ALX-chemy: adding spice to the inflammatory soup of atherosclerosis.

Nature often presents complexities, for example the formyl peptide receptor (FPR) 2/ALX that curiously can mediate either pro-inflammatory or pro-resolution of inflammation responses depending on the ligand it encounters. Formyl peptides originate from bacteria. The formyl peptide receptor may notonly respond to products derived from pathogenic organisms but also from commensals in the intestinal and other endogenous microbiomes, whose contribution to atherosclerosis has garnered considerable recent interest. The ALX designation derives from the response of this family of receptors to lipoxin A4. This receptor binds other ligands relevant to atherosclerosis, including serum amyloid A (SAA). Given this variety of agonists, the role of FPR2/ALX in atherogenesis has proved confusing. The study by Petri et al. provides a comprehensive re-evaluation of the role of FPR2/ALX in atherosclerosis. In a thorough series of investigations, these authors have established the presence of this receptor in specimens of human atherosclerosis, documenting its expression presence on inflammatory cells and intrinsic vascular wall cells in plaques but not in normal arteries. The messenger RNA encoding FPR2/ALX in the retrieved carotid endarterectomy specimens correlated with symptomatic cerebral ischaemia. Joined with these observations on human plaques, the authors showed delayed atherosclerosis and fewer inflammatory cells in LDL receptor-deficient mice with global lack of FPR2. Bone marrow chimera experiments suggested that bone marrow cellderived FPR2/ALX participated in atherogenesis and inflammation. The compound mutant mice also showed a defect in collagen metabolism that conferred characteristics associated with a propensity to rupture in human plaques. Thus, the duality of FPR2/ALX not only dependson its ligandsbut alsoon thecell types thatbear it. Its expression on inflammatory leucocytes appears to promote atherogenesis but its presence on smooth muscle cells associates with plaques that may prove less likely to rupture. This study derives strength from the combination of observations on human specimens with mechanistic studies conducted in vitro and in mice.