Olfactory receptor 2 (Olfr2) and its human ortholog OR6A2 expressed in macrophages drive NLRP3 inflammasome activation and exacerbate atherosclerosis in mice

Abstract 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 in olfactory epithelium and are responsible for the sense of smell. We found that macrophages in the wall of atherosclerotic mouse aortas express some olfactory receptors including Olfr2, a specific receptor for an 8 carbon fatty-aldehyde called octanal. Octanal is detectable in food, mouse and human blood plasma, elevated by western diet, and partially derived from gut microbiota. Ligation of Olfr2 or its human orthologue OR6A2, expressed in human atherosclerotic plaque and in human monocyte-derived macrophages, is strongly pro-inflammatory, activates the NLRP3 inflammasome and, in synergy with LPS, induces secretion of IL-1β. Knockdown of Olfr2/OR6A2 in macrophages significantly reduced inflammatory cytokine secretion. To test the role of Olfr2 in atherosclerosis, we treated Apoe−/− mice with octanal or the Olfr2 antagonist citral. Octanal significantly exacerbated while citral significantly inhibited atherosclerosis. We generated Olfr2−/− mice by Crispr-Cas9. Ldlr−/− mice reconstituted with Olfr2−/− bone marrow developed ~50% smaller lesions on high cholesterol diet than littermate controls reconstituted with Olfr2+/+ bone marrow. Our findings suggest that small molecule inhibitors of Olfrs like OR6A2 are promising targets for drug development to prevent and treat atherosclerosis-based cardiovascular diseases.