ATVB in Focus
Modulation of Atherosclerotic Lesions by Circulating Cells:
The Translational Spectrum
Series Editors: Theo J. van Berkel and Johan Kuiper
Monocyte Fate in Atherosclerosis
Ingo Hilgendorf, Filip K. Swirski, Clinton S. Robbins
Abstract—Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis,
a lipid-driven inflammatory disease. Lipid-laden macrophages, known as foam cells, reside in early lesions and advanced
atheromata. Our understanding of how monocytes accumulate in the growing lesion, differentiate, ingest lipids, and
contribute to disease has advanced substantially over the last several years. These cells’ remarkable phenotypic and
functional complexity is a therapeutic opportunity: in the future, treatment and prevention of cardiovascular disease and
its complications may involve specific targeting of atherogenic monocytes/macrophages and their products. (Arterioscler
Thromb Vasc Biol. 2015;35:272-279. DOI: 10.1161/ATVBAHA.114.303565.)
Key Words: atherosclerosis ◼ cardiovascular disease ◼ inflammation ◼ macrophage ◼ monocyte
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
C
In humans, classical CD14++CD16– monocytes similarly
convert to CD14+CD16++ nonclassical monocytes through a
CD14++CD16+ monocyte intermediate.11
Monocytes are essential to the development and exacerbation of atherosclerosis. As disease worsens, the number of Ly-6Chigh monocytes in the blood rises.12–14 A large
body of evidence shows that in addition to increasing in
number, Ly-6Chigh monocytes preferentially adhere to activated endothelium, infiltrate the vessel wall, and become
lesional macrophages. The role of Ly6Clow monocytes in
atherosclerosis progression is less clear. Although able to
ingest oxidized lipoproteins,15 Ly6Clow monocytes do not
contribute directly to the lesional macrophage pool.10,16,17
Atherosclerosis is aggravated in Nur77-deficient mice—
which lack Ly6Clow monocytes18—in some studies, but not
in others.16,17,19 Interpreting these data is further complicated by the function of Nur77 in other processes, including the regulation of macrophage polarization and TLR
signaling pathways.
In humans, studies suggest that circulating monocyte
levels predict cardiovascular risk. In a large prospective
cohort of 951 patients undergoing elective coronary angiography, increased numbers of intermediate CD14++CD16+
monocytes independently predicted cardiovascular death,
myocardial infarction (MI) and stroke over a period of 2
and a half years.20 In a general population (n=659) with
no known cardiovascular disease, increased numbers of
classical CD14++CD16– monocytes in the blood predicted
cardiovascular events within a mean 15-year follow-up
independently of sex, age, and classical cardiovascular risk
ardiovascular and cerebrovascular diseases are the leading
cause of morbidity and mortality worldwide.1 The main
cause of vascular disease is atherosclerosis or build-up of plaque
in the arteries. Myeloid cells are key cellular protagonists of the
inflammatory response that drives atherogenesis.2,3 Circulating
monocytes adhere to the activated endothelium, infiltrate the
vessel wall, become lesional macrophages, and participate decisively in the development and exacerbation of atherosclerosis.
In this brief review, we discuss the current understanding of
monocyte biology in atherosclerosis.
Please see http://atvb.ahajournals.org/site/misc/
ATVB_in_Focus.xhtml for all articles published
in this series.
Monocytes Are Protagonists of Atherosclerosis
Renewed interest in monocyte biology began with the
subdivision of monocytes into 2 main subsets.4 In mice,
monocytes can be distinguished based on their cell surface
expression of the glycoprotein Ly6C. Ly6Chigh monocytes—
CD14++CD16– and CD14++CD16+ cells in humans—are
short-lived, transport tissue antigens to lymph nodes,5 and
accumulate at sites of inflammation4 where they differentiate to macrophages and dendritic cells. Ly6Clow monocytes—CD14+CD16++ monocytes in humans—are longer
lived, patrol the vasculature, respond early to infection,6
and survey endothelial integrity.7 Sophisticated fate mapping studies recently confirmed a long-held theory that
Ly6Clow monocytes arise from circulating Ly6Chigh cells.8–10
Received on: November 2, 2014; final version accepted on: December 12, 2014.
From the Department of Cardiology and Angiology, Heart Center, University of Freiburg, Freiburg, Germany (I.H.); Center for Systems Biology,
Massachusetts General Hospital, Boston, MA (F.K.S.); and Departments of Laboratory Medicine and Pathobiology and Immunology, Peter Munk Cardiac
Centre, Toronto General Research Institute, University of Toronto, Toronto, ON, Canada (C.S.R.).
Correspondence to Ingo Hilgendorf, MD, Heart Center, University of Freiburg, Department of Cardiology and Angiology I, Hugstetter St 55, 79106
Freiburg, Germany. E-mail [email protected]; or Clinton S. Robbins, PhD, Peter Munk Cardiac Centre, Toronto General
Research Institute, Departments of Laboratory Medicine and Pathobiology and Immunology, University of Toronto, Canada, 101 College Street, University
Health Network, TMDT 3–906, Toronto, ON M5G 1L7, Canada. E-mail [email protected]
© 2014 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at http://atvb.ahajournals.org
272
DOI: 10.1161/ATVBAHA.114.303565
Hilgendorf et al Monocyte Fate in Atherosclerosis 273
Nonstandard Abbreviations and Acronyms
CCL
CCR
CD
HSPC
Msr1
chemokine (C-C motif) ligand
C-C chemokine receptor
cluster of differentiation
hematopoietic stem and progenitor cell
type 1 macrophage scavenger receptor class A
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
factors.21 During acute MI, the number of circulating classical and intermediate monocytes increased acutely over 3
days22,23 and were associated with impaired left ventricular
function and larger infarct size.24 Furthermore, preferential
accumulation of CD14++CD16– cells in the infarct border
zone has been observed in the myocardium of patients that
succumb to acute MI.25 Increased mobilization and recruitment of classical monocytes into the heart may be attributed
to the monocyte chemotactic factor, monocyte chemotactic protein 1, whose levels are increased in acute coronary
syndrome and is associated with increased cardiovascular
mortality.26
Long-term follow-up studies have shown that within the
first week after acute MI, elevated levels of classical and intermediate monocytes are associated with decreased left ventricular function for ≤6 months.22,23,27 Moreover, compared with
cells in patients with stable coronary artery disease, circulating classical monocytes are more adhesive and increase in
number in patients with heart failure.28,29 Assessing nonculprit
coronary plaque size in 90 acute MI patients during the acute
phase and 7-month later found that peak monocyte counts in
the blood independently predicted plaque progression after
ST-elevation MI.30 Intravascular optical coherence tomography of nonculprit lesions in patients with unstable angina
showed that increased fibrous cap thickness—a measure
of plaque stability—inversely correlated with an increased
CD16+ (nonclassical and intermediate) blood monocyte fraction during a 9-month follow up31. In a 5-year follow up of 255
ST-elevation MI patients, the peak blood monocyte count after
infarction also predicted major adverse cardiac and cerebrovascular events, including cardiac death, sudden death, nonfatal MI, unstable angina, and stroke.32
Is there any evidence that targeting monocytes in patients
with cardiovascular disease is therapeutically beneficial?
