REVIEWS

Role of innate and adaptive immune

mechanisms in cardiac injury and
repair
Slava Epelman1, Peter P. Liu2 and Douglas L. Mann3
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.

1
Toronto Medical Discovery
Tower, 101 College Street,
TMDT 3903 Toronto, Ontario,
M5G 1L7, Canada.
2
University of Ottawa Heart
Institute, 40 Ruskin Street,
Ottawa, Ontario, K1Y 4W7,
Canada.
3
Center for Cardiovascular
Research, Division of
Cardiology, Department of
Medicine, Washington
University School of Medicine,
St. Louis, Missouri 63110,
USA.
Correspondence to S.E.
e-mail: slava.epelman@
uhnresearch.ca
doi:10.1038/nri3800
The cardiovascular system evolved ~600 million years
ago as a means to transport nutrients and cells within
multicellular organisms1. Primitive organisms such as
Drosophila possess a single chamber that functions as
both a pumping tube and a simple vascular system2. More
complex organisms have compartmentalized cardio­
vascular systems, comprising venous and arterial vascular
systems that are connected to a multi-chamber muscular
myocardium that continually receives and ejects blood
components. Despite the more complex nature of the
mammalian cardiovascular system, its primary functions
remain the same, and its importance to health and dis­
ease is highlighted by the fact that cardiovascular disease
is the leading cause of death worldwide, with an increasing
burden over the past decade3. Therefore, understanding
both how cardiac tissue is injured and how cardiac tissue
regenerates is of prime importance to global health.
The immune system evolved to enable host defence
against invading pathogens but also to promote tissue
growth and repair during development or following sterile
tissue injury, such as that which can occur within the
myocardium (BOX 1). In this Review, we detail the roles of
individual immune cell subsets and immune signalling
pathways in both sterile and infectious cardiac injury.
We also use examples from the cardiac system to suggest
the idea that the immune system evolved to promote
tissue homeostasis, but that this beneficial activity comes
at a cost of increased ‘bystander damage’ when the
immune system overreacts to internal injury.
Immune anatomy of the resting heart
As in most tissues, the primary immune cells that
reside in the heart are macrophages, which are typically
observed near endothelial cells or within the interstitial
space, while very few, if any, monocytes are found within
cardiac tissue4–7 (FIG. 1). Sparse populations of dendritic
cells (DCs) have been found within cardiac tissue, some
of which are localized in cardiac valves, where they
presumably sample antigens5,8. Mast cells are found in
resting cardiac tissue, and are thought to be important
early triggers of immune responses9. A small number of
B cells and regulatory T cell subsets are also present in
cardiac tissue in resting conditions, whereas neutrophils
are typically not found within non-inflamed cardiac tis­
sue5,10,11. Whether from sterile or infectious triggers,
cardiac tissue injury initiates a dynamic cellular cascade
that initially activates resident immune cells, and over
time this evolves in a coordinated manner that leads to
the recruitment of diverse leukocyte populations into
inflamed tissue.
Mechanisms of cardiac injury
The myocardium can be injured by various pathophysio­
logical processes, which can be grouped broadly into
ischaemic and non-ischaemic aetiologies. In terms of
global disease burden, ischaemic injury is the primary
pathophysiological mechanism of injury 3,12. Occlusion
of a coronary vessel after acute plaque rupture can lead
to two potential outcomes: a completed myocardial

