Cardiovascular Research 2007 73(1):26-36; doi:10.1016/j.cardiores.2006.08.009
Copyright © 2006, European Society of Cardiology
Innate immunity and inflammation – New frontiers in comparative cardiovascular pathology
Annika Lindea,
Derek Mosierb,
Frank Blechaa and
Tonatiuh Melgarejoc,*
aDepartments of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA
bDiagnostic Medicine and Pathobiology, Kansas State University, Manhattan, KS 66506, USA
cHuman Nutrition, Kansas State University, Manhattan, KS 66506, USA
* Corresponding author. Email address: tmelgare{at}ksu.edu
Received 21 February 2006; revised 27 July 2006; accepted 10 August 2006
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Abstract
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Innate immunity and inflammation play key roles in a wide range
of pathology – including heart disease and vasculopathies.
Current thinking suggests "damage" rather than "foreignness"
as the actual trigger of the immune system, which has caused
a dramatic change in how we tend to view the etiopathology of
most types of heart disease. The future potential of certain
anti-inflammatory therapeutic strategies in addressing heart
disease is intriguing. Still, the Janus face of immunity/inflammation
cannot be over emphasized as adverse manipulation of these systems
may prove ineffectual or worse, damaging. Knowledge on functional
characteristics of individual immune mediators is undoubtedly
a central theme, but in depth understanding of the multiple
biological actions of these molecules, as well as their contextual
function, is the corner stone in deciding on potential future
targets for pharmacologic manipulation. Animal models of human
heart disease are currently being investigated and clinical
trials conducted to gain further knowledge in this essential
area of cardiovascular research, but the scarcity of cardiovascular
research focusing on signaling molecules and pathways of innate
immunity is still evident. Genomic and proteomic research in
heart disease is going through its formative years, and much
is still unknown about the complex pathway dynamics utilized
by the innate immune system. This review will provide an overview
of the current literature focusing on innate immunity and the
heart, and hopefully will spark an interest in further basic
as well as clinical research. As more information on cardiovascular
immunity becomes available, this will provide a better understanding
and thus act as the foundation for potential development of
new treatment strategies for treatment of cardiovascular disorders.
KEYWORDS Toll like receptors; Antimicrobial peptides; Nuclear factor kappa beta; Innate immunity
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1. Innate immunity and inflammation in heart disease
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Virtually all organisms live under constant exposure to a variety
of infectious as well as non-infectious environmental microorganisms.
External and internal surfaces, including the cutaneous epithelia
and the mucosal linings constitute an immediate and proficient
barrier towards potential pathogens
[1]. The vast majority of
microorganisms that succeeds in passing this first-line-of intrinsic
defense will be eliminated by an array of other defense mechanisms
of the innate immune response, including accumulation of macrophages
and phagocytic neutrophils at the infection site
[1]. In addition
to this cellular innate immune response, plasma proteins, including
complement components, join at the site of infection, constituting
humoral innate immunity
[1]. Modern perspectives recognize inflammation
as a reaction involved in a variety of diseases including those
of non-pathogenic (i.e. without microbial involvement) origin
[2]. A key feature of inflammation in non-pathogenic disease
is the more recent recognition that sentinel cells of all tissues
can elicit as well as participate in the inflammatory response
along with classically circulating leukocytes and cells of the
lymphoid organs
[2]. Classically, the term sentinel cells has
been used in reference to dendritic cells qua their localization
along the major routes of entry for microorganisms and their
capacity to link innate and adaptive immune responses
[3,4].
Recently, however, the term "sentinel" has been applied more
widely to include different cell types which continuously sense
the environment and produce mediators which may act to either
activate or silence particular immune functions
[5–8].
