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Abstract | Despite the advances that have been made in developing new therapeutics,
cardiovascular disease remains the leading cause of worldwide mortality. Therefore,
understanding the mechanisms underlying cardiovascular tissue injury and repair is of
prime importance. Following cardiac tissue injury, the immune system has an important
and complex role in driving both the acute inflammatory response and the regenerative
response. This Review summarizes the role of the immune system in cardiovascular
disease focusing on the idea that the immune system evolved to promote tissue
homeostasis following injury and/or infection, and that the inherent cost of this
evolutionary development is unwanted inflammatory damage.
REVIEWS
Box 1 | The immune system during tissue growth and regeneration
A careful examination of examples from the natural world reveals temporal and
phylogenetic characteristics that predict the ability of tissues to regenerate in diverse
organisms. More primitive organisms such as invertebrates, reptiles and amphibians
have a striking regenerative potential when compared with mammals. For example,
both the zebrafish and newt heart can fully regrow after experiencing substantial
injury, and the salamander can fully regrow its limbs after amputation functions that
are not possessed by adult mammals141143. Very young mammals also retain this
regenerative capacity. The neonatal heart can fully regenerate after apical resection
of the left ventricle, myocardial infarction or necrotic injury, but this capacity is lost
after the first weeks of life8385. One important similarity between more primitive
organisms and very young mammals is a more limited (primitive) immune system144.
The macrophage is a specialized mononuclear phagocyte that resides in all tissues
from the earliest stages of development57,145. Loss of macrophages leads to
abnormalities in growth of complex vascular and neuronal networks, increased
mortality and stunted growth146152. Beyond supporting growth, macrophages also have
an important and more generalized role in the clearance of senescent cells during
embryonic development87,88. Importantly, non-selective depletion of all macrophages
impairs the ability of primitive organisms and young mammals to regenerate,
highlighting the crucial role these cells have in tissue growth and repair8385. Although
macrophages possess important regenerative functions, they can also mediate
pathology. Excessive expansion of macrophage populations during ischaemic injury
impairs tissue healing, indicating that certain macrophage subsets can interfere with
the regenerative process78. Understanding when macrophages do or do not promote
tissue repair is a crucial first step if we are to understand why the adult human heart has
only a limited regenerative capacity.
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2015 Macmillan Publishers Limited. All rights reserved
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Immune cell activation in cardiac injury
Acute ischaemic injury is the best characterized model
of cardiac injury and repair. Following injury, necrotic
Cardiomyocyte
cell death leads to the activation of tissue-resident
immune and non-immune cells. These cells produce
pro-inflammatory cytokines and chemokines that are
Macrophage
responsible for recruiting inflammatory leukocytes
from the blood into the area of tissue injury 35. The initial
Blood
DC
vessel
inflammatory phase is followed by a proliferative phase
that is characterized by the expansion of neutrophil
Endothelial
TReg cell
and macrophage populations that are responsible for
cell
Mast cell
removing dead cells and matrix debris, as well as releas
ing cytokines and growth factors that lead to the forma
Neutrophil
tion of a highly vascularized granulation tissue, which is
B cell
composed of connective tissue and new blood vessels.
The final maturation phase is characterized by fibroblast
activation and endothelial cell proliferation, culminating
in reparative myocardial fibrosis and angiogenesis36.
During the very early stages of ischaemic injury, mast
cells and soluble complement proteins become impor
tant initiators of inflammation a process that is ampli
Figure 1 | Immune cells in the resting heart. The majority of immune cells in the resting
fied following coronary reperfusion. Immediately after
heart are macrophages, which are found primarily surrounding
endothelial
but are
Nature
Reviewscells
| Immunology
blood flow is restored, resident cardiac mast cells release
also seen in the interstitium amongst cardiomyocytes. Mast cells, dendritic cells (DCs),
pre-formed pro-inflammatory mediators (for example,
Bcells and regulatory T (TReg) cells are found sparsely in cardiac tissue, while neutrophils
tumour necrosis factor (TNF), histamine and mast cell
and monocytes are not observed within myocardial tissue, but can be observed as
contaminants found in the vasculature during steady state5.
proteases) that initiate an amplification loop involving
adjacent cells, such as endothelial cells, resident macro
phages and, subsequently, infiltrating neutrophils9.
