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ACKNOWLEDGMENTS
We thank the many researchers who collected field data
and assembled the databases that are used in this analysis.
Funding:This work was supported by a National Socio-
Environmental Synthesis Center postdoctoral fellowship under
funding from the National Science Foundation award number
DBI-1639145 to E.C.F., the VILLUM Investigator project
“Biodiversity Dynamics in a Changing World”,fundedbyVILLUM
FONDEN grant 16549 to J.-C.S., and an AUFF starting grant
number AUFF-F-2018-7-8 to A.O.Author contributions:The
project was conceptualized by E.C.F. and J.-C.S.; E.C.F. and H.S.R.
conducted data curation; E.C.F., J.-C.S., and A.O. developed
methodology; E.C.F. and A.O. performed formal analysis; E.C.F.
developed visualizations and wrote the original draft; all authors
contributed to review and editing.Competing interests:The
authors declare that they have no competing interests.Data
and materials availability:Data and R scripts to reproduce
analyses and figures are available via Zenodo ( 36 ).
SUPPLEMENTARY MATERIALS
science.org/doi/10.1126/science.abk3510
Materials and Methods
Figs. S1 to S4
Tables S1 to S4
References ( 37 Ð 90 )
MDAR Reproducibility Checklist
8 July 2021; accepted 18 November 2021
10.1126/science.abk3510
ATHEROSCLEROSISOlfactory receptor 2 in vascular macrophages drives
atherosclerosis by NLRP3-dependent IL-1 production
Marco Orecchioni^1 , Kouji Kobiyama1,2, Holger Winkels1,3, Yanal Ghosheh^1 , Sara McArdle^4 ,
Zbigniew Mikulski^4 , William B. Kiosses^4 , Zhichao Fan1,5, Lai Wen^1 , Yunmin Jung^1 , Payel Roy^1 ,
Amal J. Ali^1 , Yukiko Miyamoto^6 , Matthew Mangan^7 , Jeffrey Makings^1 , Zhihao Wang^1 , Angela Denn^4 ,
Jenifer Vallejo^1 , Michaela Owens^1 , Christopher P. Durant^1 , Simon Braumann^3 , Navid Mader^8 , Lin Li^9 ,
Hiroaki Matsunami^10 , Lars Eckmann^6 , Eicke Latz^7 , Zeneng Wang^9 , Stanley L. Hazen9,11, Klaus Ley1,12*Atherosclerosis is an inflammatory disease of the artery walls and involves immune cells such as
macrophages. Olfactory receptors (OLFRs) are G proteinÐcoupled chemoreceptors that have a central
role in detecting odorants and the sense of smell. We found that mouse vascular macrophages express
the olfactory receptorOlfr2and 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-1bsecretion 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 ofOlfr2in mice significantly reduced
atherosclerotic plaques. Our findings suggest that inhibiting OR6A2 may provide a promising strategy
to prevent and treat atherosclerosis.O
lfactory receptors (OLFRs) ( 1 ) constitute
the largest family of G protein–coupled
receptors (GPCRs), with ~1100 genes in
mice and ~400 in humans ( 2 ). Many
OLFRs require the transporters Rtp1
and Rtp2 for surface expression ( 3 ). OLFRs
couple through a specialized Gasubunit [Gaolf,
encoded by G protein subunit alpha L (Gnal)]
( 4 )toadenylatecyclase3(Adcy3)( 5 , 6 ). Some
OLFRs are also expressed in nonolfactory tis-
sues ( 7 – 9 ).
In atherosclerotic mice, plaques contain
several phenotypically distinct macrophage
subsets that behave differently ( 10 , 11 ). In a
transcriptomic study of vascular macrophages
isolated from aortas of atherosclerosis-prone
Apoe−/−mice, we unexpectedly detected ex-
pression ofOlfrs,Gaolf(Gnal),Adcy3,Rtp1,
Rtp2, and the cyclic nucleotide-gated (CNG)
ion channel subunitsCnga1,Cnga2,Cnga3,
Cnga4, andCngb1( 12 ). Here, we focus onOlfr2, which binds medium-chain aliphatic
aldehydes such as octanal with a median ef-
fective concentration (EC 50 )of~10mM( 13 – 15 ).
Octanal is produced by reduction of the car-
boxy group of octanoic acid or through lipid
peroxidation during oxidative stress ( 16 ). We
studied Olfr2 expression, function, regula-
tion, and disease relevance in mice in vitro
and in vivo and its human ortholog, OR6A2, in
human macrophages.
In aortas explanted fromApoe−/−and wild-
type (WT) mice, we measuredOlfr2(fig. S1, A
and B) andRtp1,Rtp2,Adcy3,Gnal,Cnga1,
Cnga2,Cnga3,Cnga4,and Cngb1mRNA ex-
pression by quantitative real-time polymerase
chain reaction (qRT-PCR) (fig. S1A).Olfr2
expression increased inApoe−/−mice after 2
weeks of eating a western diet (WD), which
mimics the fat and calorie content in food
consumed in western countries.Olfr2expres-
sion did not change further at 4, 8, or 12 weeks
(fig. S1B), although the canonical macrophage
marker CD64 (Fcgr1) continued to increase
(fig. S1C). Confocal microscopy and flow cyto-
metry [fluorescence-activated cell sorting
(FACS)] revealed Olfr2 protein expression in
~30% of vascular macrophages (Mφ) (Fig. 1A
andfigs.S2andS3A).Thesedatasuggestthat
only a subset of vascular Mφexpress Olfr2.
Sorted live CD45+F4/80+vascular macro-
phages from the aortas ofApoe−/−mice ex-
pressedOlfr2mRNA (fig. S3B). Other cells,
such as CD45−CD31+endothelial cells (ECs)
and CD45−CD31−cells including possible
transdifferentiated smooth muscle cells (SMCs)
( 17 , 18 ), also expressed someOlfr2mRNA (fig.
S3B). Olfr2GFPmice ( 19 ) showed green fluo-
rescent protein (GFP) expression in vascular
Mφ(Fig.1Bandfig.S3,CtoE).CD45−CD31+214 14 JANUARY 2022•VOL 375 ISSUE 6577 science.orgSCIENCE
(^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.
*Corresponding author. Email: [email protected]
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