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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 re‑grow after experiencing substantial
injury, and the salamander can fully re‑grow its limbs after amputation — functions that
are not possessed by adult mammals141–143. 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 life83–85. 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 growth146–152. 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 repair83–85. 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.
infarction occurs if blood flow is not restored, result­
ing in permanent anoxic and low-nutrient tissue injury.
If blood flow is re-established to ischaemic (yet viable)
tissue, inflammatory ‘reperfusion injury’ can also occur
(discussed below). Non-ischaemic cardiomyopathy is
a composite diagnosis that includes myocarditis that
occurs after viral or bacterial infections or toxin admin­
istration. In addition, there are cardiomyopathies that
develop secondary to chronic hypertension. All these
forms of injury are influenced by genetic predisposition,
which can itself lead to early onset cardiac dysfunction13.
Whether through acute ischaemic injury or through
the gradual impairment of cardiac function following a
variety of clinical pathologies, irreversible heart failure
often develops. As we are coming to understand, the
immune system can contribute both during the initial
insult and during the chronic phase of cardiac injury
— and despite the investment of substantial research
into understanding the contribution of immune cells
to cardiac injury and repair, much remains unknown.
Innate sensing of cardiac injury
Mammalian hearts use both innate and adaptive
immunity to respond to tissue injury resulting from
pathogens or environmental injury (for example,
ischaemia or haemodynamic overloading). Resident
cardiac immune cells are triggered by the detection
of pathogen-associated molecular patterns (PAMPs)
or damage-associated molecular patterns (DAMPs) by
a fixed number of germline encoded pattern recogni­
tion receptors (PRRs). Classic examples of pathogen-
associated molecular patterns include the lipopolysac­
charides (LPSs) of Gram-negative microorganisms,
the teichoic acids of Gram-positive microorganisms,
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© 2015 Macmillan Publishers Limited. All rights reserved
the zymosans of yeast, the glycolipids of mycobacterium,
or the double-stranded RNAs of viruses (FIG. 2). More
recently it has become clear that cardiac PRRs also rec­
ognize the molecular patterns of endogenous material
released by dying or injured myocardial cells. Cells that
die by accidental necrosis, regulated necrosis (that is,
necroptosis) and/or secondary apoptosis release their
cytosolic contents into the extracellular space, thereby
initiating a brisk inflammatory response through the
engagement of an ensemble of extracellular or intra­
cellular PRRs14. The time course of the inflamma­
tory response that ensues following tissue injury is
remarkably consistent, irrespective of the specific cause
of the injury, and it is associated with the rapid influx of
neutrophils, and subsequently monocytes, into the area
of tissue injury. This inflammatory response has been
referred to as ‘sterile inflammation’, insofar as the inflam­
mation following tissue injury occurs in the absence of
a known pathogenic infection15,16.
Many PRRs encountering PAMPs and DAMPs trig­
ger signalling cascades that activate nuclear factor‑κB
(NF‑κB), activator protein 1 (AP-1), and interferon
regulatory factor (IRF) transcription factors, that in
turn regulate target genes that encode pro-inflammatory
cytokines and interferons (IFNs) in the heart 17. Another
subset of PRRs in the heart trigger a distinct pro-
inflammatory mechanism that requires assembly of
cytosolic protein complexes called inflammasomes18.
Canonical inflammasomes convert pro-caspase 1 into
the catalytically active caspase 1 protease that is respon­
sible the production of interleukin‑1β (IL‑1β) and
IL‑18 — cytokines that are sufficient to trigger
inflammatory responses in the heart 18.
PRRs can be subdivided into two major classes
based on their subcellular localization. Toll-like recep­
tors (TLRs) and C‑type lectin receptors are found on
plasma membranes or endosomes, where they can
detect the presence of PAMPs or DAMPs. A second
class of PRRs resides in intracellular compartments,
and includes retinoic-acid inducible gene I (RIG-I)‑like
receptors (RLRs), NOD-like receptors (NLRs) and
absent-in‑melanoma 2 (AIM2) receptors19,20.
Little is known of how TLR expression is regulated in
the heart. However, TLR4 seems to be upregulated in the
failing human heart and on circulating monocytes at
the time of myocardial infarction21–23. In animal studies,
loss of TLR4 in haematopoietic cells is protective
in the setting of sepsis-induced cardiac dysfunction and
the loss of TLR2 in haematopoietic cells is protective
during ischaemic injury 24–26. The loss of TLR4 is also
protective following ischaemic injury, although it is not
known whether this is attributable to the absence of
TLR4 activity in haematopoietic or other cell types25–28.
During haemodynamic stress, mitochondria are typi­
cally damaged; if the degradation of mitochondrial
DNA is inhibited in this setting, a TLR9‑dependent
inflammation-induced cardiomyopathy develops29.
NLRs function as cytosolic sensors of intra­cellular
DAMPs and PAMPs. In humans, the NLR family is
composed of 22 intracellular PRRs that share a central
NACHT domain and a carboxy-terminal leucine-rich
 REVIEWS

Monocyte 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
Macrophage pro-inflammatory cytokines and chemokines that are
responsible for recruiting inflammatory leukocytes
Blood DC from the blood into the area of tissue injury 35. The initial
vessel inflammatory phase is followed by a proliferative phase
Endothelial TReg cell
that is characterized by the expansion of neutrophil
cell and macrophage populations that are responsible for
Mast cell removing dead cells and matrix debris, as well as releas­
Neutrophil ing cytokines and growth factors that lead to the forma­
B cell tion of a highly vascularized granulation tissue, which is
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
Figure 1 | Immune cells in the resting heart.  The majority of immune cells in the resting
tant initiators of inflammation — a process that is ampli­
heart are macrophages, which are found primarily surrounding endothelial
Nature Reviewscells but are
| Immunology fied following coronary reperfusion. Immediately after
also seen in the interstitium amongst cardiomyocytes. Mast cells, dendritic cells (DCs), blood flow is restored, resident cardiac mast cells release
B cells and regulatory T (TReg) cells are found sparsely in cardiac tissue, while neutrophils pre-formed pro-inflammatory mediators (for example,
and monocytes are not observed within myocardial tissue, but can be observed as tumour necrosis factor (TNF), histamine and mast cell
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.
repeat region . Analysis of human tissue has revealed that Timely restoration of blood flow to viable tissue is cru­
30