Anti-platelet treatment reduces monocyte–platelet aggregation, a process thought to promote atherogenesis in patients
with acute coronary syndrome.23,33–36 In addition to lowering
cholesterol levels, life-saving statin therapy attenuates the
production of inflammatory cytokines and coagulant factors
and decreases the expression of cell adhesion molecules by
circulating monocytes in hypercholesterolemic patients.37–39
Angiotensin-converting enzyme inhibitors reduce tissue
factor and serum levels of monocyte chemotactic protein
1 in patients after acute MI,40 decelerating the coagulationinflammation-thrombosis cascade. Furthermore, addition of
the renin inhibitor aliskiren suppresses circulating numbers
of classical monocytes and increases myocardial salvage after
acute MI.41 A direct role for monocytes in the progression of
coronary artery disease was recently observed in a prospective, placebo-controlled phase II clinical trial assessing the
effects of intravenous administration of liposomal alendronat
(LABR-312, Biorest) on percutaneous coronary intervention
and stenting. Monocytes and macrophages are transiently
depleted after the uptake of LABR-312 liposomes as a result
of intracellular accumulation of toxic levels of bisphosphonates and the induction of apoptosis. Strikingly, diabetic
patients and those with elevated monocyte counts responded
to treatment with reduced in-stent restenosis for ≥6 months.42
Collectively, these studies suggest an association between
increased cardiovascular disease risk and elevated levels of
circulating classical and intermediate monocytes. Improved
clinical outcome is associated with treatment regimens that
reduce monocytosis.
Monocyte Production, Mobilization, and
Accumulation in Developing Lesions
Monocytes arise from proliferating and differentiating hematopoietic stem and progenitor cells in the bone marrow.
Hematopoietic stem cells progress through increasingly committed progenitors, the most restricted toward the monocyte
lineage being common monocyte progenitor cells.43 Increased
production of bone marrow monocytes in experimental models of atherogenesis has been reported in hypercholesterolemic swine, rabbits, and rodents.44,45 More recently, it was
shown that hypercholesterolemia also induces monopoiesis in
extramedullary organs, including the spleen.46 During atherosclerosis, medullary and extramedullary monopoiesis are regulated by the growth factors granulocyte macrophage–colony
stimulating factor and interleukin 3.46,47 Cell intrinsic factors
also influence hypercholesterolemia-associated monopoiesis. Proteoglycan-bound apolipoprotein E on the surface of
hematopoietic stem and progenitor cell (HSPC) promotes
cholesterol efflux via the ATP-binding cassette transporters
ATP-binding cassette transporter 1 and ABCG145. Genetic
deficiencies in the reverse cholesterol transport machinery
results in increased plasma membrane lipids and upregulation of the common β chain of the interleukin-3/granulocyte
macrophage–colony stimulating factor receptor.48 Notably,
infusion of high-density lipoprotein and Liver-X Receptor
agonists in this setting restores reverse cholesterol transport
and reduces hypercholesterolemia-induced hematopoietic
stem and progenitor cell proliferative responses.45 In the clinical setting, familial hypercholesterolemia is similarly associated with blood monocytosis.49
Bone marrow HSPC mobilization to peripheral tissues
occurs in many inflammatory contexts.46,50–52 In experimental atherogenesis, extramedullary monopoiesis is driven by
HSPC mobilization.46 Although the mechanisms that regulate HSPC exit from the bone marrow remain incompletely
understood, HSPC mobilization after MI is regulated by
β3-adrenergic receptor signaling and downregulation of the
HSPC homing and retention factor CXCL1253. It was recently
shown that accelerated myelopoiesis associated with chronic
stress is similarly regulated by the sympathetic nervous system.54 Mobilization of monocytes from the bone marrow is
also regulated by chemokine/chemokine receptor interactions.
C-C chemokine receptor (CCR)2 blockade in murine models
of atherogenesis, for example, impairs monocyte exit from the
274 Arterioscler Thromb Vasc Biol February 2015
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
bone marrow and is associated with a dramatically reduced
atherosclerosis burden.55 Consistent with these observations,
MI leads to the production of MCP-3/CCL7 (chemokine (C-C
motif) ligand 7), another ligand of CCR2, by B lymphocytes,
which regulates mobilization of Ly6Chigh monocytes from the
bone marrow into the ischemic myocardium.56
The trafficking of monocytes into atherosclerotic lesions is
dependent on several chemokine/chemokine receptor interactions. Numerous studies have demonstrated the importance of
CCR2/MCP-1, CX3CR1/fractalkine, and CCR5/CCL2/CCL5
interactions in the progression of experimental atherosclerosis.14,55,57 Although CCL2 may predominantly affect monocyte mobilization from the bone marrow, CCL5 and CXCL1
directly attract monocytes to atherosclerotic lesions.58 CCL20
mobilizes as well as recruits Ly6Chigh monocytes to plaques
through interactions with CCR6.59 Additionally, CX3CR1 signaling in monocytes and macrophages supports cell survival.60
Monocytes accumulate in plaques at sites of endothelial dysfunction/activation—areas associated with increased expression
of cell adhesion molecules, including endothelial vascular cell
adhesion molecule-1.61 Platelets and neutrophils also facilitate
monocyte recruitment into plaques (Figure). Platelet binding
of the endothelium precedes the appearance of leukocytes in
plaques62 and induces bidirectional expression of adhesion molecules and the production of monocyte attracting chemokines.63
P-selectin glycoprotein ligand-1/P-selectin interactions mediate
binding of monocytes to endothelial cells as well as platelets.64,65
Degranulation and surface expression of P-selectin increases
on platelet activation, enabling monocyte–platelet aggregation.
Aggregated platelets release chemokines (eg, CCL5, CXCL4)
and cytokines (eg, interleukin1β), whereas monocytes increase
integrin activity and expression of inflammatory mediators (eg,
CCL2, tumor necrosis factor α, tissue factor), further propagating monocyte recruitment to lesions.66 Neutrophils promote
monocyte recruitment into atherosclerotic lesions by producing
cathelicidin, which binds formyl-peptide receptor 2 on Ly6Chigh
monocytes, inducing integrin activation.67,68
Figure. Monocyte action and interaction in atherosclerosis. Ly6Chigh monocyte are recruited to activated endothelium guided by chemokines. Interaction with platelets and neutrophil-derived CRAMP stimulates surface expression of adhesion molecules, thereby facilitating
attachment and extravasation. Ly6Chigh monocytes in the lesion can directly contribute to plaque inflammation, differentiate into proliferating lesional macrophages, exit the plaque, for example, via the lymphatics for antigen presentation in draining lymph nodes or die locally.
In the circulation, Ly6Chigh monocytes convert into Ly6Clow monocytes that patrol the vasculature. When detecting endothelial damage in
a CX3CR1- and TLR7-dependent manner, Ly6Clow monocytes attract neutrophils that induce focal endothelial necrosis for subsequent
disposal of the cellular debris by Ly6Clow monocytes. Dashed arrows depict spatial relationship; solid arrows depict developmental and
functional relationships. ROS indicates reactive oxygen species; and SR, scavenger receptors.
Hilgendorf et al Monocyte Fate in Atherosclerosis 275
Monocyte Fate in Atherosclerosis
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
During the development and exacerbation of atherosclerosis, monocytes infiltrate the vessel wall and become lesional
macrophages. Macrophages ingest oxidized lipoproteins via
scavenger receptors and, as lipid-rich foam cells, contribute to
the physical bulk of developing plaques.2 These insights have
contributed to the perception that macrophage accumulation
results from the continuous recruitment of blood monocytes.
