1. Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production
- Author
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Marco Orecchioni, Kouji Kobiyama, Holger Winkels, Yanal Ghosheh, Sara McArdle, Zbigniew Mikulski, William B. Kiosses, Zhichao Fan, Lai Wen, Yunmin Jung, Payel Roy, Amal J. Ali, Yukiko Miyamoto, Matthew Mangan, Jeffrey Makings, Zhihao Wang, Angela Denn, Jenifer Vallejo, Michaela Owens, Christopher P. Durant, Simon Braumann, Navid Mader, Lin Li, Hiroaki Matsunami, Lars Eckmann, Eicke Latz, Zeneng Wang, Stanley L. Hazen, and Klaus Ley
- Subjects
Adult ,Aging ,Inflammasomes ,General Science & Technology ,Interleukin-1beta ,NLR Family ,Receptors, Odorant ,Inbred C57BL ,Cardiovascular ,Mice ,Interleukin-1alpha ,NLR Family, Pyrin Domain-Containing 3 Protein ,Receptors ,Animals ,Humans ,2.1 Biological and endogenous factors ,Aetiology ,Aorta ,Aldehydes ,Multidisciplinary ,Macrophages ,Neurosciences ,Middle Aged ,Atherosclerosis ,Pyrin Domain-Containing 3 Protein ,Mice, Inbred C57BL ,Oxidative Stress ,Odorant ,Lipid Peroxidation ,Interleukin-1 ,Signal Transduction - Abstract
Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as macrophages. Olfactory receptors (OLFRs) are G protein–coupled chemoreceptors that have a central role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express the olfactory receptor Olfr2 and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome and induces interleukin-1β secretion in human and mouse macrophages. We found that human and mouse blood plasma contains octanal, a product of lipid peroxidation, at concentrations sufficient to activate Olfr2 and the human ortholog olfactory receptor 6A2 (OR6A2). Boosting octanal levels exacerbated atherosclerosis, whereas genetic targeting of Olfr2 in mice significantly reduced atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy to prevent and treat atherosclerosis.
- Published
- 2022