Olfactory Receptors in Vascular Macrophages Drive Atherosclerosis by NLRP3-Dependent IL-1 Production

Atherosclerosis is an inflammatory disease of the arterial wall driven by macrophages and other immune cells. Olfactory receptors (OLFRs) are G-protein coupled receptors expressed primarily in olfactory epithelium and are responsible for the sense of smell. OLFRs expressed in multiple extra-nasal tissues have been implicated in diverse biological processes. Here we show that mouse vascular macrophages express many olfactory receptors including Olfr2 (also known as I7), a receptor for octanal. They also express Rtp1, Rtp2, Adcy3, Gnal and the cyclic nucleotide-gated ion channel subunits Cnga1, 2, 3, 4 and Cngb1, accessory molecules needed for Olfr signaling and trafficking. Ligation of Olfr2 and its human orthologue (OR6A2), expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, activates the NLRP3 inflammasome and, in synergy with LPS, induces secretion of IL-1α and β. Knocking out Olfr2 and Nlrp3 in mouse or knocking down OR6A2 in human macrophages abolishes IL-1β secretion in response to octanal. Mouse and human blood plasma contain micromolar levels of octanal, which are positively correlated with cholesterol and triglyceride levels. Boosting octanal levels exacerbates and knocking out Olfr2 significantly reduces atherosclerosis in the aortic arch and root. Our findings suggest that inhibitors of OR6A2 are promising targets for drug development to prevent and treat atherosclerosis-based cardiovascular diseases.