Granulation tissue
This is tissue that arises
after cardiac tissue injury,
when the replacement of
cardiomyocytes with collagen
and extracellular matrix occurs
in order to maintain the
integrity of the myocardial wall. investigations.
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
ischaemia–reperfusion 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 RIG‑I, melanoma CD11b–CD18 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 deficits39–41.
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 immune cells.
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
C‑type 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 tissue injury. 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
for PRRs. Beyond the few examples given here, it is not prevent expansion of otherwise harmless pathogens43.
clear what differential roles various PRRs have within However, their role in the response to cardiac injury is
individual immune and non-immune cell subsets almost entirely pathological and, as such, neutrophils
during the process of cardiac tissue injury and repair, are the best example of a cell type that promotes overall
which represents an important avenue for further longevity, but in the setting of sterile injury, they have no
known protective role.

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REVIEWS
Heart
DAMPs
Receptors
• dsRNA
• TLR3
Thrombus • CpG
• TLR9
• Uric acid
Cell necrosis crystal
• NLRP3
•TLR2–TLR4–RAGE
• HMGB1
• P2Y11 and P2X7
• ATP
• TLR4
• HSP
• IL-1α
• IL-1R
Ischaemic area
DAMPs
• Hyaluronan Receptors
ECM
degradation
fragment • CD44–TLR4
• Heparan • TLR4
sulphate
Immune cell recruitment
and activation
Figure 2 | Cardiac injury and sensing damaged tissue.  The figure shows a coronary
artery occlusion (black) that leads to ischaemic tissue injuryNature
(grey zone).
ReviewsFrom within the
| 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 box 1;
HSP, heat shock protein; IL, interleukin; IL-1R, IL-1 receptor; NLRP3, NOD-, LRR-
and pyrin domain-containing 3; P2Y, P2Y purinoceptor; P2X, P2X purinoceptor;
RAGE, receptor for advanced glycation end-products; TLR, Toll-like receptor.
Neutrophil recruitment is mediated in two phases
(FIG. 3a); the first phase is peripheral activation prior to
infiltration. Mitochondria in all cell types, including
cardiomyocytes, contain formylated peptides and mito­
chondrial DNA, both of which are structurally similar
to bacterial components. In an analogous system (skel­
etal muscle necrosis), these mitochondrial DAMPs are
released. Formylated peptides and mitochondrial DNA
are sensed by formyl peptide receptor 1 (FPR1) and
TLR9, respectively, and the triggering of these receptors
promotes neutrophil activation and their recruitment to
inflamed tissues29. It is important to confirm whether
similar mechanisms are involved in neutrophil activation
following cardiomyocyte necrosis. The ability to sense
mitochondrial motifs is not surprising as mitochondria
are endosymbionts and related to microorganisms in
many ways. However, the exact role of mitochondrial
motifs in cardiac injury remains to be defined.
The second phase of neutrophil activation depends on
cardiac endothelial cells. Pro-inflammatory mediators,
such as TNF, IL‑1β and histamine, activate endothelium
and induce the upregulation of adhesion molecules that
enable neutrophil transmigration between and through
endothelial cells to reach the site of tissue injury 9,44.
Detailed imaging studies in other organ systems have
aided our understanding of how neutrophils enter
damaged tissue. For example, following necrotic tissue
injury in the liver, neutrophils adhere to more remote
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© 2015 Macmillan Publishers Limited. All rights reserved
sites, where viable tissue is present. Initially, migration is
dependent on chemokines, and subsequently neutrophils
follow necrotic signals, such as liberated intra­cellular
ATP (which is a DAMP), in order to precisely home to
the site of tissue injury 45. The reason neutrophils (and
perhaps other recruited immune cells) take this more
convoluted path is that necrotic tissue is usually non- (or
under) perfused, and transendothelial migration at the
site of injury is not possible. Unfortunately, such detailed
imaging of migrating neutrophils has yet to be done in
the injured beating heart, but techniques to achieve this
are being developed46. Such studies will be highly inform­
ative for understanding the spatial dynamics of resident
macrophages, recruited neutrophils and monocytes
during the progression of ischaemic cardiac injury.
An important early mediator of tissue injury seems
to be IL‑6, which is produced in an autocrine fashion by
cardiomyocytes and recruited myeloid cells (both neutro­
phils and macrophages)47,48. IL‑6 upregulates intracellular
adhesion molecule 1 (ICAM1) expression on cardio­
myocytes, inducing neutrophil binding and stimulating
cytotoxic activity 49–51. The role of neutrophils following
cardiac injury may be more pronounced when major
areas of the myocardium are at risk of cell death (but have
not yet died), such as following ischaemia–reperfusion
injury. Neutrophils produce numerous proteases that
contribute to injury, and blockade of neutrophil recruit­
ment seems to be most effective during more limited
episodes of ischaemia, rather than during longer episodes
in which cardiomyocyte death is largely secondary to
anoxia and nutrient deprivation52–54.
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 5,56–61. 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 and repair.
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
in vivo. 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
 REVIEWS