30
repeat region . Analysis of human tissue has revealed that Timely restoration of blood flow to viable tissue is cru
NOD1, NOD2 and the NLR family members NOD-, LRR- cial to prevent cardiomyocyte death; however, reperfu
and pyrin domain-containing 2 (NLRP2) and NLRP3 sion comes at the cost of exposing complement proteins
are expressed in the heart. Both NOD1 and NLRP3 have to injured endothelial cells and myocardium (see REF.37
been shown to activate canonical inflammasomes in for a review). Activated complement proteins trigger
the heart, and these molecules have an important role further mast cell degranulation, release of histamine
in the adverse cardiac remodelling events that follow and vasogenic oedema37. Cleaved complement proteins
ischaemiareperfusion injury and myocardial infarction; such as C5a both attract neutrophils and induce their
however, the cell types involved are not known18,31.
transendothelial migration into the injured tissue via the
The RLR family is composed of RIGI, melanoma CD11bCD18 complex 38 (FIG.3a). If reperfusion is not
differentiation-associated gene 5 (MDA5) and LGP2. established, cardiomyocyte cell death ensues through
RLRs are localized in the cytoplasm and recognize the a variety of pathways that lead to additional DAMP
genomic RNA of double-stranded RNA (dsRNA) viruses release. The exact role of resident mast cells is in part
and the dsRNA that is generated as the replication inferred, as models of mast cell deficiency generally use
intermediate of single-stranded RNA (ssRNA) viruses. Kit/ animals, which have other immune-cell deficits3941.
MDA5 is the best characterized receptor in this family, However, mast cells, the complement cascade, oxidative
and the loss of MDA5 expression in cardiomyocytes stress and pro-inflammatory cytokine and chemokine
leads to uncontrolled viral replication and rapid death in production immediately after injury initiate a complex
mice infected with encephalomyocarditis virus (EMCV), interplay between innate and adaptive immunecells.
whereas over-expression of MDA5 in the heart protects
against lethal myocarditis32,33. A final set of PRRs that Neutrophil recruitment during cardiac injury
are expressed in human and mouse heart tissue are the Following either cardiac ischaemic injury or pres
Ctype lectin receptors, which are calcium-dependent sure overload, neutrophils are the first innate immune
carbohydrate-binding receptors34. However, very little is cells recruited to the myocardium in large numbers42.
known about their roles in cardiac tissueinjury.
Patients deficient in neutrophils or neutrophil function
One important issue that has been only partially suffer from devastating disseminated bacterial infec
addressed is the delineation of cell-type-specific roles tions, indicating a clear requirement for this cell type to
Granulation tissue
for PRRs. Beyond the few examples given here, it is not prevent expansion of otherwise harmless pathogens43.
This is tissue that arises
after cardiac tissue injury,
clear what differential roles various PRRs have within However, their role in the response to cardiac injury is
when the replacement of
individual immune and non-immune cell subsets almost entirely pathological and, as such, neutrophils
cardiomyocytes with collagen
during the process of cardiac tissue injury and repair, are the best example of a cell type that promotes overall
and extracellular matrix occurs
which represents an important avenue for further longevity, but in the setting of sterile injury, they have no
in order to maintain the
integrity of the myocardial wall.
investigations.
known protectiverole.
Monocyte
REVIEWS
Heart
Cell necrosis
DAMPs
dsRNA
CpG
Uric acid
crystal
HMGB1
ATP
HSP
IL-1
Receptors
TLR3
TLR9
NLRP3
TLR2TLR4RAGE
P2Y11 and P2X7
TLR4
IL-1R
ECM
degradation
DAMPs
Hyaluronan
fragment
Heparan
sulphate
Receptors
CD44TLR4
TLR4
Thrombus
Ischaemic area
Figure 2 | Cardiac injury and sensing damaged tissue. The figure shows a coronary
artery occlusion (black) that leads to ischaemic tissue injuryNature
(grey zone).