However, it has recently been shown that in some inflammatory contexts,69,70 the accumulation of tissue macrophages
may not depend on monocyte recruitment. The adventitia also
harbors hematopoietic progenitors,71,72 suggesting additional
explanations for how atherosclerosis evolves. Our recently
published data shows that lesional macrophage accumulation
also depends on considerable proliferation of macrophages
locally within the developing plaque.73
Macrophage proliferation in atherosclerotic lesions has
been observed in humans, rabbits, and mice. In vitro studies
have also shown that macrophages can proliferate in response
to oxidized low-density lipoprotein.74,75 It is surprising then
how little is known about the role proliferation plays in plaque
growth. Using parabiosis, a surgical procedure that allows
joining and exchange of circulations between congenic mouse
strains, the relative importance of monocyte influx versus
macrophage proliferation to plaque development was recently
assessed. Local proliferation, it was shown, accounted for
≈90% of macrophage accumulation in established disease.73
In contrast, monocyte recruitment played a much larger role in
lesion development during early atherogenesis.3,76 Therefore,
understanding the complexity of atherosclerosis progression
will necessitate determining the relative contribution of proliferation versus monocyte recruitment to plaque growth during
different stages of disease. The balance between them may be
crucial to plaque development and stability. The data suggest
that as atherosclerosis progresses, lesional macrophage accumulation depends increasingly on local proliferation rather
than monocyte influx. Our study also reconciles some of the
conflicting data in the field. On the one hand, monocyte influx
is absolutely necessary to atherosclerosis: in the absence of
chemokine receptors that facilitate monocyte trafficking, atherosclerosis is diminished.12–14,57,77,78 On the other hand, interference of monocyte development or recruitment has little, if
any, effect on established atherosclerosis in some contexts.79–82
We and others show that the mechanisms orchestrating
the generation and influx of monocytes differ from mechanisms that orchestrate the proliferation of monocyte-derived
macrophages.13,46,73 The 2 major processes by which lesions
grow, therefore, may be independently targeted for therapy.
Furthermore, in early atherosclerosis, lesional proliferation
is mediated by granulocyte macrophage–colony stimulating
factor,76 whereas in established atherosclerosis, macrophage
proliferation occurs independent of granulocyte macrophage–
colony stimulating factor, but is mediated by the type 1
macrophage scavenger receptor class A (Msr1).73 Scavenger
receptors promote the uptake of modified lipoproteins, induce
macrophage apoptosis, clear apoptotic cells and debris, and
activate cellular signal transduction.83 Msr1 is one of the most
important receptors in the uptake of oxidized low-density
lipoprotein84 and is expressed on monocytes and macrophages,
smooth muscle cells, and endothelial cells.85 Its role in atherogenesis is multifaceted. In vivo, Msr1 may contribute to lesion
complexity by facilitating plaque foam cell formation, inducing macrophage apoptosis and promoting inflammatory gene
expression.86–91 Macrophages with targeted deletion of Msr1
uptake oxidized low-density lipoprotein poorly in vitro.92 In
addition, Msr1-mediated internalization of lysophosphatidylcholine, a phospholipid component of oxidized low-density
lipoprotein, induces proliferation in peritoneal macrophages
in vitro.93 Our recently published in vivo data shows that
Msr1 promotes local macrophage proliferation within developing plaques.73 Additional work is required to determine
whether lesional macrophage proliferation is a general feature
of scavenger receptor activity or regulated by Msr1 alone.
Macrophage receptor with collagenous structure is another
class A scavenger receptor with considerable homology to
Msr1, but whose role in atherosclerosis is not known. CD36
is a class B scavenger receptor that has been implicated in
the development of necrotic lesions in advanced atherosclerosis.94 Although CD36 promotes vascular smooth muscle cell
proliferation and induces neointimal hyperplasia,95 its role in
regulating macrophage proliferation is unknown.
In vitro studies establish that macrophages can be classified
into functionally distinct subsets.96 Functional polarization
is also observed in vivo under physiological and pathological conditions.97–100 Macrophages undergo either classical
M1 or alternative M2 activation, although other subsets have
been described.101–104 M1 macrophages express high levels
of inflammatory cytokines, increased production of reactive nitrogen and oxygen intermediates, and promote Th1
responses.96,105 M2 macrophages participate in tissue remodeling, wound healing, and immune regulation106; are highly
phagocytic; express high levels of scavenging molecules,
mannose, and galactose receptors; and produce ornithine and
polyamines through the arginase pathway.97 The functional
profile of macrophages in atherosclerotic disease is poorly
understood,106 but is likely influenced by their responsiveness to the microenvironment. Our unpublished data suggest
that macrophages within atherosclerotic lesions comprise a
spectrum of M1- and M2-like phenotypes. Notably, our data
suggest proliferation within the developing plaque influences macrophage function. Proliferation profoundly alters
the transcriptional profile of lesional macrophages, as well as
increases macrophage expression of inflammatory mediators,
including interleukin-12 and inducible nitric oxide synthase
(NOS2; Robbins and Hilgendorf, unpublished observations).
Therefore, proliferation adds not only to the physical bulk of
the plaque, but may promote inflammation through expansion
and polarization of macrophages toward an inflammatory M1
phenotype.
Is macrophage proliferation a protective response to
increase the number of cells capable of sequestering lipids?
Alternatively, proliferating macrophages may be more inflammatory than nonproliferating macrophages, more susceptible
to apoptosis, and contribute to lesion bulk. Given the importance of macrophage proliferation, is it necessary to re-evaluate the role of monocyte recruitment? Perhaps monocytes
276 Arterioscler Thromb Vasc Biol February 2015
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
contribute to atherogenesis independent of their function as
macrophage intermediates. Jakubzick et al recently demonstrated that during steady state conditions, Ly6Chigh monocytes differentiate minimally as they transport antigens from
peripheral tissues to draining lymph nodes.5 Ly6Clow monocytes patrol the vasculature scavenging debris and maintain
endothelial integrity during inflammation.6,7 We have shown
that during atherosclerosis, undifferentiated monocytes entering developing lesions produce inflammatory cytokines, proteolytic enzymes, and reactive oxygen species.46
For decades, it was believed that tissue macrophages derive
exclusively from bone marrow progenitors and their monocyte
descendants.107 However, recent studies show that in many tissues, resident macrophages originate embryonically from the
primitive yolk sac, independent of hematopoietic stem cells
and circulating monocytes and are maintained in adulthood
by in situ proliferation.70,108–110 The function of tissue-resident macrophages in adult tissue, however, is not yet clear. It
remains to be determined whether yolk sac macrophages colonize the artery wall, and if so, what their contribution might be
to inflammatory responses in atherogenesis.
Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis, a
lipid-driven inflammatory disease. Our understanding of how
monocytes accumulate in the growing lesion, differentiate,
ingest lipids, and contribute to disease has advanced substantially over the last several years. However, important questions
in monocyte/macrophage biology in atherosclerosis remain to
be answered. What contributes more to disease progression,
monocyte influx, or—as our recent work suggests—local
macrophage proliferation? What are the relative numeric and
functional contributions of each process to disease progression? How does the balance between the 2 processes change
with age, diet, comorbidities, therapy? Does one process influence the other? Which of the 2 is the better therapeutic target? These questions are significant to human health because
current preclinical trials are assessing the benefits of blocking
leukocyte recruitment, and indeed, pharmaceutical companies are thinking seriously about bringing these approaches
to humans. According to our observations, caution is required,
and additional and alternative approaches should be explored.