a 24 hours post ischaemic injury DAMPs

Necrotic Endothelial
cardiomyocyte cell activation

Histamine,
DAMPs TNF and IL-1β
Infarct
zone

Mast cell Peripheral

degranulation C5a
C5 neutrophil
activation
Proteinases and
Phagocytosis of collagenases
necrotic cells

Neutrophil
recruitment

Ischaemia and anoxia

b 3–4 days post ischaemic injury IL-17A promotes

neutrophil production
in bone marrow
IL-17A induces
apoptosis IL-17A TReg cell

Apoptotic γδ T cell IL-10 IL-10 suppresses

cardiomyocyte IL-17A monocyte activation
Apoptotic
neutrophil IL-23
Activated Endothelial cell
monocyte

Monocytes produce CCL7

pro-inflammatory
cytokines and
IL-10 chemokines
and TGFβ CCR2-dependent
TGFβ monocyte recruitment
Innate
B cell
Monocytes ingest
apoptotic cells and Innate B cells activated
release anti-inflammatory in response to DAMPs
cytokines Fibroblast
TGFβ induces
fibrosis

Nature Reviews | Immunology

Figure 3 | Immune response to ischaemic injury in adult animals.  a | Early after ischaemic injury (within 24 hours),
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 interleukin‑1β (IL‑1β)), 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 (3–4 days), there is recruitment of LY6Chi
monocytes from the blood into ischaemic cardiac tissue. Some of these monocytes originate from ‘reservoirs’ in the
spleen. Innate B cells that express immunoglobulins IgM and IgD are also recruited into the myocardium and produce
CC‑chemokine ligand 7 (CCL7), which promotes further monocyte recruitment10. Innate B cell 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-β (TGFβ) and IL‑10, and thereby decrease leukocyte
recruitment. Monocytes produce IL‑23, which drives the production of IL‑17A by γδ T cells. IL‑17A 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 IL‑23 is produced in the tissue. CCR2, CC-chemokine receptor 2;
TReg, regulatory T cell.