From
within the
Reviews
| Immunology
ischaemic area, cell necrosis, extracellular matrix (ECM) degradation and recruitment
of immune cells all lead to the production of specific damage-associated molecular
patterns (DAMPs), which are recognized by pattern recognition receptors. This leads
to the generation of inflammatory responses to internal injury signals. CpG, CpG
dinucleotides; dsRNA, double-stranded RNA; HMGB1, high-mobility group box1;
HSP, heat shock protein; IL, interleukin; IL-1R, IL-1 receptor; NLRP3, NOD-, LRRand pyrin domain-containing 3; P2Y, P2Y purinoceptor; P2X, P2X purinoceptor;
RAGE, receptor for advanced glycation end-products; TLR, Toll-like receptor.
Cardiac macrophages
The dominant view for the past half century has been
that bone marrow-derived haematopoietic stem cells
(HSCs) give rise to circulating blood monocytes, which
enter into tissues and become tissue macrophages55.
However, in the past few years a series of more definitive
publications have drastically revised our understand
ing of monocyte and macrophage origin by showing
that many tissue-resident macrophage populations are
established during embryonic development, and they
are subsequently maintained by self-renewal, rather than
through blood monocyte input 5,5661. Given the impor
tance of monocytes and macrophages to cardiovascular
disease, we review recent insights into the origin of
functions of these subsets and how they contribute to
cardiac tissue injury andrepair.
There are two main subsets of circulating mono
cytes in mice, LY6Chi monocytes and LY6Clow monocytes.
LY6C+ monocyte progenitors give rise to LY6Chi mono
cytes and, through a nuclear receptor subfamily 4
group A member 1 (NR4A1)-dependent transcrip
tional programme, LY6C hi monocytes differentiate
into LY6Clow monocytes58,62,63. Global transcriptional
profiling has shown these monocyte subsets are con
served in humans64 and they have very different roles
invivo. LY6Clow monocytes adhere to and move along
the endothelium, both clearing damaged cells and
triggering inflammatory responses without entering
tissue65,66. During cardiac stress, LY6Chi monocytes are
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2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
a 24 hours post ischaemic injury
DAMPs
Necrotic
cardiomyocyte
Endothelial
cell activation
Histamine,
TNF and IL-1
DAMPs
Infarct
zone
Mast cell
degranulation
C5
Peripheral
neutrophil
activation
C5a
Proteinases and
collagenases
Phagocytosis of
necrotic cells
Neutrophil
recruitment
Ischaemia and anoxia
IL-17A promotes
neutrophil production
in bone marrow
IL-17A induces
apoptosis
Apoptotic
cardiomyocyte
Apoptotic
neutrophil
IL-10
and TGF
IL-17A
IL-17A
T cell
IL-23
Activated
monocyte
Endothelial cell
CCL7
Monocytes produce
pro-inammatory
cytokines and
chemokines
TGF
Monocytes ingest
apoptotic cells and
release anti-inammatory
cytokines
TReg cell
CCR2-dependent
monocyte recruitment
Innate
B cell
Innate B cells activated
in response to DAMPs
Fibroblast
TGF induces
brosis
Nature Reviews | Immunology
Figure 3 | Immune response to ischaemic injury in adult animals. a | Early after ischaemic injury (within 24hours),
endogenous danger-associated molecular patterns (DAMPs) are released from necrotic cardiomyocytes and activate
resident mast cells, causing mast cell degranulation and release of preformed pro-inflammatory cytokines and vasogenic
compounds (such as histamine, tumour necrosis factor (TNF) and interleukin1 (IL1)), which activate endothelial cells.
Necrotic cardiomyocytes also release mitochondrial DAMPs (such as formylated peptides and mitochondrial DNA) into
the circulation, which causes systemic neutrophil activation. Activated neutrophils adhere to activated endothelium
and transmigrate into the cardiac tissue following a chemokine gradient. Neutrophils secrete proteases that digest
tissue (and also activate chemoattractants, such as complement component C5a), which further potentiates leukocyte
recruitment. Neutrophils are directed to ischaemic areas by following gradients of DAMPs (such as ATP). Neutrophils
may then phagocytose dying cells, but they can also induce apoptosis in healthy cardiomyocytes themselves through
the release of reactive oxygen species. b | In the later phases of ischaemic injury (34days), there is recruitment of LY6Chi
monocytes from the blood into ischaemic cardiac tissue. Some of these monocytes originate from reservoirs in the
spleen. Innate Bcells that express immunoglobulins IgM and IgD are also recruited into the myocardium and produce
CCchemokine ligand 7 (CCL7), which promotes further monocyte recruitment10. Innate Bcell activation is MYD88
(myeloid differentiation primary response protein 88) dependent (suggesting Toll-like receptor and DAMP involvement).