Acknowledgments
We thank Bani Bali for her administrative assistance.
Sources of Funding
This work was supported in part by DFG (German Research
Foundation) grant HI 1573/2-1 (to I. Hilgendorf), the Canadian
Institutes of Health Research grant 311523 (to C.S. Robbins), and
the Peter Munk Chair in Aortic Disease Research (to C.S. Robbins).
Disclosures
None.
References
1.Statistics Canada. Mortality, Summary List of Causes 2008. Released
October 18, 2011.
2. Hansson GK, Libby P. The immune response in atherosclerosis: a doubleedged sword. Nat Rev Immunol. 2006;6:508–519. doi: 10.1038/nri1882.
3. Libby P, Ridker PM, Hansson GK. Progress and challenges in translating
the biology of atherosclerosis. Nature. 2011;473:317–325. doi: 10.1038/
nature10146.
4. Geissmann F, Jung S, Littman DR. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity. 2003;19:71–82.
5.Jakubzick C, Gautier EL, Gibbings SL, et al. Minimal differentiation
of classical monocytes as they survey steady-state tissues and transport
antigen to lymph nodes. Immunity. 2013;39:599–610. doi: 10.1016/j.
immuni.2013.08.007.
6. Auffray C, Fogg D, Garfa M, Elain G, Join-Lambert O, Kayal S, Sarnacki
S, Cumano A, Lauvau G, Geissmann F. Monitoring of blood vessels and
tissues by a population of monocytes with patrolling behavior. Science.
2007;317:666–670. doi: 10.1126/science.1142883.
7. Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, VizcayBarrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F. Nr4a1dependent Ly6C(low) monocytes monitor endothelial cells and orchestrate
their disposal. Cell. 2013;153:362–375. doi: 10.1016/j.cell.2013.03.010.
8. Sunderkötter C, Nikolic T, Dillon MJ, Van Rooijen N, Stehling M, Drevets
DA, Leenen PJ. Subpopulations of mouse blood monocytes differ in maturation stage and inflammatory response. J Immunol. 2004;172:4410–4417.
9. Yona S, Kim KW, Wolf Y, Mildner A, Varol D, Breker M, Strauss-Ayali
D, Viukov S, Guilliams M, Misharin A, Hume DA, Perlman H, Malissen
B, Zelzer E, Jung S. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity. 2013;38:79–
91. doi: 10.1016/j.immuni.2012.12.001.
10. Hilgendorf I, Gerhardt LM, Tan TC, Winter C, Holderried TA, Chousterman
BG, Iwamoto Y, Liao R, Zirlik A, Scherer-Crosbie M, Hedrick CC, Libby
P, Nahrendorf M, Weissleder R, Swirski FK. Ly-6Chigh monocytes
depend on Nr4a1 to balance both inflammatory and reparative phases in
the infarcted myocardium. Circ Res. 2014;114:1611–1622. doi: 10.1161/
CIRCRESAHA.114.303204.
11.Korkosz M, Bukowska-Strakova K, Sadis S, Grodzicki T, Siedlar
M. Monoclonal antibodies against macrophage colony-stimulating
factor diminish the number of circulating intermediate and nonclassical (CD14(++)CD16(+)/CD14(+)CD16(++)) monocytes in rheumatoid arthritis patient. Blood. 2012;119:5329–5330. doi: 10.1182/
blood-2012-02-412551.
12.Swirski FK, Pittet MJ, Kircher MF, Aikawa E, Jaffer FA, Libby P,
Weissleder R. Monocyte accumulation in mouse atherogenesis is progressive and proportional to extent of disease. Proc Natl Acad Sci U S A.
2006;103:10340–10345. doi: 10.1073/pnas.0604260103.
13. Swirski FK, Libby P, Aikawa E, Alcaide P, Luscinskas FW, Weissleder R,
Pittet MJ. Ly-6Chi monocytes dominate hypercholesterolemia-associated
monocytosis and give rise to macrophages in atheromata. J Clin Invest.
2007;117:195–205. doi: 10.1172/JCI29950.
14. Tacke F, Alvarez D, Kaplan TJ, Jakubzick C, Spanbroek R, Llodra J, Garin
A, Liu J, Mack M, van Rooijen N, Lira SA, Habenicht AJ, Randolph GJ.
Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to
accumulate within atherosclerotic plaques. J Clin Invest. 2007;117:185–
194. doi: 10.1172/JCI28549.
15. Wu H, Perrard XD, Wang Q, Perrard JL, Polsani VR, Jones PH, Smith
CW, Ballantyne CM. CD11c expression in adipose tissue and blood and its
role in diet-induced obesity. Arterioscler Thromb Vasc Biol. 2010;30:186–
192. doi: 10.1161/ATVBAHA.109.198044.
16. Hanna RN, Shaked I, Hubbeling HG, Punt JA, Wu R, Herrley E, Zaugg
C, Pei H, Geissmann F, Ley K, Hedrick CC. NR4A1 (Nur77) deletion polarizes macrophages toward an inflammatory phenotype and
increases atherosclerosis. Circ Res. 2012;110:416–427. doi: 10.1161/
CIRCRESAHA.111.253377.
17. Hamers AA, Vos M, Rassam F, Marinković G, Marincovic G, Kurakula
K, van Gorp PJ, de Winther MP, Gijbels MJ, de Waard V, de Vries
CJ. Bone marrow-specific deficiency of nuclear receptor Nur77
enhances atherosclerosis. Circ Res. 2012;110:428–438. doi: 10.1161/
CIRCRESAHA.111.260760.
18. Hanna RN, Carlin LM, Hubbeling HG, Nackiewicz D, Green AM, Punt
JA, Geissmann F, Hedrick CC. The transcription factor NR4A1 (Nur77)
controls bone marrow differentiation and the survival of Ly6C- monocytes. Nat Immunol. 2011;12:778–785. doi: 10.1038/ni.2063.
19.Chao LC, Soto E, Hong C, Ito A, Pei L, Chawla A, Conneely OM,
Tangirala RK, Evans RM, Tontonoz P. Bone marrow NR4A expression
is not a dominant factor in the development of atherosclerosis or macrophage polarization in mice. J Lipid Res. 2013;54:806–815. doi: 10.1194/
jlr.M034157.
20. Rogacev KS, Seiler S, Zawada AM, Reichart B, Herath E, Roth D, Ulrich
C, Fliser D, Heine GH. CD14++CD16+ monocytes and cardiovascular
Hilgendorf et al Monocyte Fate in Atherosclerosis 277
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
outcome in patients with chronic kidney disease. Eur Heart J. 2011;32:84–
92. doi: 10.1093/eurheartj/ehq371.
21.Berg KE, Ljungcrantz I, Andersson L, Bryngelsson C, Hedblad B,
Fredrikson GN, Nilsson J, Björkbacka H. Elevated CD14++CD16- monocytes predict cardiovascular events. Circ Cardiovasc Genet. 2012;5:122–
131. doi: 10.1161/CIRCGENETICS.111.960385.
