Olfr2 Regulates oxLDL Signaling and Processing, Driving a Pro-inflammatory Foamy Macrophage Phenotype 2259845

Introduction Atherosclerosis is a lipid-driven, chronic inflammation of arterial wall, characterized by plaque formation within the intima. A central pathogenic event is the accumulation of oxidized LDL (oxLDL), which drives macrophages toward a lipid-laden “foamy” state. Under sustained lipid stress, foam cells transition into a proinflammatory phenotype that fuels lesion progression, a process whose molecular mechanisms remain incompletely understood. Methods Here, we identify Olfr2, a G-protein-coupled receptor previously shown to confer protection when deleted, as a critical regulator of inflammatory switch in macrophages, by in vitro and in vivo assays. Results Loss of Olfr2 in bone marrow-derived macrophages (BMDMs) attenuated oxLDL uptake and foam-cell formation, as evidenced by a markedly reduced BODIPY and DIL-oxLDL lipid signal compared to wild-type (WT) cells. In vivo, pharmacologic blockade of Olfr2 using its antagonist citral for four weeks significantly decreased BODIPY staining in aortic macrophages of high-fat-diet-fed mice. Moreover, inhibition of Olfr2-mediated Ca²+ influx with diltiazem suppressed oxLDL internalization, suggesting that oxLDL engages the Olfr2 receptor to trigger downstream lipid uptake pathways. Mechanistically, Olfr2 deficiency dampened oxidative stress: oxLDL-induced cellular and mitochondrial ROS generation was reduced in Olfr2-/- macrophages compared with WT macrophages. Transcriptomic profiling revealed activation of the LXR pathway and upregulation of cholesterol efflux genes (Abca1, Abcg1), alongside increased expression of anti-inflammatory genes such as Il10 and Il1r2. Similarly, Olfr2-/- macrophages exhibited diminished Nos2 expression and nitric oxide production, indicating reduced proinflammatory signaling. Conclusion These findings reveal Olfr2 as a key regulator linking lipid metabolism, calcium signaling, and macrophage inflammatory response. By modulating this pathway, it may be possible to rebalance macrophage function to restore vascular homeostasis. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)