Recruited monocytes secrete pro-inflammatory cytokines and chemokines, and they drive inflammatory processes.
A proportion of recruited monocytes ingest apoptotic cells, including neutrophils, which increases the secretion of
anti-inflammatory cytokines, such as transforming growth factor- (TGF) and IL10, and thereby decrease leukocyte
recruitment. Monocytes produce IL23, which drives the production of IL17A by Tcells. IL17A has two main roles
in perpetuating the inflammatory response: it drives neutrophil production in the bone marrow and causes cardiomyocyte
death. As inflammatory responses diminish, less IL23 is produced in the tissue. CCR2, CC-chemokine receptor 2;
TReg, regulatory T cell.
NATURE REVIEWS | IMMUNOLOGY
REVIEWS
the primary subset recruited to the heart, either follow
ing ischaemic injury or hypertensive stress; whereas
LY6Clow monocytes do not seem to be directly recruited
into the myocardium5,59,61,67,68. Monocytes recruited into
ischaemic myocardium are found in the blood, but the
spleen is also a monocyte reservoir that can be used
when blood and bone marrow stores are insufficient69,70.
Splenic monocytes also seem to have a protective role, as
splenectomy leads to impaired infarct healing 71. Monocyte
recruitment is in part dependent on innateBcells, which
are also recruited to the ischaemic myocardium, and
these B cells drive monocyte population expansion
through a CCchemokine ligand 7 (CCL7)-dependent
process10 (FIG.3b). Once monocytes enter the tissue they
begin to differentiate into macrophages. For many years,
it has been very challenging to separate recruited mono
cytes from resident macrophages and, as a result, they
have been analysed as a single population. However,
as we describe below, these populations have different
ontological lineages, and this has important functional
implications.
Innate Bcells
These cells are thought to
become rapidly activated in
the absence of classical
Tcell-dependent antigen
presentation mechanisms.
They are mobilized by other
cell types and/or inflammatory
triggers.
ApoE-deficient mice
These mice are used to model
atherosclerosis. They have
increased total plasma
cholesterol levels and
increased bone marrow
production of monocytes and
heightened inflammatory
responses.
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2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
a
Adult heart
MHC class IIhi
macrophage MHC class IIlow
macrophage
IIlow fetal
MHC class
monocyte-derived macrophage
Monocyte
Blood
vessel
Embryonically
derived macrophages
proliferate in situ
MHC class IIhi macrophages develop
from MHC class IIlow populations
Neonatal heart
Adult heart
Receptive
neonatal
cardiomyocyte
Quiescent
adult
cardiomyocyte
Tissue injury
Expansion
of resident
macrophage
populations
Angiogenesis
Cardiomyocyte proliferation
Inammation
Tissue injury
Regeneration of
cardiac tissue
Angiogenesis
Cardiomyocyte proliferation
Inammation
Impeded regeneration
of cardiac tissue
Scar formation
and adult animals (where there is minimal tissue regeneration). In the neonate,
Nature Reviews | Immunology
resident embryonically derived macrophage populations expand without
notable monocyte input. Embryonically derived macrophages promote
angiogenesis, cardiomyocyte proliferation and drive minimal inflammation
when stimulated by damage-associated molecular patterns (DAMPs). These
properties of neonatal macrophage populations facilitate cardiac
regeneration85. Following cardiac injury in the adult, there is marked expansion
of CCR2 + monocyte and macrophage populations. Notably, these
macrophages possess a limited ability to promote angiogenesis and
cardiomyocyte population expansion, but have notable capacity to drive
inflammatory responses, which impedes tissue regeneration5,85. Importantly,
neonatal cardiomyocytes are primed to divide and therefore are receptive to
regenerative signals84,153,154. Adult cardiomyocytes are much less receptive
to regenerative signals, and growth signals from embryonically derived cardiac
macrophages are one of many important components of cardiac regeneration
promotion in adult tissues. A key therapeutic goal would be to recapture the
neonatal response to injury in the injured adult heart.
REVIEWS
an important function in the setting of ischaemic injury.