22. Tsujioka H, Imanishi T, Ikejima H, et al. Impact of heterogeneity of human
peripheral blood monocyte subsets on myocardial salvage in patients with
primary acute myocardial infarction. J Am Coll Cardiol. 2009;54:130–
138. doi: 10.1016/j.jacc.2009.04.021.
23.Tapp LD, Shantsila E, Wrigley BJ, Pamukcu B, Lip GY. The
CD14++CD16+ monocyte subset and monocyte-platelet interactions in
patients with ST-elevation myocardial infarction. J Thromb Haemost.
2012;10:1231–1241. doi: 10.1111/j.1538-7836.2011.04603.x.
24. van der Laan AM, Hirsch A, Robbers LF, Nijveldt R, Lommerse I, Delewi
R, van der Vleuten PA, Biemond BJ, Zwaginga JJ, van der Giessen WJ,
Zijlstra F, van Rossum AC, Voermans C, van der Schoot CE, Piek JJ. A
proinflammatory monocyte response is associated with myocardial injury
and impaired functional outcome in patients with ST-segment elevation
myocardial infarction: monocytes and myocardial infarction. Am Heart J.
2012;163:57–65.e2. doi: 10.1016/j.ahj.2011.09.002.
25. van der Laan AM, Ter Horst EN, Delewi R, Begieneman MP, Krijnen PA,
Hirsch A, Lavaei M, Nahrendorf M, Horrevoets AJ, Niessen HW, Piek JJ.
Monocyte subset accumulation in the human heart following acute myocardial infarction and the role of the spleen as monocyte reservoir. Eur
Heart J. 2014;35:376–385. doi: 10.1093/eurheartj/eht331.
26. de Lemos JA, Morrow DA, Blazing MA, Jarolim P, Wiviott SD, Sabatine
MS, Califf RM, Braunwald E. Serial measurement of monocyte chemoattractant protein-1 after acute coronary syndromes: results from the
A to Z trial. J Am Coll Cardiol. 2007;50:2117–2124. doi: 10.1016/j.
jacc.2007.06.057.
27. Montange D, Davani S, Deschaseaux F, Séronde MF, Chopard R, Schiele
F, Jehl J, Bassand JP, Kantelip JP, Meneveau N. The number of circulating CD14(+) cells is related to infarct size and postinfarct volumes in ST
segment elevation myocardial infarction but not non-ST segment elevation
myocardial infarction. Exp Clin Cardiol. 2012;17:131–135.
28.Wrigley BJ, Shantsila E, Tapp LD, Lip GY. CD14++CD16+ mono
cytes in patients with acute ischaemic heart failure. Eur J Clin Invest.
2013;43:121–130. doi: 10.1111/eci.12023.
29. Wrigley BJ, Shantsila E, Tapp LD, Lip GY. Increased expression of cell
adhesion molecule receptors on monocyte subsets in ischaemic heart failure. Thromb Haemost. 2013;110:92–100. doi: 10.1160/TH13-02-0088.
30. Nozawa N, Hibi K, Endo M, Sugano T, Ebina T, Kosuge M, Tsukahara K,
Okuda J, Umemura S, Kimura K. Association between circulating monocytes and coronary plaque progression in patients with acute myocardial
infarction. Circ J. 2010;74:1384–1391.
31.Imanishi T, Ikejima H, Tsujioka H, Kuroi A, Ishibashi K, Komukai K,
Tanimoto T, Ino Y, Takeshita T, Akasaka T. Association of monocyte subset counts with coronary fibrous cap thickness in patients with unstable
angina pectoris. Atherosclerosis. 2010;212:628–635. doi: 10.1016/j.
atherosclerosis.2010.06.025.
32. Takano NK, Hibi K, Konishi M, et al. Monocytosis after myocardial infarction accelerates atherosclerosis: results of a five-year follow-up study. J
Am Coll Cardiol. 2013;61(10_S). doi: 10.1016/S0735-1097(13)60199-0.
33.Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I. Increased
platelet binding to circulating monocytes in acute coronary syndromes.
Circulation. 2002;105:2166–2171.
34. Zeng S, Zhou X, Ge L, Ji WJ, Shi R, Lu RY, Sun HY, Guo ZZ, Zhao JH,
Jiang TM, Li YM. Monocyte subsets and monocyte-platelet aggregates in
patients with unstable angina. J Thromb Thrombolysis. 2014;38:439–446.
doi: 10.1007/s11239-014-1083-4.
35.Harding SA, Sarma J, Din JN, Maciocia PM, Newby DE, Fox KA.
Clopidogrel reduces platelet-leucocyte aggregation, monocyte activation
and RANTES secretion in type 2 diabetes mellitus. Heart. 2006;92:1335–
1337. doi: 10.1136/hrt.2005.083006.
36.Braun OO, Johnell M, Varenhorst C, James S, Brandt JT, Jakubowski
JA, Winters KJ, Wallentin L, Erlinge D, Siegbahn A. Greater reduction
of platelet activation markers and platelet-monocyte aggregates by prasugrel compared to clopidogrel in stable coronary artery disease. Thromb
Haemost. 2008;100:626–633.
37. Ferro D, Parrotto S, Basili S, Alessandri C, Violi F. Simvastatin inhibits
the monocyte expression of proinflammatory cytokines in patients with
hypercholesterolemia. J Am Coll Cardiol. 2000;36:427–431.
38. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid
lowering–are they clinically relevant? Eur Heart J. 2003;24:225–248.
39.Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrom
botic drugs. Circulation. 2013;127:251–257. doi: 10.1161/
CIRCULATIONAHA.112.145334.
40.Soejima H, Ogawa H, Yasue H, Kaikita K, Takazoe K, Nishiyama K,
Misumi K, Miyamoto S, Yoshimura M, Kugiyama K, Nakamura S, Tsuji
I. Angiotensin-converting enzyme inhibition reduces monocyte chemoattractant protein-1 and tissue factor levels in patients with myocardial
infarction. J Am Coll Cardiol. 1999;34:983–988.
41. Ozaki Y, Imanishi T, Tanimoto T, Kashiwagi M, Tsujioka H, Sougawa H,
Orii M, Shiono Y, Shimamura K, Ishibashi K, Komukai K, Ino Y, Kitabata
H, Akasaka T. Effect of direct renin inhibitor, aliskiren, on peripheral
blood monocyte subsets and myocardial salvage in patients with primary
acute myocardial infarction. Circ J. 2012;76:1461–1468.
42.Banai S, Finkelstein A, Almagor Y, Assali A, Hasin Y, Rosenschein U,
Apruzzese P, Lansky AJ, Kume T, Edelman ER. Targeted anti-inflammatory systemic therapy for restenosis: the Biorest Liposomal Alendronate
with Stenting sTudy (BLAST)-a double blind, randomized clinical trial.
Am Heart J. 2013;165:234–40.e1. doi: 10.1016/j.ahj.2012.10.023.
43. Hettinger J, Richards DM, Hansson J, Barra MM, Joschko AC, Krijgsveld
J, Feuerer M. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol. 2013;14:821–830. doi: 10.1038/ni.2638.
44.Averill LE, Meagher RC, Gerrity RG. Enhanced monocyte progenitor
cell proliferation in bone marrow of hyperlipemic swine. Am J Pathol.