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REVIEWS
Innate B cells
These cells are thought to
become rapidly activated in
the absence of classical
T cell-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.
122 | FEBRUARY 2015 | VOLUME 15 www.nature.com/reviews/immunol
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 innate B cells, which
are also recruited to the ischaemic myocardium, and
these B cells drive monocyte population expansion
through a CC‑chemokine 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.
Cardiac macrophage subsets. Recently, studies using
genetic fate mapping, parabiosis and adoptive transfer
techniques have defined resident cardiac macrophage
populations in much more detail. Rather than being a
homogenous population, resident cardiac macrophages
comprise three discrete subsets that have different ori­
gins and functions5 (FIG. 4a). These three macrophage
subsets are defined by their differential expression
of MHC class II and CC chemokine receptor 2 (CCR2).
MHC class IIhi and MHC class IIlow cardiac macrophages
are both CCR2− and are, numerically, the dominant
subsets in the heart 5. These macrophage subsets are
primarily derived from embryonic progenitors, with
a substantial number arising from embryonic yolk sac
precursors, and they renew through in situ proliferation,
rather than through monocyte input. After birth, there
is some dilution of embryonically derived macrophages
by recruited monocyte-derived macrophages in the
heart, but in adult mice the majority of resident cardiac
macrophages remain of embryonic origin5,72.
The third cardiac macrophage subset is made up
of CCR2+ macrophages, which are derived from, and
slowly replenished by, circulating blood monocytes.
Detailed studies during hypertensive stress suggest that
embryonically derived macrophage populations expand
solely through in situ proliferation, whereas monocyte-
derived macrophages require monocyte input prior to
proliferative expansion in the tissue5. CCR2+ macro­
phages express high levels of pro-inflammatory genes,
including those associated with the NLPR3 inflamma­
some, which is required to process and deliver IL‑1β to
the heart during cardiac stress5. Inflammasome acti­
vation promotes adverse cardiac remodelling follow­
ing ischaemic injury, genetic cardiac hypertrophy and
hyper­tensive cardiac disease18,73,74; it is likely that CCR2+
cardiac macrophages are involved in inflamma­some acti­
vation in each of these settings. The robust pro-inflam­
matory gene signature of CCR2+ cardiac macro­phages
suggests that they are important for immune protection
© 2015 Macmillan Publishers Limited. All rights reserved
against invading pathogens, but their in­appropriate
activation in the setting of sterile inflammation may
lead to unwanted pathology 75,76. Prior studies have used
dichotomous expression of two classical myeloid cell
markers (F4/80 and CD11b) in order discern embry­
onic versus adult monocyte origin57. However, differ­
ent cardiac macrophage lineages (embryonic and adult)
cannot be distinguished by these cell surface markers
alone and, as such, genetic fate mapping remains the
most accurate method for lineage discrimination of
cardiac macrophages in adult mice5,72.
Functions of cardiac macrophages. One of the interest­
ing challenges in the setting of cardiac tissue injury is to
define the roles of recruited monocytes and monocyte-
derived macrophages. Non-selective depletion strategies
have shown that in the absence of both monocytes and
macrophages, scar formation is impaired after cardiac
ischaemic injury, with decreased collagen production,
decreased angiogenesis and increased mortality due
to myocardial rupture6,77. However, experiments using
ApoE‑deficient mice (apolipoprotein-E-deficient mice) sug­
gest that excessive expansion of macrophage populations
can have a detrimental effect on infarct healing, leading to
excessive inflammation and impaired cardiac function78.
Furthermore, studies of cardiac injury in Ccr2−/− mice,
which lack circulating monocytes, indicate that monocyte
recruitment and the associated inflammatory response
leads to increased cardiac pathology 79–81. The loss of
LY6Chi monocytes also prevents hypertension-induced
cardiac fibrosis and improves left ventricle function after
myocardial infarction. Taken together, these data suggest
that recruited monocytes have a pathological role in the
setting of sterile cardiac injury, but that resident embry­
onically derived macrophages are likely to have important
roles in the tissue-repair response6,67,82.
Interestingly, as already mentioned, the neonatal heart
has a remarkable capacity to regenerate in response to
multiple forms of tissue injury, but the regenerative pro­
cess is lost if resident embryonically derived macrophages
are eliminated83–85. In fact, the neonatal heart supports
the expansion of tissue-resident embryonically derived
macro­phage populations following injury, as opposed
to the recruitment of monocytes, and this seems to be a
fundamental difference between the neonatal and adult
heart. Neonatal cardiac macrophages promote endothelial
cell activation and cardiomyocyte growth, and they gener­
ate minimal inflammation after stimulation through TLR
and inflammasome pathways85 (FIG. 4b). These data suggest
that that the neonatal heart avoids excessive inflamma­
tory responses, which may be a crucial factor that aids the
regenerative process, although this benefit may come at
the cost of being more susceptible to infections86.
Macrophage subsets that are primarily derived from
embryonic precursors are more efficient at internaliz­
ing debris and engulfing apoptotic cardiomyocytes, sug­
gesting they have important homeostatic roles. Indeed,
these functions are reminiscent of embryonic macrophage
functions during development and could suggest that
some of these functions are ‘hard-wired’ into the adult
macrophages5,87,88. The uptake of dead or dying cells is
 REVIEWS

a Early in embryonic development Later in embryonic development Adult heart

MHC class IIhi
MHC class IIlow yolk sac- MHC class IIlow fetal macrophage MHC class IIlow
monocyte-derived macrophage macrophage
Cardiomyocyte derived macrophage

Monocyte

Blood
vessel

Embryonically
Developing heart seeded by derived macrophages
yolk sac-derived macrophages proliferate in situ

Heart seeded by macrophages MHC class IIhi macrophages develop

derived from fetal monocytes from MHC class IIlow populations
Adult monocytes give rise to MHC class IIhi
and MHC class IIlow macrophages and
short-lived CCR2+ macrophages

b
Neonatal heart Adult heart

Receptive
neonatal
cardiomyocyte
Quiescent
adult
cardiomyocyte

Tissue injury Expansion

of resident Tissue injury
macrophage
populations

↑ Angiogenesis ↓ Angiogenesis
↑ Cardiomyocyte proliferation ↓ Cardiomyocyte proliferation
↓ Inflammation ↑ Inflammation

