Olfactory receptor 2 activation in macrophages: novel mediator of atherosclerosis progression

Abstract

In a recent study published in Science, Orecchioni et al. provide insights that olfactory receptor 2 (OLFR2) in vascular macrophages plays a substantial role during atherosclerosis formation, identifying an alternative target for the prevention and treatment of ASCVD. 1 Hypercholesterolemia and high low-density lipoprotein (LDL) levels have been identified as a major risk factor of atherosclerotic cardiovascular disease (ASCVD), the leading cause of death in humans.LDL-lowering therapies effectively reduce ASCVD risk by ~30-50% 2 and are recommended for primary and secondary prevention.However, a considerable number of patients with ASCVD show poor responses to LDL-lowering treatment; therefore, identifying and controlling additional risk factors are key to the reduction of ASCVD morbidity.Olfactory receptors (ORs) belong to a structurally diverse family of proteins capable of detecting a large spectrum of odorants in the environment.In vertebrates, including humans, ORs are typically located on the surface of sensory neurons in the olfactory epithelium.However, ORs also occur in tissues outside the olfactory epithelium.Parmentier et al. first identified OR gene transcripts expressed outside the olfactory epithelium in mammalian germ cells. 3Subsequent studies have shown that ORs are also located in other human tissues, including the lungs, testis, intestines, heart, skin, and blood. 4Although ORs outside the olfactory system are thought to participate in several essential physiological and pathophysiological processes, including pathfinding, cell growth, migration, secretion, differentiation, and apoptosis, 4 understanding of their functions in the cardiovascular system remains poor.Ley and colleagues unexpectedly found a high expression of ORs in mouse macrophages from the atherosclerotic aorta in a transcriptomic study. 5They extended these findings and confirmed that OLFR2 was expressed in macrophages derived from atherosclerotic aorta and bone marrow, with specific biological functions.Octanal, an important OLFR2 ligand, is generated by lipid peroxidation and has been detected in oxidized low-density lipoprotein (oxLDL), which is one of the most important risk factors for atherosclerosis.These results suggest that octanal and OLFR2 are associated with atherosclerosis, encouraging the authors to investigate the function and regulation of OLFR2, and especially its relevance to atherosclerosis.To investigate the downstream function of OLFR2, the authors performed RNA sequencing and pathway analysis and found that the most pronounced pathway altered in response to octanal stimulation was the oxidative stress pathway.This was further

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