1989;135:369–377.
45.Murphy AJ, Akhtari M, Tolani S, Pagler T, Bijl N, Kuo CL, Wang M,
Sanson M, Abramowicz S, Welch C, Bochem AE, Kuivenhoven JA, YvanCharvet L, Tall AR. ApoE regulates hematopoietic stem cell proliferation,
monocytosis, and monocyte accumulation in atherosclerotic lesions in
mice. J Clin Invest. 2011;121:4138–4149. doi: 10.1172/JCI57559.
46.Robbins CS, Chudnovskiy A, Rauch PJ, et al. Extramedullary hematopoiesis generates Ly-6C(high) monocytes that infiltrate atherosclerotic lesions. Circulation. 2012;125:364–374. doi: 10.1161/
CIRCULATIONAHA.111.061986.
47. Wang M, Subramanian M, Abramowicz S, Murphy AJ, Gonen A, Witztum
J, Welch C, Tabas I, Westerterp M, Tall AR. Interleukin-3/granulocyte macrophage colony-stimulating factor receptor promotes stem cell expansion,
monocytosis, and atheroma macrophage burden in mice with hematopoietic ApoE deficiency. Arterioscler Thromb Vasc Biol. 2014;34:976–984.
doi: 10.1161/ATVBAHA.113.303097.
48. Yvan-Charvet L, Pagler T, Gautier EL, Avagyan S, Siry RL, Han S, Welch
CL, Wang N, Randolph GJ, Snoeck HW, Tall AR. ATP-binding cassette
transporters and HDL suppress hematopoietic stem cell proliferation.
Science. 2010;328:1689–1693. doi: 10.1126/science.1189731.
49.Tolani S, Pagler TA, Murphy AJ, Bochem AE, Abramowicz S, Welch
C, Nagareddy PR, Holleran S, Hovingh GK, Kuivenhoven JA, Tall
AR. Hypercholesterolemia and reduced HDL-C promote hematopoietic stem cell proliferation and monocytosis: studies in mice
and FH children. Atherosclerosis. 2013;229:79–85. doi: 10.1016/j.
atherosclerosis.2013.03.031.
50. Massberg S, Schaerli P, Knezevic-Maramica I, Köllnberger M, Tubo N,
Moseman EA, Huff IV, Junt T, Wagers AJ, Mazo IB, von Andrian UH.
Immunosurveillance by hematopoietic progenitor cells trafficking through
blood, lymph, and peripheral tissues. Cell. 2007;131:994–1008. doi:
10.1016/j.cell.2007.09.047.
51. Leuschner F, Rauch PJ, Ueno T, et al. Rapid monocyte kinetics in acute
myocardial infarction are sustained by extramedullary monocytopoiesis. J
Exp Med. 2012;209:123–137. doi: 10.1084/jem.20111009.
52.Cortez-Retamozo V, Etzrodt M, Newton A, et al. Origins of tumor
associated macrophages and neutrophils. Proc Natl Acad Sci U S A.
2012;109:2491–2496. doi: 10.1073/pnas.1113744109.
53. Dutta P, Courties G, Wei Y, et al. Myocardial infarction accelerates atherosclerosis. Nature. 2012;487:325–329. doi: 10.1038/nature11260.
54. Heidt T, Sager HB, Courties G, et al. Chronic variable stress activates hematopoietic stem cells. Nat Med. 2014;20:754–758. doi: 10.1038/nm.3589.
55. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion formation in
CCR2-/- mice reveals a role for chemokines in the initiation of atherosclerosis. Nature. 1998;394:894–897. doi: 10.1038/29788.
56. Zouggari Y, Ait-Oufella H, Bonnin P, et al. B lymphocytes trigger monocyte mobilization and impair heart function after acute myocardial infarction. Nat Med. 2013;19:1273–1280. doi: 10.1038/nm.3284.
57.Combadière C, Potteaux S, Rodero M, Simon T, Pezard A, Esposito
B, Merval R, Proudfoot A, Tedgui A, Mallat Z. Combined inhibition of CCL2, CX3CR1, and CCR5 abrogates Ly6C(hi) and Ly6C(lo)
278 Arterioscler Thromb Vasc Biol February 2015
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
monocytosis and almost abolishes atherosclerosis in hypercholesterolemic mice. Circulation. 2008;117:1649–1657. doi: 10.1161/
CIRCULATIONAHA.107.745091.
58. Soehnlein O, Drechsler M, Döring Y, et al. Distinct functions of chemokine receptor axes in the atherogenic mobilization and recruitment of
classical monocytes. EMBO Mol Med. 2013;5:471–481. doi: 10.1002/
emmm.201201717.
59. Manthey HD, Cochain C, Barnsteiner S, Karshovska E, Pelisek J, Koch M,
Chaudhari SM, Busch M, Eckstein HH, Weber C, Koenen RR, Zernecke
A. CCR6 selectively promotes monocyte mediated inflammation and atherogenesis in mice. Thromb Haemost. 2013;110:1267–1277. doi: 10.1160/
TH13-01-0017.
60.Landsman L, Bar-On L, Zernecke A, Kim KW, Krauthgamer R,
Shagdarsuren E, Lira SA, Weissman IL, Weber C, Jung S. CX3CR1 is
required for monocyte homeostasis and atherogenesis by promoting cell
survival. Blood. 2009;113:963–972. doi: 10.1182/blood-2008-07-170787.
61.Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a mono
nuclear leukocyte adhesion molecule during atherogenesis. Science.
1991;251:788–791.
62. Massberg S, Brand K, Grüner S, Page S, Müller E, Müller I, Bergmeier W,
Richter T, Lorenz M, Konrad I, Nieswandt B, Gawaz M. A critical role of
platelet adhesion in the initiation of atherosclerotic lesion formation. J Exp
Med. 2002;196:887–896.
63. van Gils JM, Zwaginga JJ, Hordijk PL. Molecular and functional interactions among monocytes, platelets, and endothelial cells and their relevance for cardiovascular diseases. J Leukoc Biol. 2009;85:195–204. doi:
10.1189/jlb.0708400.
64. An G, Wang H, Tang R, Yago T, McDaniel JM, McGee S, Huo Y, Xia L.
P-selectin glycoprotein ligand-1 is highly expressed on Ly-6Chi monocytes and a major determinant for Ly-6Chi monocyte recruitment to
sites of atherosclerosis in mice. Circulation. 2008;117:3227–3237. doi:
10.1161/CIRCULATIONAHA.108.771048.
65. Duerschmied D, Bode C, Ahrens I. Immune functions of platelets. Thromb
Haemost. 2014;112:678–691. doi: 10.1160/TH14-02-0146.
66.von Hundelshausen P, Weber C. Platelets as immune cells: bridging
inflammation and cardiovascular disease. Circ Res. 2007;100:27–40. doi:
10.1161/01.RES.0000252802.25497.b7.
67. Döring Y, Drechsler M, Wantha S, Kemmerich K, Lievens D, Vijayan S,
Gallo RL, Weber C, Soehnlein O. Lack of neutrophil-derived CRAMP
reduces atherosclerosis in mice. Circ Res. 2012;110:1052–1056. doi:
10.1161/CIRCRESAHA.112.265868.