Regeneration of • Impeded regeneration

cardiac tissue of cardiac tissue
• Scar formation

Figure 4 | Role of embryonically derived macrophages during tissue injury
and repair.  a | During embryonic development, extra-embryonic yolk-sac
derived macrophages (shown in blue) initially seed the developing heart. The
cells express low levels of MHC class II molecules. Later during development,
fetal monocyte-derived macrophages (shown in orange) also infiltrate the
heart, and both of these embryonic macrophage populations expand further
during development, and after birth, by in situ proliferation. MHC class IIhi
macrophages develop from these populations of MHC class IIlow macrophages
after weaning5,72. During this time, haematopoietic stem cell-derived
monocytes infiltrate the heart and also differentiate into MHC class IIhi
macrophages (dark green) and MHC class IIlow macrophages (light green).
MHC class IIhi and MHC class IIlow macrophages persist in the tissue as an
ontologically mixed population, primarily composed of embryonically derived
macrophages5. Monocytes that infiltrate the heart can also become short-lived
CC-chemokine receptor 2 (CCR2)+ macrophages, which are entirely derived
from blood monocytes5. b | The figure shows a comparison of the macrophage
response to tissue injury in neonatal animals (which regenerate cardiac tissue)
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.

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© 2015 Macmillan Publishers Limited. All rights reserved

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
IL‑10 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 (REFS 91,92). Together, these data suggest that
strategies that target newly recruited monocytes while
sparing resident macrophages may yield therapeutic
benefit during cardiac injury.
Adaptive immune cells and heart injury
Lymphocytes have been reported to have diverse roles
during cardiac tissue injury and repair. CD4‑deficient
mice, MHC class II‑deficient mice and mice that express
a single transgenic T cell receptor show impaired wound
healing and increased monocyte population expansion
after ischaemic injury. This suggests that CD4+ T cells
have protective functions during cardiac injury, and
that auto-antigens may be presented to CD4+ T cells by
MHC class II‑expressing cells (such as macrophages and
DCs), which then drives immunosuppressive responses
in the myocardium93. Interestingly, it may be that regu­
latory T cells are the key CD4+ T cell subset involved
here, and regulatory T cells have been shown to promote
myo­cardial recovery through an IL‑10‑dependent path­
way 94,95. Another study found that recombination acti­
vating gene (RAG)-deficient mice (which lack T cells
and B cells) have decreased infarct sizes after ischaemic
injury, and that the transfer of CD4+ T cells into the RAG-
deficient mice had a negative effect on infarct healing.
Therefore, in certain situations CD4+ T cells may have
pathogenic roles following ischaemic injury96. In addi­
tion, RAG-deficient mice have decreased levels of circu­
lating IgG antibodies, and these antibodies are known to
have immunosuppressive effects (as reviewed in REF. 97).
CD8+ T cells have also been shown to have regula­
tory roles following ischaemic injury. CD8+ T cells
express type 2 angiotensin II receptor (AGTR2), which
is known to drive anti-inflammatory responses98,99.
Angiotensin II is part of the renin–angiotensin system,
which has long been known to be a crucial pathological
pathway in heart disease100,101. Angiotensin II is thought
to primarily induce cardiomyocyte hypertrophy and
increase vascular tone by signalling through AGTR1,
in a process that is amplified by blockade of AGTR2
(as reviewed in REF. 102). After ischaemia–reperfusion
injury AGTR2‑expressing CD8+ T cells, inhibit inflam­
mation and decrease infarct size by producing IL‑10 in an
angiotensin II‑dependent fashion, and this subsequently
dampens the immune response98.
124 | FEBRUARY 2015 | VOLUME 15 www.nature.com/reviews/immunol
© 2015 Macmillan Publishers Limited. All rights reserved
In addition to these roles of T cells, other lympho­
cytes have been shown to shape inflammatory responses
in cardiac tissue. Natural killer (NK) cells were reported
to infiltrate the myocardium and have protective effects
following ischaemic injury 103. The adoptive transfer of
activated NK cells into mice was shown to protect against
left ventricle dysfunction following ischaemia by pre­
venting fibrosis and enhancing angiogenesis through a
contact-dependent interaction with endothelial cells.
Transition from acute inflammation to fibrosis
One of the first important steps that limits tissue injury
and promotes the transition to tissue healing is the
resolution of neutrophil recruitment. Macrophages
are believed to initiate the process through two key
mechanisms that have been linked to their phagocytic
capacity. First, it has been well described in vitro and
in vivo that macrophages that have ingested apoptotic
cells increase their production of anti-inflammatory
and pro-fibrotic cytokines, such as IL‑10 and TGFβ,
while they decrease production of pro-inflammatory
cytokines, such as IL‑1β and TNF 104,105. Following
ischaemic injury, if all cardiac macrophages are absent,
or they if they lack the phagocytic receptor MERTK,
there is neutrophil persistence within infarcted myo­
cardial tissue and ongoing inflammation. This suggests
that the activation of cardiac macrophage phagocytic
pathways limits inflammation, and that the loss of the
phagocytic macrophages results in an accumulation of
apoptotic material in the infarct zone5,6,89.The transi­
tion from inflammatory to pro-fibrotic macrophages
has been classically thought to involve polarization
changes (from an ‘M1’ to an ‘M2’ macrophage pheno­
type); however, it is becoming clear that macrophages
are very heterogeneous and fit along a broad spectrum
of possibilities, rather than into clearly defined subsets.
Further work is required to define where individual
cardiac macrophage subsets fit into the M1 and M2
framework106.
The second mechanism involves a complex cytokine
cascade that depends on γδ T cells and their production
of IL‑23 and IL‑17A. The production of IL‑17A leads to
neutrophil production and release from bone marrow
stores107. Interestingly, IL‑17A is regulated by secretion
of IL‑23 by macrophages, and the ingestion of apoptotic
neutrophils decreases IL‑23 production, which leads to
decreased IL‑17A levels and decreased neutrophil pro­
duction in the bone marrow 107–109. Following ischaemic
cardiac injury, γδ T cells and neutrophils themselves seem
to be important sources of IL‑17A production within the
myocardium, and mice that lack IL‑23 have reduced
IL‑17A levels in cardiac tissue, reduced neutrophil accu­
mulation, increased γδ T cell population expansion and
improved infarct healing 110. Indeed, IL‑17A seems to also
be directly toxic to cardiomyocytes, and neutralization
of IL‑17A improves infarct healing 111 (FIG. 3b).
Additional work has shown an important link between
IL‑17A production and activation of fibrotic pathways
within the heart that lead to collagen deposition, both fol­
lowing ischaemia and haemodynamic strain112,113. In this
context, and in contrast to the work described above, the
 REVIEWS

