The role of the FPR2/ALX receptor in atherosclerosis development and plaque stability

Abstract

AimsThe formyl peptide receptor (FPR) subtype FPR2/ALX transduces pro-inflammatory responses and participates in the resolution of inflammation depending on activation. The aim of the present study was to unravel the role of FPR2/ALX signalling in atherosclerosis.Methods and resultsExpression of FPR2/ALX was analysed in 127 human carotid atherosclerotic lesions and revealed that this receptor was expressed on macrophages, smooth muscle cells (SMCs), and endothelial cells. Furthermore, FPR2/ALX mRNA levels were significantly up-regulated in atherosclerotic lesions compared with healthy vessels. In multiple regression, age, creatinine, and clinical signs of increased cerebral ischaemia were independent predictors of FPR2/ALX expression. To provide mechanistic insights into these observations, we generated Ldlr−/−xFpr2−/− mice, which exhibited delayed atherosclerosis development and less macrophage infiltration compared with Ldlr−/−xFpr2+/+ mice. These findings were reproduced by transplantation of Fpr2−/− bone marrow into Ldlr−/− mice and further extended by in vitro experiments, demonstrating a lower inflammatory state in Fpr2−/− macrophages. FPR2/ALX expression correlated with chemo- and cytokines in human atherosclerotic lesions and leucocytes. Finally, atherosclerotic lesions in Ldlr−/−xFpr2−/− mice exhibited decreased collagen content, and Fpr2−/− SMCs exhibited a profile of increased collagenase and decreased collagen production pathways.ConclusionFPR2/ALX is proatherogenic due to effects on bone marrow-derived cells, but promoted a more stable plaque phenotype through effects on SMCs. Taken together, these results suggest a dual role of FPR2/ALX signalling in atherosclerosis by way of promoting disease progression and but increasing plaque stability.

Differential regulation of monocytic expression of leukotriene and lipoxin receptors

“…Both the BLT 1 receptor [4] and FPR2/ALX [5] are expressed in several cell types within human atherosclerotic plaques, such as macrophages, vascular smooth muscle cells (SMC), and endothelial cells.…”

“…In addition, knock-out of the mouse homologue of the human FPR2/ALX receptor exacerbates mesentery ischemia-reperfusion, paw edema and arthritis [8]. However, in other murine disease models, such as OVA/alum-induced allergic airway inflammation and atherosclerosis [5], FPR2/ALX deficiency is associated with reduced disease and cytokines levels [5,9]. In contrast, protective effects of BLT 1 receptor deficiency has been replicated in several inflammatory mouse models, such as atherosclerosis, abdominal aortic aneurysms and arthritis [10].…”

The role of lipoxins in cardiometabolic physiology and disease

“…Furthermore, LXs modulate plateletderived growth factor-stimulated migration of vascular SMCs isolated from human saphenous veins [66]. Interestingly, the pluripotent FPR2/ALX receptor may play a dual role in atherosclerosis, promoting disease progression through proatherogenic effects on bone marrow-derived cells, but increasing plaque stability by promoting SMC collagen synthesis and cross-linking [104]. In this context, it is worth highlighting that the characteristic expression of SMC and MΦ surface markers may be altered in the pathophysiological milieu of the atherosclerotic plaque so that MΦs may express SMC markers (e.g.…”

Qiliqiangxin improves oxidized low-density lipoprotein-induced human coronary artery endothelial cells injury

“…It has also been demonstrated that ECs apoptosis induced atherosclerotic lesion development and plaque shedding [3][4][5]. Oxidized Low-Density Lipoprotein (ox-LDL), an important atherosclerotic risk factor, may induce ECs apoptosis during the pathogenesis of AS [6][7][8].…”