As such, sentinel cells can thus also include endothelial cells,
cardiomyocytes, fibroblasts and mast cells (which are found
copiously in the heart)
[2]. The endothelium in particular figures
prominently in any consideration of the role of inflammation
as endothelial cells are now recognized for their ability to
switch from an anti-inflammatory function into a pro-inflammatory
mode
[2]; just as inflammation at large has been analogized
with a "Janus Face" – qua its capacity to heal as well
as destroy
[2]. Inflammation is a fundamental reaction instigated
against virtually all injury types. Not surprisingly many forms
of cardiovascular diseases therefore involve cells and mediators
of the inflammatory system
[2]. Even though cardiomyocytes do
not fall within the category of traditional immune cells, they
do respond to injury by producing some of the mediators (including
different cytokines) that are classically associated with cells
of the innate immune system
[9]. The innate immune response,
including inflammation, may therefore play an important role
– on a local as well as systemic level – in a range
of heart diseases that were not traditionally considered immunologic
in etiology. Mediators of an innate immune and inflammatory
response affect the cardiovascular system: 1) through direct
immune and inflammatory reactions within the heart; including
pathology such as cardiac remodeling, heart failure, ischemia
and reperfusion injury, and 2) by constituting a central role
in atherosclerosis and other types of vascular diseases; a role
which has been reported in recent reviews
[10,11]. Adding to
the outlined local innate response mechanisms within the myocardium
comes an activation of the immune system on a systemic level,
as is seen in chronic heart failure patients with increased
levels of pro-inflammatory cytokines in both plasma as well
as the failing myocardium
[12,13]. As such, the resulting overall
innate immune response defending the heart against any given
danger is therefore likely an orchestration between "non-immune
derived" mediators operating within the myocardium as an "immediate
first-line-of-defense" and a systemic reaction including recruitment
of traditional bone marrow derived professional immune cells.
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2. Toll-like receptors are expressed in the heart
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Toll-like receptors (TLRs) are classic pattern recognition receptors
(PRRs), which are gene-encoded proteins used by the innate immune
system to recognize largely invariant pathogen-associated molecular
patterns (PAMPs) that are shared by pathogen groups, but at
the same time not present in the host
[14]. Examples of PAMPs
are lipopolysaccharides of bacteria and double-stranded RNA
of different viruses
[14]. TLRs are characterized by an extracellular
leucine-rich repeat domain and a cytoplasmatic toll/interleukin-1
receptor homology domain (TIR). Thirteen different transmembrane
proteins of the TLR family have been identified so far, with
a number of specific ligands associated whose binding result
in activation and transcription of appropriate host-defense
genes
[15]. Virtually all cells of the heart express TLRs
[16].
TLR-2 to -4, and TLR-6 are readily detectable in cardiomyocytes,
while TLR-1 to TLR-6 are found in endotheliocytes, smooth muscle
cells and macrophages of the vasculature
[16]. The ligands for
TLR-2, -3, -4 and TLR-9 are the most well-characterized to date.
A variety of pathogens, including different bacteria and yeast,
is recognizable by TLR-2, whereas TLR-3 is the PRR for viral
double-stranded RNA
[17]. The first mammalian TLR described
was TLR-4, and hence this is the best described receptor of
the family
[18]. TLR-4 is the PRR for LPS, which is the major
component of the outer-membrane of Gram-negative bacteria and
a compound that can induce a robust increase in the pro-inflammatory
cytokines TNF-
and IL-1β within the myocardium (
Fig. 1 – Immediate Effects)
[19]. In addition, TLR-4 recognizes
a variety of PAMPs from other invading pathogens as well as
additional non-pathogenic ligands, including some chemotherapeutic
agents
[19]. TLRs can set off a complete immune response including
innate immune activity through macrophages activated by induction
of pro-inflammatory cytokines and antimicrobial molecules (e.g.
nitric oxide), which enables macrophages to fight invading pathogens,
as well as an adaptive immune response by activating dendritic
cells, which can stimulate T-cell expansion and differentiation
[16]. TLRs are furthermore able to maintain this adaptive immune
response by providing the necessary co-stimulatory molecules
[16]. The TLR family can initiate an immune response that is
both cell and pathogen specific. Members of the TLR system are
expressed differentially among immune and parenchymal cells,
and many TLRs are activated by more than a single class of PAMPs
[16]. In addition, distinct cell signaling pathways are triggered
by different TLR classes, such that TLR-2 responses involve
IL-8, IL-12 and IL-23 secretion, whereas TLR-4 responses include
release of cytokines such as IL-10, IFN-β and IL-12. This
allows for some degree of specificity even for the TLR-dependent
innate immunity signaling pathways, which permit different immune
responses for various PAMPs
[16]. In the case of TLR-4, LPS
initially binds to LPS binding protein (LBP) which transfers
LPS to CD14 (
Fig. 2A). It has, however, been reported that LPS-induced
activation of signal transduction likely occur via a CD-14 independent
mechanism in cardiomyocytes
[20], even though CD14 and LBP expression
have been reported on cardiomyocytes
[20,21].