Expression of the MER tyrosine kinase (MERTK) a
phagocytic receptor that is a highly specific marker
of tissue macrophages is upregulated on cardiac
macrophages after myocardial infarction, and loss of
MERTK expression leads to the accumulation of apop
totic cardiomyocytes, increased neutrophil persistence
and decreased levels of the anti-inflammatory cytokine
IL10 in the myocardium89,90. This ongoing inflamma
tion ultimately results in decreased cardiac function89,90.
Phagocytosis of apoptotic cells (efferocytosis) in skeletal
muscle results in the transition of macrophages to a more
anti-inflammatory state through the upregulation of the
intracellular signalling kinase AMPK, which is associated
with downregulation of pro-inflammatory genes (such as
Tnf) and the upregulation of anti-inflammatory genes,
such as Il10 (REFS91,92). Together, these data suggest that
strategies that target newly recruited monocytes while
sparing resident macrophages may yield therapeutic
benefit during cardiacinjury.
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Coxsackievirus B
TLR2
or TLR4
MYD88
CAR
DAF
Cardiomyocyte
FYN
or ABL
LCK
Endosome
Viral entry
Viral nucleic
acids
MDA5
RIG-I
Activation of
cytosolic PRRs
IRAK4
NF-B
TLR7
TLR3
TRIF
Activation of
endosomal PRRs
IRF3
p50 p65
NF-B activation
IRF activation
Type I IFN
production
Protective
immune response
Figure 5 | Interaction of coxsackievirus B with the host innate and acquired immune
system. Coxsackievirus B (CVB) engages the internalizingNature
receptor
coxsackievirus
and
Reviews
| Immunology
adenovirus receptor (CAR), and the receptor-associated tyrosine kinases FYN and ABL
can facilitate viral remodelling of the cell cytoskeleton to promote viral cell entry. This
process is further aided by the coreceptor decay accelerating factor (DAF) and its
associated tyrosine kinase LCK. Viral components can be detected by the intracellular
pattern recognition receptors (PRRs) melanoma differentiation-associated gene 5
(MDA5) and retinoic acid-inducible gene I (RIGI) leading to the activation of nuclear
factorB (NFB)dependent inflammatory pathways. NF-Bdependent responses can
also be activated following the engagement of CVB with cell surface-expressed Toll-like
receptors (TLRs), which signal through the myeloid differentiation primary response
protein 88 (MYD88) adaptor and downstream signal intermediates such as IL1-receptorassociated kinase 4 (IRAK4) and TNF receptor-associated factor 6 (TRAF6). These
pathways facilitate viral proliferation and host immune-mediated tissue damage. By
contrast, activation of interferon regulatory factor 3 (IRF3) following the triggering of
the TIR-domain-containing adapter-inducing IFN (TRIF) pathway by CVB leads to the
production of protective typeI interferons (IFNs). There is mutual counter-regulation of
the MYD88 IRAK4 and TRIFIRF3 pathways. The subsequent maturation of CD4+ and
CD8+ Tcell subsets is also detrimental for the host, whereas regulatory Tcells are
host-protective. Cross-talk between acquired and innate immune signalling pathways
also modulates the host response to CVB infection.
REVIEWS
dysfunction and inflammation following viral infection,
suggesting that entry into cardiomyocytes is required
for tissue damage130. However, although viral entry and
subsequent viral proliferation trigger disease, they are
not necessarily the primary determinants of disease out
comes. Both the innate and adaptive immune responses
have crucial roles in the progression of viral myocar
ditis, as shown by the fact that genetic deletion of the
TLR-signalling proteins myeloid differentiation pri
mary response protein 88 (MYD88) or IL1R-associated
kinase 4 (IRAK4), or deletion of the T cell receptorassociated tyrosine kinase LCK, ameliorates myocardial
inflammation and improves survival in mice, despite
increased levels of viral proliferation131134.
Following viral entry into the target cell, such as an
immune cell or cardiomyocyte, the virus can engage
intracellular NLRs, including RIGI and MDA5. The
endosomal degradation of the virus can also lead to the
activation of TLR3 and TLR732,133. The signalling cas
cades induced by such PRR activation can have detri
mental consequences for the host. As stated above, the
MYD88IRAK4 pathway, showed a very marked protec
tive benefit in mice during CVB3 infection. At least four
different mechanisms are thought to mediate protection
in this setting. First, the loss of MYD88IRAK4 signal
ling decreases downstream activation of TNF receptorassociated factor6 (TRAF6) and nuclear translocation of
the NFB complexes, resulting in reduced pro-inflam
matory cytokine production and Tcell activation135.
