Masquelier, J., Cani, P. D., Lambert, D. M., & Muccioli, G. G. (2013). Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6. Proceedings of the National Academy of Sciences of the United States of America, 110(43), 17558-63. https://doi.org/10.1073/pnas.1314017110
Alhouayek M, et al. Implication of the Anti-inflammatory Bioactive Lipid Prostaglandin D2-glycerol Ester in the Control of Macrophage Activation and Inflammation By ABHD6. Proc Natl Acad Sci U S A. 2013 Oct 22;110(43):17558-63. PubMed PMID: 24101490.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Implication of the anti-inflammatory bioactive lipid prostaglandin D2-glycerol ester in the control of macrophage activation and inflammation by ABHD6. AU - Alhouayek,Mireille, AU - Masquelier,Julien, AU - Cani,Patrice D, AU - Lambert,Didier M, AU - Muccioli,Giulio G, Y1 - 2013/10/07/ PY - 2013/10/9/entrez PY - 2013/10/9/pubmed PY - 2014/1/1/medline KW - COX-2 KW - FAAH KW - anandamide KW - glyceryl prostaglandin KW - prostaglandin synthase SP - 17558 EP - 63 JF - Proceedings of the National Academy of Sciences of the United States of America JO - Proc Natl Acad Sci U S A VL - 110 IS - 43 N2 - 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 D2-glycerol ester (PGD2-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 PGD2-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 PGD2-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 PGD2-G as a bioactive lipid with potential anti-inflammatory properties in vivo. SN - 1091-6490 UR - https://www.unboundmedicine.com/medline/citation/24101490/Implication_of_the_anti_inflammatory_bioactive_lipid_prostaglandin_D2_glycerol_ester_in_the_control_of_macrophage_activation_and_inflammation_by_ABHD6_ L2 - http://www.pnas.org/cgi/pmidlookup?view=long&pmid=24101490 DB - PRIME DP - Unbound Medicine ER -