Fig. 2A shows
the CD14/LBP-dependent LPS-mediated NF-
B-signaling via TLR4,
since less is known about the specific details of the CD14-independent
pathway.
Fig. 2B is a schematic of the reported pathways for
LPS-mediated CD14/LBP-independent signaling in cardiomyocytes
[22]. LBP and CD14 are both expressed on the plasma membrane
and activate TLR-4 after associating with MD2
[16]. Once activated,
signaling continues via the intracytoplasmatic TIR homology
domain, following either a "MyD88 dependent" or "MyD88 independent"
pathway
[23]. The MyD88 dependent route involves recruitment
of the cytoplasmic adapter protein MyD88 and IRAK (interleukin
receptor associated kinase), which is associated with TOLLIP
(toll interacting protein). IRAK consequently becomes autophosphorylated
and dissociates from the receptor complex after which TRAF-6
(TNF receptor-associated factor 6) is recruited. This activates
downstream kinases including the inhibitory
B kinase complex
that directly phosphorylates I
B
leading to nuclear translocation
of NF-kB and initiation of gene-transcription (
Fig. 2A)
[24].
NF-
B activation is among the best-characterized pathways, but
studies strongly suggests that several other yet unidentified
pathways may exist as well
[25].
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Fig. 1 Different types of myocardial injuries can activate an inherent cardiac stress response, which includes the expression of pro-inflammatory cytokines. The innate stress response plays a central role in instigating and orchestrating homeostatic responses within the heart. The effect of different cytokines upon the heart is depending on factors such as time of exposure and concentration. Abbreviations – RAAS: renin–angiotensin–aldosteron system; AII: angiotensin-2; NF-b: nuclear factor kappa B; TNF: tumor necrosis factor; MAPK: mitogen-activated protein kinase; MMP: matrix metalloproteinases; TGF-β: tissue growth factor beta; MnSOD: manganese superoxide dismutase; HSPs: heat shock proteins; IL-1β: interleukin-1-beta; IL-6 family: incl. interleukin-6 (IL-6), leukemia-inhibitory factor (LIF), cardiotrophin-1 (CT-1), ciliary neurotrophic factor (CNTF), interleukin-11 (IL-11), and oncostatin M (OSM); c-IAP1 and 2: cellular inhibitors of apoptosis 1 and 2; Bcl-2: B-cell lymphoma/leukemia-2 gene; gp130 R: signal-transducing glycoprotein 130 receptor; TNFR1: tumor necrosis factor receptor-1; TIMPs: tissue inhibitors of matriz metalloproteinases; iNOS: inducible nitric oxide synthase; NO: nitric oxide; STAT3: signal transducer and activator of transcription 3; pSTAT3: phosphorylated STAT3; TRAF6: TNF receptor associated factor-6; IRAK: IL-1 receptor associated kinase; IL-18: interleukin-18 [Figure content based on information from Wilson et al. J Mol Cell Cardiol 37 (2004):801-11)].
