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

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 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.COX-2 | prostaglandin synthase | glyceryl prostaglandin | FAAH | anandamide

Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells

“…COX-2 oxygenates 2-AG to form PG-Gs, which display effects that are frequently opposite those of endocannabinoids, e.g. hyperalgesia and neuroinflammation (13)(14)(15)(16)(17)(18)(19). However, complete elucidation of the effects of PG-Gs in vivo has been challenging due to their instability to enzymatic hydrolysis (20).…”

“…1). These lipids are of growing interest because they elicit a wide array of cellular responses, including activation of calcium mobilization, modulation of synaptic transmission, induction of hyperalgesia, exacerbation of neurotoxicity and neuroinflammation, and stimulation of anti-inflammatory effects upon lipopolysaccharide stimulation (13)(14)(15)(16)(17)(18)(19).…”

α/β-Hydrolase domain-containing 6 (ABHD6) negatively regulates the surface delivery and synaptic function of AMPA receptors

“…Serine hydrolase inhibitors are used for the treatment of many diseases, including cognitive dementia, obesity, and diabetes. ABHD6 is considered an attractive therapeutic target for manipulating 2-AG signaling (44)(45)(46). Chronic WWL70 treatment after traumatic brain injury exerted a neuroprotective effect by increasing the levels of 2-AG in the brain (47).…”

The endocannabinoid system in pain and inflammation: Its relevance to rheumatic disease

“…What is less well appreciated is that COX enzyme also metabolizes endocannabinoids to prostaglandin-glycerol esters for 2-AG and prostaglandin ethanolamines for AEA, as shown in Figure 2. These bioactive lipids may have a role in inflammation (81). What (75) is also not known is the functional consequences between cyclooxygenase-2 (COX-2) inhibition and endocannabinoid effects.…”