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Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

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.

SUBMITTER: Orecchioni M

PROVIDER: S-EPMC9744443 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

Orecchioni Marco M Kobiyama Kouji K Winkels Holger H Ghosheh Yanal Y McArdle Sara S Mikulski Zbigniew Z Kiosses William B WB Fan Zhichao Z Wen Lai L Jung Yunmin Y Roy Payel P Ali Amal J AJ Miyamoto Yukiko Y Mangan Matthew M Makings Jeffrey J Wang Zhihao Z Denn Angela A Vallejo Jenifer J Owens Michaela M Durant Christopher P CP Braumann Simon S Mader Navid N Li Lin L Matsunami Hiroaki H Eckmann Lars L Latz Eicke E Wang Zeneng Z Hazen Stanley L SL Ley Klaus K

Science (New York, N.Y.) 20220113 6577

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 <i>Olfr2</i> and all associated trafficking and signaling molecules. Olfr2 detects the compound octanal, which activates the NLR family pyrin domain containing 3 (NLRP3) inflammasome ...[more]

PMID: 35025664

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Project description:ObjectiveNephrogenic systemic fibrosis (NSF) is a progressive fibrosing disorder that may develop in patients with chronic kidney disease after administration of gadolinium (Gd)-based contrast agents (GBCAs). In the setting of impaired renal clearance of GBCAs, Gd deposits in various tissues and fibrosis subsequently develops. However, the precise mechanism by which fibrosis occurs in NSF is incompletely understood. Because other profibrotic agents, such as silica or asbestos, activate the nucleotide-binding oligomerisation domain (NOD)-like receptor protein 3 (NLRP3) inflammasome and initiate interleukin (IL)-1β release with the subsequent development of fibrosis, we evaluated the effects of GBCAs on inflammasome activation.MethodsBone marrow derived macrophages from C57BL/6, Nlrp3(-/-) and Asc(-/-) mice were incubated with three Gd-containing compounds and IL-1β activation and secretion was detected by ELISA and western blot analysis. Inflammasome activation and regulation was investigated in IL-4- and interferon (IFN)γ-polarised macrophages by ELISA, quantitative real time (qRT)-PCR and NanoString nCounter analysis. Furthermore, C57BL/6 and Nlrp3(-/-)mice were intraperitoneally injected with GBCA and recruitment of inflammatory cells to the peritoneum was analysed by fluorescence-activated cell sorting (FACS).ResultsFree Gd and GBCAs activate the NLRP3 inflammasome and induce IL-1β secretion in vitro. Gd-diethylenetriaminepentaacetic acid also induces the recruitment of neutrophils and inflammatory monocytes to the peritoneum in vivo. Gd activated IL-4-polarised macrophages more effectively than IFNγ-polarised macrophages, which preferentially expressed genes known to downregulate inflammasome activity.ConclusionsThese data suggest that Gd released from GBCAs triggers a NLRP3 inflammasome-dependent inflammatory response that leads to fibrosis in an appropriate clinical setting. The preferential activation of IL-4-differentiated macrophages is consistent with the predominantly fibrotic presentation of NSF.

Dataset Information

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

Publications

Olfactory receptor 2 in vascular macrophages drives atherosclerosis by NLRP3-dependent IL-1 production.

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