Coxsackievirus B myocardial ischaemic injury that we discussed earlier, in

which either too few or too many infiltrating monocytes
impaired infarct healing 6,78. These data indicate that there
TLR2 CAR DAF are yet-to-be determined, context-dependent factors
or TLR4 that modulate whether a particular cell type or pathway
Cardiomyocyte mediates cardiac tissue repair or damage.
FYN
The activation of cardiac fibroblasts and subse­
MYD88 LCK
or ABL quent extracellular matrix deposition is an important
Viral entry Endosome component of cardiac ischaemic injury and repair.
Interestingly, cardiac fibroblasts can also become acti­
Viral nucleic vated in more subtle forms of cardiac stress that also
acids
lead to impaired cardiac function owing to increased
MDA5 RIG-I
myocardial stiffness (such as hypertension caused
TLR3 TLR7 by infusion of angiotensin II). In this setting there is
Activation of rapid recruitment of neutrophils and monocytes into
cytosolic PRRs TRIF
Activation of the myocardium and also expansion of resident car­
endosomal PRRs
IRAK4 diac macrophage populations5,114–118. Cardiac fibroblasts
become activated, leading to interstitial cardiac fibrosis,
a process dependent on input and possible differen­
tiation from monocytes117. The activation of cardiac
fibroblasts is also amplified by CD4+ and CD8+ T cells
NF-κB IRF3 through an IFNγ-dependent pathway 119,120 (reviewed
p50 p65 in detail in REF. 121).