Second, increased IRF3 or IRF5 homodimerization and
phosphorylation of signal transducers and activators of
transcription 1 (STAT1) and STAT5 occurs in the absence
of MYD88 or IRAK4, leading to increased production of
protective antiviral typeI IFNs133135. Third, IRAK4 dele
tion facilitates the mobilization of protective CCR5+
monocytes from the bone marrow into the myocar
dium133. Fourth, the absence of MYD88 or IRAK4 leads
to downregulation of CAR expression and decreased
viral proliferation135. However, the genetic deletion of
IRF3, which is activated by the TIR-domain-containing
adaptor-inducing IFN (TRIF)-dependent TLR path
way, leads to much worse outcome during virus-induced
myocarditis, with mice showing increased mortality and
greater levels of viral proliferation136. Mechanistically, this
is associated with decreased typeI interferon production
and increased activation and translocation of NF-B136.
These observations have several important implica
tions. The first is that increased expression of viral entry
receptors and enhanced viral proliferation are, paradoxi
cally, facilitated by the host innate immune response
probably an evolutionarily selected advantage for the
pathogenic virus at the expense of the host. The second
is that intracellular immune signalling pathways seem to
induce functional responses that regulate trafficking of
inflammatory cells, such as CCR5+ monocyte-derived
macrophages, from the bone marrow. Indeed this is also
the case in sterile inflammation post myocardial infarction,
in which IRAK4 signalling seems to regulate the traffick
ing and maturation of dendritic cells into the myocardium,
with subsequent orchestration of host inflammatory
responses that dictate tissue remodelling and host survival.
Future directions
The ultimate goal in terms of understanding how the
immune system directs inflammatory and reparative
programmes following cardiac injury is the develop
ment of therapeutic strategies that promote tissue
regeneration. Evolutionary pressures drove both the
development of primitive phagocytic cells that promote
tissue growth and wound healing, but also drove the
development of innate and adaptive immune mecha
nisms that promote survival of the host in the face
of infectious threats. Adaptations that both enhance
pathogen clearance and promote tissue repair may
result in a zero-sum game, whereby the very adapta
tions that enhance host defence result in a loss of repar
ative potential owing to excessive inflammation. The
ability to selectively suppress excessive inflammation
while preserving reparative functions is a novel thera
peutic avenue that can enhance recovery in patients
with a wide range of cardiovascular diseases.
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Ma,X., Cong,P., Hou,X., Edgecombe,G.D. &
Strausfeld,N.J. An exceptionally preserved arthropod
cardiovascular system from the early Cambrian.
Nature Commun. 5, 3560 (2014).
2. Bier,E. & Bodmer,R. Drosophila, an emerging model
for cardiac disease. Gene 342, 111 (2004).
3. Lozano,R. etal. Global and regional mortality from
235 causes of death for 20 age groups in 1990 and
2010: a systematic analysis for the Global Burden of
Disease Study 2010. Lancet 380, 20952128
(2012).
4. Pinto,A.R. etal. An abundant tissue macrophage
population in the adult murine heart with a distinct
alternatively-activated macrophage profile.
PLoS ONE. 7, e36814 (2012).
5. Epelman,S. etal. Embryonic and adult-derived
resident cardiac macrophages are maintained through
distinct mechanisms at steady state and during
inflammation. Immunity 40, 91104 (2014).
This is the first study to show that cardiac
macrophages are not a single population but are
composed of distinct subsets, with different origins
and functions.
6. Nahrendorf,M. etal. The healing myocardium
sequentially mobilizes two monocyte subsets with
divergent and complementary functions. J.Exp. Med.
204, 30373047 (2007).
This report shows the initial characterization of
cardiac macrophages in the resting heart and after
ischaemic injury.
7. Swirski,F.K. & Nahrendorf,M. Leukocyte behavior in
atherosclerosis, myocardial infarction, and heart
failure. Science 339, 161166 (2013).
8. Choi,J.H. etal. Identification of antigen-presenting
dendritic cells in mouse aorta and cardiac valves.
