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

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Sniffing out atherosclerosis

Olfactory receptors are best known for their presence in the nose and their role in detecting smells, but they are also present in other tissues and perform additional biological functions. For example, vascular macrophages involved in the pathogenesis of atherosclerosis express multiple subtypes of olfactory receptors. Orecchioni et al . focused on olfactory receptor 2, a receptor for the compound octanal, and identified its contribution to atherosclerosis pathogenesis and the formation of atherosclerotic plaques (see the Perspective by Rayner and Rasheed). The authors show that most of the octanal was not directly derived from the diet, but rather was generated as a by-product of lipid peroxidation, suggesting a potential pathway for intervention. —YN

Abstract

Olfactory receptor 2 and its ligand, octanal, play roles in atherosclerosis through their effects on vascular macrophages.

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.

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Most cited references 37

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The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Karen V. Swanson, Meng Deng, Jenny P.-Y. Ting (2019)

NLRP3 (NACHT, LRR and PYD domains-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase-1-dependent release of the proinflammatory cytokines, IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical basis of NLRP3 activation and regulation, and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

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A small-molecule inhibitor of the NLRP3 inflammasome for the treatment of inflammatory diseases.

Rebecca Coll, Avril A B Robertson, Jae Jin Chae … (2015)

The NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome is a component of the inflammatory process, and its aberrant activation is pathogenic in inherited disorders such as cryopyrin-associated periodic syndrome (CAPS) and complex diseases such as multiple sclerosis, type 2 diabetes, Alzheimer's disease and atherosclerosis. We describe the development of MCC950, a potent, selective, small-molecule inhibitor of NLRP3. MCC950 blocked canonical and noncanonical NLRP3 activation at nanomolar concentrations. MCC950 specifically inhibited activation of NLRP3 but not the AIM2, NLRC4 or NLRP1 inflammasomes. MCC950 reduced interleukin-1β (IL-1β) production in vivo and attenuated the severity of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis. Furthermore, MCC950 treatment rescued neonatal lethality in a mouse model of CAPS and was active in ex vivo samples from individuals with Muckle-Wells syndrome. MCC950 is thus a potential therapeutic for NLRP3-associated syndromes, including autoinflammatory and autoimmune diseases, and a tool for further study of the NLRP3 inflammasome in human health and disease.

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Vascular Smooth Muscle Cells in Atherosclerosis.

Martin Bennett, Sanjay Sinha, Gary Owens (2016)

The historical view of vascular smooth muscle cells (VSMCs) in atherosclerosis is that aberrant proliferation of VSMCs promotes plaque formation, but that VSMCs in advanced plaques are entirely beneficial, for example preventing rupture of the fibrous cap. However, this view has been based on ideas that there is a homogenous population of VSMCs within the plaque, that can be identified separate from other plaque cells (particularly macrophages) using standard VSMC and macrophage immunohistochemical markers. More recent genetic lineage tracing studies have shown that VSMC phenotypic switching results in less-differentiated forms that lack VSMC markers including macrophage-like cells, and this switching directly promotes atherosclerosis. In addition, VSMC proliferation may be beneficial throughout atherogenesis, and not just in advanced lesions, whereas VSMC apoptosis, cell senescence, and VSMC-derived macrophage-like cells may promote inflammation. We review the effect of embryological origin on VSMC behavior in atherosclerosis, the role, regulation and consequences of phenotypic switching, the evidence for different origins of VSMCs, and the role of individual processes that VSMCs undergo in atherosclerosis in regard to plaque formation and the structure of advanced lesions. We think there is now compelling evidence that a full understanding of VSMC behavior in atherosclerosis is critical to identify therapeutic targets to both prevent and treat atherosclerosis.

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Author and article information

Contributors

Marco Orecchioni: (View ORCID Profile)

Holger Winkels: (View ORCID Profile)

Yanal Ghosheh: (View ORCID Profile)

Sara McArdle: (View ORCID Profile)

Zbigniew Mikulski: (View ORCID Profile)

William B. Kiosses: (View ORCID Profile)

Zhichao Fan: (View ORCID Profile)

Lai Wen: (View ORCID Profile)

Yunmin Jung: (View ORCID Profile)

Payel Roy: (View ORCID Profile)

Amal J. Ali: (View ORCID Profile)

Yukiko Miyamoto: (View ORCID Profile)

Zhihao Wang: (View ORCID Profile)

Angela Denn: (View ORCID Profile)

Jenifer Vallejo: (View ORCID Profile)

Christopher P. Durant: (View ORCID Profile)

Navid Mader: (View ORCID Profile)

Lin Li: (View ORCID Profile)

Hiroaki Matsunami: (View ORCID Profile)

Lars Eckmann: (View ORCID Profile)

Zeneng Wang: (View ORCID Profile)

Stanley L. Hazen: (View ORCID Profile)

Klaus Ley: (View ORCID Profile)

Journal

Title: Science

Abbreviated Title: Science

Publisher: American Association for the Advancement of Science (AAAS)

ISSN (Print): 0036-8075

ISSN (Electronic): 1095-9203

Publication date Created: January 14 2022

Publication date (Print): January 14 2022

Volume: 375

Issue: 6577

Pages: 214-221

Affiliations

[1 ]La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

[2 ]Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.

[3 ]Department of Internal Medicine III, Division of Cardiology, Heart Center, University Hospital of Cologne, 50937 Cologne, Germany.

[4 ]Histology and Microscopy Core Facility, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.

[5 ]Department of Immunology, School of Medicine, UConn Health, University of Connecticut, Farmington, CT 06030, USA.

[6 ]Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.

[7 ]Institute of Innate Immunity, University Hospital Bonn, 53127 Bonn, Germany.

[8 ]Department of Cardiothoracic Surgery, Heart Center, University Hospital of Cologne, 50937 Cologne, Germany.

[9 ]Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

[10 ]Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27708, USA.

[11 ]Heart and Vascular Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

[12 ]Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.

Article

DOI: 10.1126/science.abg3067

PubMed ID: 35025664

SO-VID: 3bbf7564-a7ad-4af4-b418-4fc50fe68135

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