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3. Nf-B signaling in the heart
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NF-
B (nuclear factor kappa-B) was first discovered in 1986
[26],
and found to contain subunit proteins involving Rel-homology
domains (i.e. Rel family members), which are well preserved
central components of the innate immune response
[27]. To date,
five mammalian NF-
B subunit genes have been identified (RelA,
cRel, RelB, NF-
B1, and NF-
B2) and NF-
B exists as dimers of these
subunit proteins
[27]. NF-
B dimers are complexed to one of seven
known members of the I
B (inhibitory kappa-B) family which interacts
with the Rel-homology domain of NF-
B
[27]. The most common of
the I
B proteins are the I
B
and I
Bβ which are both expressed
in the heart
[28]. Contrary to the common perception, evidence
indicates that NF-
B and I
B
, as well as components of the upstream
signaling cascade, shuttle between the nucleus and the cytoplasm
[29]. Thus NF-
B activation may occur via I
B phosphorylation
in both compartments (
Fig. 2A)
[29]. The prevailing model dictates
that the I
B proteins regulate NF-
B activity by: 1) maintaining
equilibrium between the nucleus and the cytoplasm, where NF-
B
levels are quite low, in the absence of any stimuli, and 2)
inhibition of NF-
B's DNA-binding activity via interaction between
NF-
B and the C-terminal PEST
1 domain of I
B
[30]. NF-
B can, however,
be activated by two pathways. Degradation of I
B inhibitors leads
the way for the so called canonical (NF-
B1) signaling pathway,
which is present in the heart
[28,31]. A second non-canonical
(NF-
B2) pathway has been described for NF-
B activation, which
is based on regulated NF-
B2 processing rather than I
B degradation
[32]. The canonical pathway may be activated by an array of
signaling cascades including the JAK/STAT pathways
[27]. As
with many transcription factors phosphorylation increases the
transactivational activity of NF-
B. NF-
B is a multi-tasking
transcription factor implicated in an array of normal biological
phenomena as well as different states of pathology such as cell
growth and cell death, atherosclerosis, and innate immunity
including inflammation
[27]. Activating stimuli, such as cytokines,
that result in initiation of transcription of genes which would
otherwise remain silent or become transcribed at a very low
rate in the responding cell, is a central theme in immunology.
NF-
B can be considered a prototype, when discussing transcription
factors, since it plays a central role in a number of different
immunological reactions. Synthesis of pro-inflammatory cytokines
and adhesion molecules is principally mediated by NF-
B, which
itself is activated in response to a wide range of stimuli including
cytokines, pathogenic microorganisms, viruses, mitogens, oxidative
stress and modified LDL
[33]. One of the recently identified
nucleotide-binding oligomerization domain proteins (aka caspase
recruitment domain-containing proteins), Nod1, has also been
associated with NF-
B activation, and Nod1 furthermore appears
to play a key role in endothelial cell immunity
[34]. Nod proteins
are implicated in intracellular pattern recognition, and Nod1
and Nod2 mRNA expression have both been identified in the heart
[35]. The recently established Nod1 and Nod2 knockout mice will
therefore help shed light on the specific role played by these
newly identified peptides within the intrinsic cardiac immune
system and its potential interaction with other organs
[34].
NF-
B signaling in the heart is quite complex, since this factor
is positioned as an integrator of diverse signaling pathways
at multiple levels
[27]. NF-
B activity is normally undetectable
in the myocardium, suggesting that it acts predominantly in
response to various stimuli to the heart
[27]. Activation of
NF-
B can tip the normal homeostatic balance of opposing processes
in the myocardium, but the precise effect on the cardiac physiology
or pathophysiology depends largely on the specific cell type
and the set of NF-
B-dependent genes that is activated as well
as the immediate environment
[27]. The functional ambivalence
can be exemplified by the fact that NF-
B activity seems to be
involved in angiogenesis after hypoxia
[36], while activation
of NF-
B after ischemia/reperfusion has been implicated in a
pro-cell death effect
[27]. Multiple biological processes can
be affected by NF-
B in the heart
[37]. NF-
B activates gene expression
that affects processes such as cardiomyocyte growth, contractile
function and death as well as extracellular matrix remodeling
and inflammation (
Fig. 1)
[27]. A compendium of all identified
NF-
B regulated genes is maintained by courtesy of Dr. Gilmore
at Boston University
2. It is critical to note, that NF-
B regulate
genes that are involved in paradoxical responses given that
this has profound implications for understanding the role of
NF-
B in pathology
[27]. Understanding how the output of numerous
parallel signaling pathways is integrated by NF-
B (as well as
other transcription factors) resulting in gene expression with
specific effects on the heart is a fundamental first step towards
developing rational molecular therapies to address the injurious
while retaining the protective aspects of transcriptional signaling
networks activated by NF-
B in different types of cardiovascular
disease
[27]. Also, NF-
B activation occurs in several different
types of cells and organs and may be primarily protective in
one location while injurious in another
[27]. Consequently,
knowledge about NF-
B gene activation from one organ- or cell
type cannot be immediately extrapolated to the immunophysiological
mechanisms in the heart.