J.Exp. Med. 206, 497505 (2009).
9. Frangogiannis,N.G. etal. Resident cardiac mast cells
degranulate and release preformed TNF-, initiating
the cytokine cascade in experimental canine
myocardial ischemia/reperfusion. Circulation 98,
699710 (1998).
10. Zouggari,Y. etal. B lymphocytes trigger monocyte
mobilization and impair heart function after acute
myocardial infarction. Nature Med. 19, 12731280
(2013).
11. Saxena,A. etal. Regulatory Tcells are recruited in
the infarcted mouse myocardium and may modulate
fibroblast phenotype and function. Am. J.Physiol.
Heart Circ. Physiol. 307, H1233H1242 (2014).
12. Roger,V.L. etal. Heart disease and stroke
statistics2012 update: a report from the American
Heart Association. Circulation 125, e2e220
(2012).
13. Jacoby,D. & McKenna,W.J. Genetics of inherited
cardiomyopathy. Eur. Heart J. 33, 296304 (2012).
14. Sangiuliano,B., Perez,N.M., Moreira,D.F. &
Belizario,J.E. Cell death-associated molecularpattern molecules: inflammatory signaling and
control. Mediators Inflamm. 2014, 821043
(2014).
15. Matzinger,P. Tolerance, danger, and the extended
family. Annu. Rev. Immunol. 12, 9911045 (1994).
16. Janeway,C. A. Jr. Approaching the asymptote?
Evolution and revolution in immunology.
Cold Spring Harb. Symp. Quant. Biol. 54Pt. 1, 113
(1989).
17. Mann,D.L., Topkara,V.K., Evans,S. & Barger,P.M.
Innate immunity in the adult mammalian heart: for
whom the cell tolls. Trans. Am. Clin. Climatol. Assoc.
121, 3450 (2010).
18. Mezzaroma,E. etal. The inflammasome promotes
adverse cardiac remodeling following acute myocardial
infarction in the mouse. Proc. Natl Acad. Sci. USA
108, 1972519730 (2011).
19. Takeuchi,O. & Akira,S. Pattern recognition receptors
and inflammation. Cell 140, 805820 (2010).
20. Rathinam,V.A. etal. The AIM2 inflammasome is
essential for host defense against cytosolic bacteria
and DNA viruses. Nature Immunol. 11, 395402
(2010).
21. Frantz,S. etal. Toll4 (TLR4) expression in cardiac
myocytes in normal and failing myocardium.
J.Clin. Invest. 104, 271280 (1999).
22. Birks,E.J. etal. Increased toll-like receptor 4 in the
myocardium of patients requiring left ventricular assist
devices. J.Heart Lung Transplant. 23, 228235
(2004).
23. Kashiwagi,M. etal. Differential expression of Toll-like
receptor 4 and human monocyte subsets in acute
myocardial infarction. Atherosclerosis 221, 249253
(2012).
1.
REVIEWS
71. Leuschner,F. etal. Rapid monocyte kinetics in acute
myocardial infarction are sustained by extramedullary
monocytopoiesis. J.Exp. Med. 209, 123137
(2012).
72. Molawi,K. etal. Progressive replacement of embryoderived cardiac macrophages with age. J.Exp. Med.
211, 21512158 (2014).
73. Bracey,N.A. etal. Mitochondrial NLRP3 protein
induces reactive oxygen species to promote Smad
protein signaling and fibrosis independent from the
inflammasome. J.Biol. Chem. 289, 1957119584
(2014).
74. Bracey,N.A. etal. The Nlrp3 inflammasome
promotes myocardial dysfunction in structural
cardiomyopathy through interleukin1.
Exp. Physiol. 98, 462472 (2013).
75. Dunay,I.R. etal. Gr1+ inflammatory monocytes
are required for mucosal resistance to the pathogen
Toxoplasma gondii. Immunity 29, 306317
(2008).
76. Kim,Y.G. etal. The Nod2 sensor promotes intestinal
pathogen eradication via the chemokine
CCL2dependent recruitment of inflammatory
monocytes. Immunity 34, 769780 (2011).
77. van Amerongen,M.J., Harmsen,M.C.,
van Rooijen,N., Petersen,A.H. & van Luyn,M.J.