68. Wantha S, Alard JE, Megens RT, van der Does AM, Döring Y, Drechsler
M, Pham CT, Wang MW, Wang JM, Gallo RL, von Hundelshausen P,
Lindbom L, Hackeng T, Weber C, Soehnlein O. Neutrophil-derived
cathelicidin promotes adhesion of classical monocytes. Circ Res.
2013;112:792–801. doi: 10.1161/CIRCRESAHA.112.300666.
69. Jenkins SJ, Ruckerl D, Cook PC, Jones LH, Finkelman FD, van Rooijen
N, MacDonald AS, Allen JE. Local macrophage proliferation, rather than
recruitment from the blood, is a signature of TH2 inflammation. Science.
2011;332:1284–1288. doi: 10.1126/science.1204351.
70.Schulz C, Gomez Perdiguero E, Chorro L, Szabo-Rogers H, Cagnard
N, Kierdorf K, Prinz M, Wu B, Jacobsen SE, Pollard JW, Frampton J,
Liu KJ, Geissmann F. A lineage of myeloid cells independent of Myb
and hematopoietic stem cells. Science. 2012;336:86–90. doi: 10.1126/
science.1219179.
71.Psaltis PJ, Harbuzariu A, Delacroix S, Witt TA, Holroyd EW, Spoon
DB, Hoffman SJ, Pan S, Kleppe LS, Mueske CS, Gulati R, Sandhu GS,
Simari RD. Identification of a monocyte-predisposed hierarchy of hematopoietic progenitor cells in the adventitia of postnatal murine aorta.
Circulation. 2012;125:592–603. doi: 10.1161/CIRCULATIONAHA.
111.059360.
72.Psaltis PJ, Puranik AS, Spoon DB, Chue CD, Hoffman SJ, Witt TA,
Delacroix S, Kleppe LS, Mueske CS, Pan S, Gulati R, Simari RD.
Characterization of a resident population of adventitial macrophage progenitor cells in postnatal vasculature. Circ Res. 2014;115:364–375. doi:
10.1161/CIRCRESAHA.115.303299.
73.Robbins CS, Hilgendorf I, Weber GF, et al. Local proliferation dominates lesional macrophage accumulation in atherosclerosis. Nat Med.
2013;19:1166–1172. doi: 10.1038/nm.3258.
74. Hamilton JA, Myers D, Jessup W, Cochrane F, Byrne R, Whitty G, Moss
S. Oxidized LDL can induce macrophage survival, DNA synthesis, and
enhanced proliferative response to CSF-1 and GM-CSF. Arterioscler
Thromb Vasc Biol. 1999;19:98–105.
75.
Martens JS, Reiner NE, Herrera-Velit P, Steinbrecher UP.
Phosphatidylinositol 3-kinase is involved in the induction of
macrophage growth by oxidized low density lipoprotein. J Biol Chem.
1998;273:4915–4920.
76.Zhu SN, Chen M, Jongstra-Bilen J, Cybulsky MI. GM-CSF regulates
intimal cell proliferation in nascent atherosclerotic lesions. J Exp Med.
2009;206:2141–2149. doi: 10.1084/jem.20090866.
77.Saederup N, Chan L, Lira SA, Charo IF. Fractalkine deficiency markedly reduces macrophage accumulation and atherosclerotic lesion
formation in CCR2-/- mice: evidence for independent chemokine functions in atherogenesis. Circulation. 2008;117:1642–1648. doi: 10.1161/
CIRCULATIONAHA.107.743872.
78.Ye D, Zhao Y, Hildebrand RB, Singaraja RR, Hayden MR, Van Berkel
TJ, Van Eck M. The dynamics of macrophage infiltration into the arterial
wall during atherosclerotic lesion development in low-density lipoprotein
receptor knockout mice. Am J Pathol. 2011;178:413–422. doi: 10.1016/j.
ajpath.2010.11.007.
79. Aiello RJ, Perry BD, Bourassa PA, Robertson A, Weng W, Knight DR,
Smith AH, Frederick KS, Kalgutkar A, Gladue RP. CCR2 receptor blockade alters blood monocyte subpopulations but does not affect atherosclerotic lesions in apoE(-/-) mice. Atherosclerosis. 2010;208:370–375. doi:
10.1016/j.atherosclerosis.2009.08.017.
80. Calin MV, Manduteanu I, Dragomir E, Dragan E, Nicolae M, Gan AM,
Simionescu M. Effect of depletion of monocytes/macrophages on early
aortic valve lesion in experimental hyperlipidemia. Cell Tissue Res.
2009;336:237–248. doi: 10.1007/s00441-009-0765-2.
81. Guo J, de Waard V, Van Eck M, Hildebrand RB, van Wanrooij EJ, Kuiper
J, Maeda N, Benson GM, Groot PH, Van Berkel TJ. Repopulation of
apolipoprotein E knockout mice with CCR2-deficient bone marrow progenitor cells does not inhibit ongoing atherosclerotic lesion development.
Arterioscler Thromb Vasc Biol. 2005;25:1014–1019. doi: 10.1161/01.
ATV.0000163181.40896.42.
82.Stoneman V, Braganza D, Figg N, Mercer J, Lang R, Goddard M,
Bennett M. Monocyte/macrophage suppression in CD11b diphtheria
toxin receptor transgenic mice differentially affects atherogenesis and
established plaques. Circ Res. 2007;100:884–893. doi: 10.1161/01.
RES.0000260802.75766.00.
83. Moore KJ, Freeman MW. Scavenger receptors in atherosclerosis: beyond
lipid uptake. Arterioscler Thromb Vasc Biol. 2006;26:1702–1711. doi:
10.1161/01.ATV.0000229218.97976.43.
84.Hazen SL. Oxidized phospholipids as endogenous pattern recognition
ligands in innate immunity. J Biol Chem. 2008;283:15527–15531. doi:
10.1074/jbc.R700054200.
85. Kodama T, Freeman M, Rohrer L, Zabrecky J, Matsudaira P, Krieger M.
Type I macrophage scavenger receptor contains alpha-helical and collagen-like coiled coils. Nature. 1990;343:531–535. doi: 10.1038/343531a0.
86. Moore KJ, Kunjathoor VV, Koehn SL, Manning JJ, Tseng AA, Silver JM,
McKee M, Freeman MW. Loss of receptor-mediated lipid uptake via scavenger
receptor A or CD36 pathways does not ameliorate atherosclerosis in hyperlipidemic mice. J Clin Invest. 2005;115:2192–2201. doi: 10.1172/JCI24061.
87. Sakaguchi H, Takeya M, Suzuki H, Hakamata H, Kodama T, Horiuchi S,
Gordon S, van der Laan LJ, Kraal G, Ishibashi S, Kitamura N, Takahashi
K. Role of macrophage scavenger receptors in diet-induced atherosclerosis in mice. Lab Invest. 1998;78:423–434.
88. de Winther MP, Gijbels MJ, van Dijk KW, van Gorp PJ, suzuki H, Kodama
T, Frants RR, Havekes LM, Hofker MH. Scavenger receptor deficiency
leads to more complex atherosclerotic lesions in APOE3Leiden transgenic
mice. Atherosclerosis. 1999;144:315–321.