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4. Signaling via the JAK/STAT pathway in the heart
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The Janus kinase/signal transducer and activator of transcription
(JAK–STAT) signaling pathway plays a central role in cardiac
pathophysiology, and it is now recognized that a large number
of different cytokines exert their effect through binding to
receptors that activate this pathway, thus utilizing a rapid
and direct route to effect changes in gene expression in the
nucleus
[1]. The JAK–STAT pathway involves cytokines acting
via receptors associated with cytoplasmic Janus kinases (JAKs),
which have two symmetrical kinase-like domains and are thus
named after the two-headed mythical Roman god Janus
[1]. Upon
activation, the JAKs phosphorylate the cytosolic "signal transducers
and activators of transcription" (STATs) proteins, which lead
to their dimerization and translocation to the nucleus where
they activate a variety of genes, including those contributing
to lymphocyte growth and differentiation and thus adaptive immunity
[1]. A range of different JAKs and STATs exists and using different
combinations hereof ensures the specificity of signaling in
response to different cytokines
[1]. Mammals have four members
of the JAK family (JAK1–3, and Tyrosine kinase 2 [Tyk2]),
and seven members of the STAT family (STAT1–4, STAT5A,
STAT5B, and STAT6), which are all expressed in cardiac tissue
[38]. The STAT factors can function both as modulators of cytokine
signaling and as sensors responding to cellular stress
[39].
JAK–STAT signaling has been implicated in pressure overload-induced
cardiac hypertrophy and remodeling, ischemic preconditioning
and ischemia/reperfusion-induced cardiac dysfunction, while
also playing an important role in cytokine signaling in cardiomyocytes
(
Fig. 1)
[40]. Furthermore, the promoter of the prohormone angiotensinogen
gene acts as the target site for STAT proteins, thus linking
the JAK/STAT pathway to activation of the autocrine angiotensin
II loop within the heart
[41]. In addition, stress-induced activation
of matrix metalloproteinases (MMPs) is mediated by angiotensin
II acting via the JAK–STAT pathway
[42]. Activation of
specific STAT proteins constitutes the primary signaling event
in the development of myocardial hypertrophy and ischemia
[41].
Angiotensin II has been shown to activate STAT1, 3 and 5 through
JAK2 in cardiomyocytes. Despite similar structural organization,
STAT1 and STAT3 have opposing effects on the myocardium with
STAT1 exhibiting pro-apoptotic effects while STAT3 is able to
protect cardiomyocytes from apoptosis after ischemia/reperfusion
[39]. Studies have also shown that STAT5A and STAT6 are activated
during ischemia, whereas activation of STAT3 and STAT5A occurs
in myocardial hypertrophy
[41]. Much research is currently aimed
at generating strategies for targeting different STATs, and
a significant amount of attention is being paid to developing
JAK inhibitors aimed at use in the area of transplantation and
immunosuppressive treatments. A selective JAK3 inhibitor was
recently generated, which may represent a novel class of effective
immunosuppressants since it has proved effective in transplant
rejection in animal models
[43]. The JAK/STAT pathway is but
one of the stress/stretch-activated signaling pathways which
have been identified in cardiomyocytes exposed to diverse demands
[44]. Other pathways include G-proteins (guanine nucleotide-binding
proteins), MAPK (mitogen-activated protein kinases), PKC (protein
kinase C), ERK (extracellular signal-regulated protein kinases),
JNK (c-Jun NH2-terminal kinases), the protein phosphatase calcinuerin,
intracellular Ca
2+ regulation, and a number of autocrine and
paracrine factors
[45]. Not only do these stress-activated pathways
initiate and maintain the phenotypical cardiac alterations,
but they have also been implicated in affecting the cardiomyocytes
in deciding whether to survive or undergo apoptosis (
Fig. 1)
[45]. Consequently further research aimed at exploring the function
of these individual proteins might pave the way for novel therapeutic
opportunities in treatment of heart disease.