NF-κB activation
IRF activation
Type I IFN
production
Activation of immuno- Protective
pathological response, immune response
tissue damage
Figure 5 | Interaction of coxsackievirus B with the host innate and acquired immune
system.  Coxsackievirus B (CVB) engages the internalizingNaturereceptor coxsackievirus
Reviews and
| 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 co‑receptor 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 (RIG‑I) leading to the activation of nuclear
factor‑κB (NF‑κB)‑dependent inflammatory pathways. NF-κB‑dependent 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 IL‑1-receptor-
associated 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 IFNβ (TRIF) pathway by CVB leads to the
production of protective type I interferons (IFNs). There is mutual counter-regulation of
the MYD88 –IRAK4 and TRIF–IRF3 pathways. The subsequent maturation of CD4+ and
CD8+ T cell subsets is also detrimental for the host, whereas regulatory T cells are
host-protective. Cross-talk between acquired and innate immune signalling pathways
also modulates the host response to CVB infection.
loss of IL‑23 was demonstrated to impair infarct healing,
which was mechanistically linked to a failure to activate
fibroblasts, leading to impaired scar formation and myo­
cardial rupture113. These data are reminiscent of the rela­
tionship between monocyte influx and tissue healing after
Myocarditis as a model of cardiac inflammation
Myocarditis is an excellent model for dissecting the
inflammatory processes that occur in the heart. It
shows how the balance of innate and adaptive immune
mechanisms that occur following tissue injury deter­
mine whether there is progression to heart failure or
to repair of cardiac tissue. Myocarditis is most often
induced by infection with viruses, although other infec­
tious pathogens can also be involved, such as bacteria or
the protozoan parasite Trypanosoma cruzii, which is the
cause of Chagas disease, the commonest cause of heart
failure in South America122,123. Myocarditis can also
result from non-infectious triggers of DAMP release,
which activate the innate immune response leading to
sterile inflammation, such as allergic reactions to drugs
or chemicals124.
Myocarditis accounts for about one in nine cases
of heart failure and remains one of the most common
reasons for heart transplantation worldwide, as spe­
cific treatments are lacking 125. The most common viral
triggers of myocarditis include enteroviruses, such as
coxsackievirus B3 (CVB3) and CVB4, and adenovi­
ruses. Virus-induced myocarditis shows a periodicity
in its prevalence in human populations, which is pos­
sibly related to herd immunity. European studies also
show a substantial contribution of parvovirus B19,
which shows tropism for endothelial cells and the bone
marrow 126. Coxsackieviruses and adenoviruses target
host tissues, including the immune, cardiovascular and
neurological systems, through their binding and inter­
nalization by coxsackievirus and adenovirus receptor
(CAR) — which is an immune-regulated tight junc­
tion protein127,128. Internalization of the virus is assisted
by co‑binding to decay accelerating factor (DAF; also
known as CD55), a ubiquitously expressed host pro­
tein that inhibits complement activation129 (FIG. 5). Loss
of CAR expression in cardiomyocytes prevent cardiac

NATURE REVIEWS | IMMUNOLOGY VOLUME 15 | FEBRUARY 2015 | 125

© 2015 Macmillan Publishers Limited. All rights reserved

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 IL‑1R-associated
kinase 4 (IRAK4), or deletion of the T cell receptor-
associated tyrosine kinase LCK, ameliorates myocardial
inflammation and improves survival in mice, despite
increased levels of viral proliferation131–134.
Following viral entry into the target cell, such as an
immune cell or cardiomyocyte, the virus can engage
intracellular NLRs, including RIG‑I 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
MYD88–IRAK4 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 MYD88–IRAK4 signal­
ling decreases downstream activation of TNF receptor-
associated factor 6 (TRAF6) and nuclear translocation of
the NF‑κB complexes, resulting in reduced pro-inflam­
matory cytokine production and T cell 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 type I IFNs133–135. 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 IFNβ (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 type I interferon production
and increased activation and translocation of NF-κB136.
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.
126 | FEBRUARY 2015 | VOLUME 15 www.nature.com/reviews/immunol
© 2015 Macmillan Publishers Limited. All rights reserved
The activation of innate immune signalling path­
ways also sets the stage for subsequent T cell maturation
and participation in the host inflammatory response.
Genetic deletion of LCK, which impairs T cell matura­
tion, results in almost complete protection of the host
against CVB3 infection131. A similar outcome is observed
following CD4+ or CD8+ T cell subset deletion, or fol­
lowing deletion of the leukocyte tyrosine phosphatase
CD45, which is associated with upregulation of type I
IFNs132,137. Adoptive transfer of regulatory T cells into
CVB3‑infected hosts also had a marked protective
effect, again associated with a decrease in viral prolif­
eration and upregulation of type I IFNs138. Surprisingly,
there was a general downregulation of molecules asso­
ciated with TLR signalling pathways and even TLR4
itself. Moreover, beyond their role during infections,
regulatory T cells also promote recovery through an
IL‑10‑dependent pathway following ischaemic injury 95.
These data suggest that there is close cross-talk between
the regulatory T cell subsets and the innate immune sig­
nalling pathways that operate during both infectious and
sterile injury.
The above progress in understanding myocarditic
processes has moved the field forward from the ear­
lier failed attempts to use immunosuppression to treat
patients with myocarditis139. Subsequently, a Phase II
trial has demonstrated that in patients with persistent
viral proliferation, intravenous delivery of IFNβ clears
the virus and improves symptoms of myocarditis140.
Targeted immunosuppressive therapy may be indi­
cated for patients with persistent immune activation, in
which the viral proliferation phase has already passed.
Nevertheless, there are still large gaps in our knowledge,
including why there are periodic enteroviral outbreaks
in the population. Furthermore, why do some patients
develop severe viral myocarditis that requires transplan­
tation, while others are able to rebalance the immune
response and promptly recover from viral mycocarditis?
Are there biomarkers to permit one to predict an indi­
vidual patient’s susceptibility and, for those at high risk,
could vaccination be a viable option?
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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Competing interests statement
The authors declare no competing interests.
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