89.Herijgers N, de Winther MP, Van Eck M, Havekes LM, Hofker MH,
Hoogerbrugge PM, Van Berkel TJ. Effect of human scavenger receptor class A overexpression in bone marrow-derived cells on lipoprotein
metabolism and atherosclerosis in low density lipoprotein receptor knockout mice. J Lipid Res. 2000;41:1402–1409.
90.Van Eck M, De Winther MP, Herijgers N, Havekes LM, Hofker MH,
Groot PH, Van Berkel TJ. Effect of human scavenger receptor class A
overexpression in bone marrow-derived cells on cholesterol levels and
atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol.
2000;20:2600–2606.
91.Whitman SC, Rateri DL, Szilvassy SJ, Cornicelli JA, Daugherty A.
Macrophage-specific expression of class A scavenger receptors in LDL
receptor(-/-) mice decreases atherosclerosis and changes spleen morphology. J Lipid Res. 2002;43:1201–1208.
92. Kunjathoor VV, Febbraio M, Podrez EA, Moore KJ, Andersson L, Koehn
S, Rhee JS, Silverstein R, Hoff HF, Freeman MW. Scavenger receptors class
A-I/II and CD36 are the principal receptors responsible for the uptake of
modified low density lipoprotein leading to lipid loading in macrophages. J
Biol Chem. 2002;277:49982–49988. doi: 10.1074/jbc.M209649200.
Hilgendorf et al Monocyte Fate in Atherosclerosis 279
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
93. Sakai M, Miyazaki A, Hakamata H, Kodama T, Suzuki H, Kobori S,
Shichiri M, Horiuchi S. The scavenger receptor serves as a route for
internalization of lysophosphatidylcholine in oxidized low density lipoprotein-induced macrophage proliferation. J Biol Chem.
1996;271:27346–27352.
94. Manning-Tobin JJ, Moore KJ, Seimon TA, Bell SA, Sharuk M, AlvarezLeite JI, de Winther MP, Tabas I, Freeman MW. Loss of SR-A and CD36
activity reduces atherosclerotic lesion complexity without abrogating
foam cell formation in hyperlipidemic mice. Arterioscler Thromb Vasc
Biol. 2009;29:19–26. doi: 10.1161/ATVBAHA.108.176644.
95. Li W, Klenotic, PA, Silverstein, R. Thrombospondin 1/CD36 signaling
promotes vascular smooth muscle cell proliferation and contributes to
neointimal hyperplasia. Circulation. 2012;126:A16993.
96. Mosser DM, Edwards JP. Exploring the full spectrum of macrophage
activation. Nat Rev Immunol. 2008;8:958–969. doi: 10.1038/nri2448.
97. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo
veritas. J Clin Invest. 2012;122:787–795. doi: 10.1172/JCI59643.
98. Mills CD. Macrophage arginine metabolism to ornithine/urea or
nitric oxide/citrulline: a life or death issue. Crit Rev Immunol.
2001;21:399–425.
99. Mills CD. M1 and M2 macrophages: oracles of health and disease. Crit
Rev Immunol. 2012;32:463–488.
100. Mills CD, Ley K. M1 and M2 macrophages: the chicken and the egg of
immunity. J Innate Immun. 2014;6:716–726. doi: 10.1159/000364945.
101. Biswas SK, Mantovani A. Macrophage plasticity and interaction with
lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010;11:889–
896. doi: 10.1038/ni.1937.
102. Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR,
Elliott MR, Gruber F, Han J, Chen W, Kensler T, Ravichandran KS,
Isakson BE, Wamhoff BR, Leitinger N. Identification of a novel
macrophage phenotype that develops in response to atherogenic
103.
104.
105.
106.
107.
108.
109.
110.
phospholipids via Nrf2. Circ Res. 2010;107:737–746. doi: 10.1161/
CIRCRESAHA.109.215715.
Ley K, Miller YI, Hedrick CC. Monocyte and macrophage dynamics
during atherogenesis. Arterioscler Thromb Vasc Biol. 2011;31:1506–
1516. doi: 10.1161/ATVBAHA.110.221127.
Martinez FO, Sica A, Mantovani A, Locati M. Macrophage activation
and polarization. Front Biosci. 2008;13:453–461.
Martinez FO, Gordon S, Locati M, Mantovani A. Transcriptional profiling of the human monocyte-to-macrophage differentiation and polarization: new molecules and patterns of gene expression. J Immunol.
2006;177:7303–7311.
Mantovani A, Garlanda C, Locati M. Macrophage diversity and polarization in atherosclerosis: a question of balance. Arterioscler Thromb
Vasc Biol. 2009;29:1419–1423. doi: 10.1161/ATVBAHA.108.180497.
van Furth R, Cohn ZA. The origin and kinetics of mononuclear phagocytes. J Exp Med. 1968;128:415–435.
Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S, Mehler
MF, Conway SJ, Ng LG, Stanley ER, Samokhvalov IM, Merad M. Fate
mapping analysis reveals that adult microglia derive from primitive macrophages. Science. 2010;330:841–845. doi: 10.1126/science.1194637.
Hashimoto D, Chow A, Noizat C, et al. Tissue-resident macrophages
self-maintain locally throughout adult life with minimal contribution from circulating monocytes. Immunity. 2013;38:792–804. doi:
10.1016/j.immuni.2013.04.004.
Hoeffel G, Wang Y, Greter M, et al. Adult Langerhans cells derive predominantly from embryonic fetal liver monocytes with a minor contribution of yolk sac-derived macrophages. J Exp Med. 2012;209:1167–1181.
doi: 10.1084/jem.20120340.
Significance
Monocytes and their descendant macrophages are essential to the development and exacerbation of atherosclerosis, a lipid-driven inflammatory disease. As disease worsens, the number of blood monocytes rises and leukocytosis predicts for cardiovascular events in humans.
Lipid-laden macrophages, known as foam cells, reside in early lesions and advanced atheromata. Our understanding of how monocytes
accumulate in the growing lesion, differentiate, ingest lipids, and contribute to disease has advanced substantially over the last several
years. These cells’ remarkable phenotypic and functional complexity is a therapeutic opportunity: in the future; treatment and prevention
of cardiovascular disease and its complications may involve specific targeting of atherogenic monocytes/macrophages and their products.
Downloaded from http://atvb.ahajournals.org/ by guest on June 15, 2017
Monocyte Fate in Atherosclerosis
Ingo Hilgendorf, Filip K. Swirski and Clinton S. Robbins
Arterioscler Thromb Vasc Biol. 2015;35:272-279; originally published online December 23,
2014;
doi: 10.1161/ATVBAHA.114.303565
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
Greenville Avenue, Dallas, TX 75231
Copyright © 2014 American Heart Association, Inc. All rights reserved.
Print ISSN: 1079-5642. Online ISSN: 1524-4636
The online version of this article, along with updated information and services, is located on the
World Wide Web at:
http://atvb.ahajournals.org/content/35/2/272
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally published
in Arteriosclerosis, Thrombosis, and Vascular Biology can be obtained via RightsLink, a service of the
Copyright Clearance Center, not the Editorial Office. Once the online version of the published article for
which permission is being requested is located, click Request Permissions in the middle column of the Web
page under Services. Further information about this process is available in the Permissions and Rights
Question and Answer document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Arteriosclerosis, Thrombosis, and Vascular Biology is online
at:
http://atvb.ahajournals.org//subscriptions/