GRAPHIC: KELLIE HOLOSKI/
SCIENCE
SCIENCE science.orgBy Katey J. Rayner1,2and Adil Rasheed1,2I
n the blood vessel wall, atherosclerotic
plaque development (atherogenesis) oc-
curs over several decades and involves
the coordinated dysfunction of multiple
cell types and organ systems. Although
treatments targeting hypercholester-
olemia and hypertension, the major risk
factors of atherosclerosis, are effective at pre-
venting fatal complications such as heart at-
tack and stroke, there remains a
major burden of atherosclerotic
disease. Therefore, a more com-
prehensive understanding of the
cells that drive disease, and how
to therapeutically target them, is
urgently needed. On page 214 of
this issue, Orecchioni et al. ( 1 ) re-
veal an important role for olfac-
tory receptor 2 (OLFR2) in ath-
erosclerotic plaque development,
identifying an additional target
for intervention during the pro-
gression of atherosclerosis.
Olfactory receptors are a
structurally diverse family of
proteins that sense a wide range
of odorants. The human gen-
ome comprises more than 400
olfactory receptors, which are
expressed on the surface of olfac-
tory sensory neurons in the nasal
epithelium ( 2 , 3 ). However, olfac-
tory receptors are also expressed
in sperm, skin, and the intestine,
suggesting that they play a role
outside of the olfactory system.
Previous work identified the ex-
pression of Olfr2 and its down-
stream signaling components
in mouse vascular macrophages
during atherosclerosis ( 4 ).
Orecchioni et al. extend these observations
and demonstrate that octanal, the endogen-
ous ligand of the olfactory receptors, triggers
calcium-dependent induction of the NLRP3
(NACHT, LRR- and PYD domains-containing
protein 3) inflammasome and the production
of proinflammatory interleukin-1b (IL-1b) to
exacerbate atherosclerosis (see the figure).
Macrophages are present and maintainhomeostasis in virtually every tissue, in-
cluding the arterial wall, by promoting host
defense and clearing deposited lipids and
apoptotic cells. However, when these func-
tions become disabled or overwhelmed,
macrophages directly promote atherogen-
esis. The secretion of IL-1b by macrophages
in the atherosclerotic plaque is a key process
during atherosclerosis ( 5 , 6 ), and there has
been increasing clinical interest in blocking
IL-1b in patients using monoclonal anti-bodies ( 7 ). However, there are numerous
issues associated with inactivating IL-1b,
including increased risk of death from op-
portunistic infections. Given that octanal
and OLFR2 act upstream of IL-1b, this could
represent a therapeutic opportunity to block
lipid-driven inflammation in the vascular
wall without disarming host defense.
Octanal is a product of the peroxidation of
fatty acids and occurs primarily as a result of
oxidative stress in local vascular cells in the
arterial wall ( 8 ). Orecchioni et al. posit that
octanal is derived from oxidized low-densitylipoprotein (oxLDL), a modified form of
LDL cholesterol, the so-called “bad” choles-
terol that directly accumulates in the vessel
wall and causes atherosclerosis ( 5 , 6 ). The
authors show that octanal signals through
OLFR2 in macrophages, triggering down-
stream inflammation. Using aortic explants
from mice with apolipoprotein E (Apoe ) de-
letion (which increases production of chol-
esterol and atherogenic accumulation within
macrophages), they showed that octanal
could be produced by the aorta
from oleic acid, a fatty acid
prevalent in our diets. Notably,
in mouse models of atheroscler-
osis and in humans, the circulat-
ing concentrations of octanal (~2
μM) are similar, suggesting that
these mechanisms may translate
to human disease. However, the
precise source of octanal in the
vessel wall is unknown.
Orecchioni et al. demonstrate
that octanal is not sufficient to
induce the activation of IL-1b
by macrophages and that this
induction of IL-1b only occurs
with concomitant Toll-like re-
ceptor 4 (TLR4) agonism. TLR4
senses extracellular inflamma-
tory molecules, leading to the
transcriptional induction of
NLRP3. This requirement for
TLR4 ligation prior to octanal
stimulation is reminiscent of
previous studies demonstrat-
ing the two-hit activation of the
inflammasome—priming and
then activation—which is first
driven by oxLDL engagement
of TLR4 followed by signaling
induced by cholesterol crys-
tals that accumulate below the
endothelial lining of the vessel wall during
atherosclerosis ( 9 ). This raises the possi-
bility that additional TLR priming, such as
by other atherogenic ligands or by patho-
gen-associated molecular patterns (PAMPs),
may act as a priming signal to activate the
inflammasome in vascular macrophages.
Thus, this study provides further evidence of
the interplay of lipids and inflammation that
occurs in macrophages and the role of macro-
phages as major immunometabolic hubs in
atherosclerosis and other cardiometabolic
diseases, including diabetes and obesity ( 10 ).IMMUNOLOGYThe scent of atherosclerosis
Vascular macrophages sense an odorant to induce atherosclerotic plaque formation
(^1) University of Ottawa Heart Institute, Ottawa, ON,
Canada.^2 Department of Biochemistry, Microbiology and
Immunology, Faculty of Medicine, University of Ottawa,
Ottawa, ON, Canada. Email: [email protected]
Pro–
IL-1b
High circulating
LDL cholesterol
Oxidative
stress?
Modi ed
LDL
Other
priming
H signals?
Octanal
OLFR2
I L-1b
Atherosclerosis
progression
TLR4
Vascular
macrophage
Caspase-1 NLRP3
inflammasome
activation
O
Lipid
droplet
Atherogenesis involving octanal
Macrophages in the arterial wall are a hub of atherogenesis. Toll-like receptor 4
(TLR4) activation primes the NLRP3 (NACHT, LRR- and PYD domains-containing
protein 3) inflammasome, which is fully activated by olfactory receptor 2 (OLFR2).
Octanal, the OLFR2 ligand, is produced from oxidized low-density lipoprotein
(oxLDL) cholesterol. This two-hit NLRP3 activation leads to interleukin-1b (IL-1b)
production and exacerbation of atherosclerosis.
14 JANUARY 2022 • VOL 375 ISSUE 6577 145