Olfactory receptor 2 signaling enhances monocyte chemotactic migration in the atherosclerotic aorta 4009

Abstract Description Atherosclerosis is an inflammatory disease of the arterial wall initiated by monocyte recruitment and macrophage (Mφ) function. Human and mouse vascular macrophages, mouse bone marrow-derived macrophages (BMDMs), and monocytes express several olfactory receptors (ORs), including Olfr2 and its human orthologue OR6A2. Ligation of Olfr2 and OR6A2 with their ligand octanal activates the NLRP3 inflammasome pathway while knocking out (KO) Olfr2 in mice reduces atherosclerosis progression in vivo. Octanal, a product of lipid peroxidation, is proposed to derive from endothelial dysfunction (ED), which leads to atherosclerosis initiation. Recently, we identified Olfr2/OR6A2 protein expression in about 20% of monocytes, with expression increasing in disease states in humans and mice. However, the role of Olfr2 in monocytes is unknown. Interestingly, competitive adoptive transfer experiments with labeled WT and Olfr2 KO bone marrow monocytes injected into CD45.1 Apoe KO mice, revealed that WT monocytes were significantly enriched in the aorta compared to Olfr2 KO monocytes and could differentiate into Olfr2+ macrophages. In vitro, BMDMs significantly migrate in response to octanal while Olfr2 KO do not. Overall, these findings reveal Olfr2 as a previously unrecognized chemotactic receptor in monocytes and macrophages, highlighting its potential role in directing immune cell migration within the atherosclerotic aorta and as a potential therapeutic target. Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)