Controlling inflammation and macrophage activation with bioactive lipids : role of PEA and 2-AG metabolizing enzymes
(2014)
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- Bioactive lipids are implicated in several pathophysiological processes, including inflammation. In this work, two bioactive lipids of interest were investigated, the endocannabinoid 2-arachidonoylglycerol (2-AG) and the N-acylethanolamine palmitoylethanolamide (PEA), in murine models of Crohn’s disease, as well as in lipopolysaccharide (LPS)-induced macrophage activation and systemic inflammation. PEA is known to exert anti-inflammatory, analgesic and neuroprotective effects. Therefore we sought to increase PEA levels in murine models of Crohn’s disease, namely DSS-induced colitis and TNBS-induced colitis through inhibition of its hydrolytic enzymes: fatty acid amide hydrolase (FAAH) and the N-acylethanolamine hydrolyzing acid amidase (NAAA). PEA administration reduces diarrhea and macroscopic and microscopic signs of colon inflammation in both colitis models, as well as pro-inflammatory cytokines production. Interestingly, long-lasting and selective FAAH inhibition was not sufficient to increase PEA levels in the colon, whereas we observed increased PEA levels upon NAAA inhibition. Accordingly, NAAA inhibition reduced inflammatory parameters in the colon, similarly to PEA, whereas FAAH inhibition did not replicate all the anti-inflammatory effects observed with PEA in the colon. The second part of this work is dedicated to the endocannabinoid 2-AG. Endocannabinoids classically exert their actions by binding and activating two G-protein coupled receptors, the cannabinoid receptors 1 and 2. The actions of 2-AG are terminated by its hydrolysis by two lipases, monoacylglycerol lipase (MAGL) and α/β hydrolase domain 6 (ABHD6). MAGL is thought to be the primary enzyme responsible for 2-AG hydrolysis, at least in the brain. We studied the effect of 2-AG on colon inflammation by inhibiting its MAGL-mediated hydrolysis in the TNBS-induced colitis model. We show that MAGL inhibition increases 2-AG levels in the colon and leads to a reduction in all the parameters of colon inflammation, in a cannabinoid receptors-dependent manner. Macrophages are key mediators in the pathogenesis of chronic inflammatory diseases, and while acute inflammation is necessary to fight off infection or tissue injury, it becomes deleterious in a chronic setting. In this context, we thought to assess the effect of 2-AG on macrophage activation and take a closer look at the less well-studied enzyme responsible for 2-AG hydrolysis, ABHD6. Interestingly, ABHD6, not MAGL, controlled 2-AG levels in LPS-activated macrophages, and therefore ABHD6 inhibition increased 2-AG levels and decreased LPS-induced macrophage activation. We also show that the effect of 2-AG on macrophage activation is not mediated by its classical cannabinoid receptors, but rather by its oxidative metabolism by COX-2. Indeed, 2-AG is metabolized by COX-2 to give prostaglandin-glycerol esters (PG-Gs). Although the formation of these PG-Gs has been shown before, there was no indication of what their biological effects might be. Here we show that 2-AG is metabolized by COX-2 and prostaglandin D synthase, to give PGD2-G which reduces macrophage activation in vitro as well as inflammation in vivo. Moreover, ABHD6 inhibition in vivo reduces the systemic inflammation induced by LPS administration to mice, and this effect is mediated both by cannabinoid receptor activation and COX-2 metabolism of 2-AG. In conclusion, this work put forth several new leads to be investigated in the search for potential new therapeutic targets in inflammation management. We identified the anti-inflammatory role of PEA and 2-AG in inflammatory settings. We also put forth NAAA as the primary enzyme responsible for controlling PEA levels in the colon, and ABHD6 as responsible for the control of 2-AG levels in macrophages. Moreover, we identified PGD2-G as a novel bioactive lipid with anti-inflammatory properties.
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Al Houayek, M. (2014). Controlling inflammation and macrophage activation with bioactive lipids : role of PEA and 2-AG metabolizing enzymes. https://hdl.handle.net/2078.5/199209