Macrophage depletion impairs wound healing and
increases left ventricular remodeling after
myocardial injury in mice. Am. J.Pathol. 170,
818829 (2007).
78. Panizzi,P. etal. Impaired infarct healing in
atherosclerotic mice with Ly6C(hi) monocytosis.
J.Am. Coll. Cardiol. 55, 16291638 (2010).
79. Dewald,O. etal. CCL2/monocyte chemoattractant
protein1 regulates inflammatory responses critical to
healing myocardial infarcts. Circ. Res. 96, 881889
(2005).
80. Leuschner,F. etal. Therapeutic siRNA silencing in
inflammatory monocytes in mice. Nature Biotech. 29,
10051010 (2011).
81. Serbina,N.V. & Pamer,E.G. Monocyte emigration
from bone marrow during bacterial infection requires
signals mediated by chemokine receptor CCR2.
Nature Immunol. 7, 311317 (2006).
82. Zhou,L. etal. Monocyte chemoattractant protein1
induces a novel transcription factor that causes
cardiac myocyte apoptosis and ventricular
dysfunction. Circ. Res. 98, 11771185 (2006).
83. Aurora,A.B. etal. Macrophages are required for
neonatal heart regeneration. J.Clin. Invest. 124,
13821392 (2014).
84. Porrello,E.R. etal. Transient regenerative potential of
the neonatal mouse heart. Science 331, 10781080
(2011).
This is the first study to show that the mammalian
neonatal heart can regenerate fully, similarly to
what is observed in more primitive organisms.
85. Lavine,K. etal. Distinct macrophage lineages
contribute to disparate patterns of cardiac recovery
and remodeling in the neonatal and adult heart.
Proc. Natl Acad. Sci. 111, 1602916034 (2014).
This is the first study to show that resident
neonatal heart macrophages, not recruited
monocytes, have a key role in neonatal heart
regeneration. Similar findings were seen in
reference 83.
86. Marodi,L. Neonatal innate immunity to infectious
agents. Infect. Immun. 74, 19992006 (2006).
87. Munoz-Espin,D. etal. Programmed cell senescence
during mammalian embryonic development.
Cell 155, 11041118 (2013).
88. Storer,M. etal. Senescence is a developmental
mechanism that contributes to embryonic growth
and patterning. Cell 155, 11191130 (2013).
89. Wan,E. etal. Enhanced efferocytosis of apoptotic
cardiomyocytes through myeloid-epithelialreproductive tyrosine kinase links acute inflammation
resolution to cardiac repair after infarction.
Circ. Res. 113, 10041012 (2013).
90. Gautier,E.L. etal. Gene-expression profiles and
transcriptional regulatory pathways that underlie the
identity and diversity of mouse tissue macrophages.
Nature Immunol. 13, 11181128 (2012).
91. Mounier,R. etal. AMPK1 regulates macrophage
skewing at the time of resolution of inflammation
during skeletal muscle regeneration. Cell. Metab. 18,
251264 (2013).
92. Arnold,L. etal. Inflammatory monocytes recruited
after skeletal muscle injury switch into
antiinflammatory macrophages to support
myogenesis. J.Exp. Med. 204, 10571069 (2007).
www.nature.com/reviews/immunol
2015 Macmillan Publishers Limited. All rights reserved
REVIEWS
139. Mason,J.W. etal. A clinical trial of immunosuppressive
therapy for myocarditis. The Myocarditis Treatment
Trial Investigators. N.Engl. J.Med. 333, 269275
(1995).
140. Kuhl,U. etal. Interferon- treatment eliminates
cardiotropic viruses and improves left ventricular
function in patients with myocardial persistence of
viral genomes and left ventricular dysfunction.
Circulation 107, 27932798 (2003).
141. Poss,K.D., Wilson,L.G. & Keating,M.T.
Heart regeneration in zebrafish. Science 298,
21882190 (2002).
142. Laube,F., Heister,M., Scholz,C., Borchardt,T. &
Braun,T. Reprogramming of newt cardiomyocytes is
induced by tissue regeneration. J.Cell Sci. 119,
47194729 (2006).
143. Godwin,J.W., Pinto,A.R. & Rosenthal,N.A.
Macrophages are required for adult salamander
limb regeneration. Proc. Natl Acad. Sci. USA 110,
94159420 (2013).
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