The 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.

Expression 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.

FPR2/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.