The Olfr519/OR10A3 signaling Amplifies Macrophage Inflammasome Activation and Drives Atherosclerosis 2260066

Introduction Olfactory receptors (ORs), the largest family of G protein—coupled receptors, are emerging regulators of innate immunity. While specific ORs, such as Olfr2, have been linked to vascular inflammation, the broader role of OR signaling in macrophage-driven atherogenesis remains unclear. Methods Aortic macrophages from atherosclerosis-prone Apoe-/- mice were profiled by bulk RNA-seq to identify expressed ORs. Olfr519, the receptor for 3-phenylpropylpropionate (3-PPP), a potential gut microbiota—derived metabolite, was identified and confirmed by flow cytometry in aortic and bone marrow—derived macrophages. The human ortholog OR10A3 was analyzed in plaque macrophages, monocyte-derived macrophages, and circulating monocytes following stimulation with LPS and 3-PPP. Spatial transcriptomics (COSMX SMI) examined OR10A3 expression relative to markers of inflammatory macrophages. Functional assays assessed calcium flux and cytokine secretion after 3-PPP exposure, and receptor dependence was tested by siRNA knockdown and genetic deletion. In vivo studies included administration of 3-PPP in Apoe-/- mice and bone marrow transplantation in Ldlr-/- recipients. Results Olfr519 was significantly upregulated in aortic macrophages. 3-PPP stimulation induced rapid Ca²+ flux and strong IL-1β/IL-1α secretion, which were abolished by receptor knockdown or deletion. OR10A3 was expressed in human plaque macrophages and monocytes, upregulated by LPS and 3-PPP, and co-localized with IL1B and IL1A transcripts. OR10A3 silencing reduced 3-PPP—induced IL-1β release. In vivo, 3-PPP accelerated atherosclerosis in Apoe-/- mice, whereas Olfr519-deficient bone marrow reduced lesions in Ldlr-/- mice. Conclusion The here-identified macrophage-intrinsic Olfr519/OR10A3/3-PPP axis amplifies inflammasome-dependent cytokine release and promotes atherogenesis, defining a novel GPCR-mediated sensory pathway and a potential therapeutic target for vascular inflammation.