Palmitoylethanolamide promotes a proresolving macrophage phenotype and attenuates atherosclerotic plaque formation

Abstract

Objective-Palmitoylethanolamide is an endogenous fatty acid mediator that is synthetized from membrane phospholipids by Af-acyl phosphatidylethanolamine phospholipasc D. Its biological actions are primarily mediated by PPAR-a (peroxisome proliferator-activatcd receptors a) and the orphan receptor GPR55. Palmitoylethanolamide exerts potent anti-inflammatory actions but its physiological role and promise as a therapeutic agent in chronic arterial inflammation, such as atherosclerosis remain unexplored. Approach and Results-First, the polarization of mouse primary macrophages towards a proinflammatory phenotype was found to reduce JV-acyl phosphatidylethanolamine phospholipase D expression and palmitoylethanolamide bioavailability. jV-acyl phosphatidylethanolamine phospholipasc D expression was progressively downregulatcd in the aorta of apolipoprotcin E deficient (ApoE •'") mice during athcrogenesis. N-acyl phosphatidylethanolamine phospholipase D mRNA levels were also downrcgulated in unstable human plaques and they positively associated with smooth muscle cell markers and negatively with macrophage markers. Second. ApoE-∗- mice were fed a high-fat diet for 4 or 16 weeks and treated with cither vehicle or palmitoylethanolamide (3 mg/kg per day. 4 weeks) to study the effects of palmitoylethanolamide on early established and pre-established atherosclerosis. Palmitoylethanolamide treatment reduced plaque size in early atherosclerosis, whereas in pre-established atherosclerosis, palmitoylethanolamide promoted signs of plaque stability as evidenced by reduced macrophage accumulation and necrotic core size, increased collagen deposition and downrcgulation of Ml-type macrophage markers. Mechanistically, we found that palmitoylethanolamide. by activating GPR55. increases the expression of the phagocytosis receptor MerTK (proto-oncogcne tyrosinc-protein kinase MER) and enhances macrophage efferocytosis. indicative of proresolving properties. Conclusions-The present study demonstrates that palmitoylethanolamide protects against atherosclerosis by promoting an anti-inflammatory and proresolving phenotype of lesional macrophages, representing a new therapeutic approach to resolve arterial inflammation.