Abstract
Chronic inflammation is a hallmark of atherosclerosis and results from an imbalance between proinflammatory and proresolving signaling. The human GPR32 receptor, together with the ALX/FPR2 receptor, transduces biological actions of several proresolving mediators that stimulate resolution of inflammation. However, since no murine homologs of the human GPR32 receptor exist, comprehensive in vivo studies are lacking. Using human atherosclerotic lesions from carotid endarterectomies and creating a transgenic mouse model expressing human GPR32 on a Fpr2×ApoE double-KO background (hGPR32myc×Fpr2-/-×Apoe-/-), we investigated the role of GPR32 in atherosclerosis and self-limiting acute inflammation. GPR32 mRNA was reduced in human atherosclerotic lesions and correlated with the immune cell markers ARG1, NOS2, and FOXP3. Atherosclerotic lesions, necrotic core, and aortic inflammation were reduced in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice as compared with Fpr2-/-×Apoe-/- nontransgenic littermates. In a zymosan-induced peritonitis model, the hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice had reduced inflammation at 4 hours and enhanced proresolving macrophage responses at 24 hours compared with nontransgenic littermates. The GPR32 agonist aspirin-triggered resolvin D1 (AT-RvD1) regulated leukocyte responses, including enhancing macrophage phagocytosis and intracellular signaling in hGPR32mycTg×Fpr2-/-×Apoe-/- transgenic mice, but not in Fpr2-/-×Apoe-/- nontransgenic littermates. Together, these results provide evidence that GPR32 regulates resolution of inflammation and is atheroprotective in vivo.
Highlights
Resolution of acute inflammation is an active, coordinated response aimed at terminating the inflammatory response and restoring tissue homeostasis [1].regulated by a superfamily of lipid mediators called specialized pro-resolving mediators (SPMs), that consist of several structurally distinct families biosynthesized from polyunsaturated fatty acids, such as the resolvins (Rv) and lipoxins (LX)(1,2)
GPR32 receptor we found that pro-resolving signaling through GPR32 was atheroprotective independently of Fpr2, through leukocyte regulated responses, of decreased pro-inflammatory cytokines, reduced oxidized low-density liporprotein (oxLDL) uptake, and enhanced phagocytosis
The murine model identified agonist-induced signaling by GPR32 ligands, which strengthened the translational implications of the findings for human disease
Summary
Resolution of acute inflammation is an active, coordinated response aimed at terminating the inflammatory response and restoring tissue homeostasis [1].regulated by a superfamily of lipid mediators called specialized pro-resolving mediators (SPMs), that consist of several structurally distinct families biosynthesized from polyunsaturated fatty acids, such as the resolvins (Rv) and lipoxins (LX)(1,2). SPMs exert potent bioactions in both antiinflammation and pro-resolution, namely counterregulating neutrophil recruitment and production of pro-inflammatory mediators, while enchaining clearance of apoptotic neutrophils (i.e. efferocytosis), microbes and debris [1]. Without an effective and timely resolution response, the initial inflammatory insult can lead to chronic inflammation [2], a pathology associated with many widely occurring human diseases, including cardiovascular diseases. Impaired efferocytosis, SPM biosynthesis and imbalance between SPMs and pro-inflammatory mediators have recently emerged as a key feature of non-resolving inflammation in atherosclerosis [3,6]. RvD1 actions potently limit vascular inflammation, regulate vascular homeostasis [9,10] and promote plaque stability in murine models of atherosclerosis [6]. Targeting the RvD1 pathway may represent a potential strategy to stimulate resolution in atherosclerotic inflammation
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