Editorial
Interleukin-17 and Atherosclerotic Vascular Disease
Jordan S. Pober
A therosclerotic vascular disease (ASVD) involves several
overlapping pathological processes. Atherogenesis, the
process by which atherosclerotic plaques develop in the
arterial wall, involves inspissation of abnormal circulating
lipoproteins into the vessel intima, resulting in inflammation,
injury, and responses to injury.1 Mouse models of atherogen-
esis, involving impaired low-density lipoprotein clearance
due to gene knockout of either apolipoprotein E (ApoE) or
low-density lipoprotein receptor, are widely used to study this
process. The presence of plaques in humans sets the stage for
complications, such as plaque rupture or fissure that stimulate
thrombosis; intraplaque hemorrhages that may rapidly cause
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luminal impingement; more gradual but progressive vascular
stenoses due to inadequate outward remodeling that produce
chronic ischemia; inflammatory aneurysms with the potential
for catastrophic events, such as aortic rupture; or plaque
embolization, leading to infarcts in tissues distal to the plaque
site. Each of these complications arises from distinct but
overlapping causes, of which inflammation is a significant
component.2 Mouse models for the study of these complica-
tions have significant limitations.
See accompanying article on page 1565
Inflammation in ASVD is best described as chronic active,
involving acute exacerbations superimposed on a more per-
sistent, indolent process. The initial trigger for inflammation
in the vessel wall may be innate immunity, an inflammatory
process that is activated by myeloid cells or some types of
innate lymphocytes recognizing conserved motifs in microbe-
derived molecules or of endogenous molecules that are
released as a consequence of cell injury. Recognition of these
conserved molecular motifs also enables certain myeloid
(especially myeloid dendritic cells) or innate lymphoid cell
types to effectively present antigens to T cells, triggering the
adaptive immune system. Activated CD4⫹ T cells, a major
effector cell type of adaptive immunity, function by releasing
cytokines that act on myeloid cells, on other lymphocytes,
and on intrinsic tissue cells in an orchestrated response to
eradicate the source of antigen. Chronically activated CD4⫹
T effector cells may differentiate to produce a limited pattern
of cytokines that trigger specific types of responses.3 CD4⫹
T cells that release interferon (IFN)-␥ are designated T helper
(Th)1 cells and serve as the principal mediators of host
defense versus intracellular bacteria. The Th2 CD4⫹ T
From the Department of Immunobiology, Yale University School of
Medicine, New Haven, CT.
Correspondence to Jordan S. Pober, Department of Immunobiology,
Yale University School of Medicine, New Haven, CT 06520-8089.
E-mail jordan.pober@yale.edu
(Arterioscler Thromb Vasc Biol. 2011;31:1465-1466.)
© 2011 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
DOI: 10.1161/ATVBAHA.111.228338
1465
effector cell subset releases interleukin (IL)-4, IL-5, and
IL-13 and mediates host defense versus helminths and other
multicellular parasites. Recently, a third CD4⫹ T effector
cell subset has been proposed, designated Th17 because these
cells release the cytokines IL-17A and IL-17F, as well as
IL-22; Th17 cells mediate host defense versus fungi. Each of
these 3 types of Th subsets can inhibit the other 2 types.
These various Th subsets also may, when inappropriately
activated, lead to disease. Both Th1 and Th17 cells have been
linked to autoimmunity, and Th2 cells are linked to allergy.
CD4⫹ T cells infiltrate atherosclerotic plaques, and certain
aspects of ASVD may be a form of autoimmunity, meaning
that the adaptive immune system perpetuates an inflamma-
tory reaction by responding to self-derived rather than
microbe-derived antigens.4,5 Th1 cells are the major CD4⫹ T
cell subtype found in human atherosclerotic plaques and, in
mouse models of atherogenesis, exacerbate plaque formation
caused by elevated lipoproteins.6 More recently, IL-17-
producing T cells have also been found in human plaques, but
many of these cells can concomitantly produce IFN-␥,
defying their neat characterization as Th17 cells.7 Further-
more, some human CD4⫹ Th cells, especially those that
make IL-17, exhibit plasticity, changing the effector cyto-
kines they release depending on environmental stimuli and
sometimes even converting from effector cells to protective
regulatory T cells.8 Although this raises questions about what
kinds of T cells are present in plaques, and these may vary
with disease activity or complication, the effects of the
cytokines made by T cells (and other cell types) can be
studied directly. What is known about the roles of specific Th
cytokines in ASVD? IFN-␥ is a mitogen for human smooth
muscle cells within the intima or media of the vessel wall,
even though it may inhibit smooth muscle cell proliferation in
cell culture.9 It also can induce medial but not intimal smooth
muscle cells to express very high levels of the tryptophan-
degrading enzyme indoleamine 2,3-dioxygenase, depriving
infiltrating T cells of this crucial nutrient and creating a
compartment of immunoprivilege.10 At the same time, IFN-␥
may combine with other cytokines to potentiate the suscep-
tibility of human vascular cells to killing by effector cells of
the immune system.11,12 In the ApoE⫺/⫺ mouse model of
atherogenesis, genetic deletion of IFN-␥ or its receptor
inhibits plaque formation.13,14 Overall, IFN-␥ is viewed as a
proatherosclerotic cytokine. Much less is known about the
roles of IL-17A or IL-17F in ASVD. IL-17A can collaborate
with IFN-␥ to increase the elaboration of inflammatory
cytokines by human smooth muscle cells.7 It does not appear
to influence cultured smooth muscle cell growth, but it has
not been tested for mitogenic potential in the context of the
vessel wall. Neutralizing IL-17A does not prevent intimal
expansion of human vessel segments in a model of Th1-
mediated transplant rejection, a process that may share some
 1466 Arterioscler Thromb Vasc Biol July 2011
features with atherogenesis.15 However, neutralizing IL-17A
in ApoE⫺/⫺ mice does reduce plaque size,16 –19 although
results in other models of atherogenesis are less clear.19
In the present issue of the journal, Madhur and colleagues20
use a genetic approach to further address this question.
Specifically, they have cross-bred IL-17A knockout mice
with ApoE knockout mice, producing homozygous double-
knockout animals on a CB57Bl/6 background. When fed a
high-fat diet, neither the size nor the extent of plaque
development in double-knockout animals differs from that of
ApoE single-deficient mice on the same diet. The authors also
show that in humans, IL-17A levels do not correlate with
carotid intima-media ratios, a measure that correlates with
coronary artery plaque burden. These findings are consistent
with the conclusion that IL-17A is not important in athero-
genesis, contradicting the antibody neutralization studies.
However, levels of IL-17F increase, potentially compensating
for the absence of IL-17A. Madhur and colleagues do find
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that in double-knockout animals on a high-fat diet, circulating
levels of IFN-␥ are decreased and inflammatory cells within
the plaques of double-knockout animals show reduced num-
bers of myeloid cells (especially dendritic cell) and T cells
accompanied by a reduction of superoxide production and an
increase in NO generation.20 This suggests that IL-17A could
play a role in some inflammatory complications of ASVD,
such as plaque rupture. Interestingly, IL-17A did not affect
aneurysm formation induced by angiotensin II infusion but
did appear necessary for compensatory outward remodeling
of the artery wall following partial carotid ligation. Finally, in
this last model, neutralization of IL-17F did not have any
further effect, pointing to a nonredundant role for IL-17A. So
where does this leave us? As noted above, ASVD is a
complicated amalgam of multiple processes with different
components of the innate and adaptive immune systems
contributing to pathogenesis in various ways and at various
times. IL-17A could well play an important role in some of
these but not others. Madhur and colleagues have taken an
important first step in sorting these out.
Sources of Funding
Dr Pober’s research is supported by grants from the National
Institutes of Health.
Disclosures
None.
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KEY WORDS: atherogenesis 䡲 plaque instability 䡲 adaptive immunity 䡲 T
lymphocytes 䡲 cytokines
 Interleukin-17 and Atherosclerotic Vascular Disease
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Jordan S. Pober

Arterioscler Thromb Vasc Biol. 2011;31:1465-1466

doi: 10.1161/ATVBAHA.111.228338
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