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5. Cytokines and their implications in heart disease
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It is well-established that cardiac myocytes and fibroblasts
produce cytokines locally
[9]. Studies have shown that various
pro-inflammatory markers, including the cytokines TNF-
(tumor
necrosis factor alpha), IL-1 and IL-6 (interleukin 1 and 6 respectively),
are activated in different types of pathophysiologic processes
involving the heart (
Fig. 1)
[46,47]. TNF-
has furthermore been
implicated in regulation of vascular functions related to atherosclerotic
plaque stability and may as such be partially responsible for
plaque rupture
[48]. Similarly, IL-6 promotes expression of
ICAM-1 (intercellular adhesion molecule 1) and synthesis of
CRP (C-reactive protein), with potential significant implications
in atherosclerotic plaque formation and progression
[49]. Accumulating
evidence indicates that proinflammatory cytokines negatively
influence the inotrophic state of the heart as well as induce
hypertrophy and promote apoptosis or fibrosis, thereby actively
contributing to myocardial remodeling and thus development of
heart failure
[46]. TNF
is one of the proinflammatory cytokines
that has been implicated in cardiac dysfunction
[50] and recent
studies have shown that NF-
B activation and increased TNF
production
may play a central role in cardiac injury due to intracellular
Ca
2+ overload
[51]. In addition, myocyte apoptosis can be triggered
by TNF
and its second messenger sphingosine, which consequently
is partially responsible for the cardiac cachexia seen in heart
failure patients
[52]; just as cytokine-induced depression of
myocardial contractility reportedly results from production
of sphingosine due to interference with myocardial Ca
2+ handling
(
Fig. 1)
[47]. TNF
and IL1β appear to act both separately
as well as synergistically towards depressing myocardial function,
and it is likely that sphingosine also participates in this
synergistic signaling leading to injurious effects on the heart
[53]. Studies on feline cardiomyocytes have additionally shown
that agents which modulate sphingosine production also minimize
cardiodepression thus providing a potential therapeutic benefit
in clinical conditions of myocardial inflammatory injury
[54].
Paradoxically, recent studies have shown that low doses of TNF
can induce cardiac preconditioning, furthermore concluding that
there is evidence for a production and role of free radicals
in TNF
-induced cardioprotection
[55]. IL-6 is another proinflammatory
cytokine involved in cardiodepression and plasma levels of IL-6
are typically elevated in heart failure patients and inversely
correlated to left ventricular function
[56]. In addition, growing
experimental evidence suggests a role for IL-6 in mediating
part of the deleterious cardiovascular modifications observed
in heart failure
[56]. It has furthermore been suggested that
IL-6 is involved in a paracrine interaction between cardiac
myocytes and fibroblasts resulting in cardiac fibroblasts enhancing
myocyte hypertrophy and cardiac myocytes regulating fibroblast
adhesion and proliferation
[9]. Numerous endogenous mechanisms
exist for negatively regulating cytokine signaling and whether
novel therapies can be devised that exploit these mechanisms
remains to be further elucidated
[43]. Recent multi-center trials
with the anti-TNF-alpha compounds etanercept (i.e. RENEWAL trial)
and infliximab (i.e. ATTACH trial) have questioned the beneficial
effect of targeting single cytokines
[57,58]. Both trials concurred
that no safety issues was seen with regards to infliximab or
etanercept at lower dosages, but pointed out that high doses
of anti-TNF therapy may be without effect in heart failure patients
[59]. Other smaller trials (e.g. ENBREL) have, on the other
hand, reported dose-dependent improvement in heart function
with etanercept treatment
[60], whereas adverse effects including
toxicities secondary to TNF-alpha blocker therapy have been
reported by others
[13,61]. Despite the somewhat disappointing
and rather controversial results thus far, the "cytokine hypothesis"
remains an interesting concept in development of novel efficacious
therapies for heart failure patients. The studies accentuate
the complexity of the cytokine network, however, and have partially
caused a redirection of the focus towards more general immunomodulating
treatment modalities
[62]. Interestingly, nevertheless, the
pro-inflammatory cytokines are frequently induced even before
classical neurohormones such as angiotensin II and noradrenaline
in patients with chronic heart failure, and so the overactive
immune system still remains a promising target for therapeutical
interventions aimed at slowing down cardiac disease progression.
On the other extreme, a number of cytokines, including G-CSF
(granulocyte colony stimulating factor), leukemia inhibitory
factor and EPO (erythropoietin) have proven to have beneficial
effects on cardiac remodeling after infarction
[40,63]. Furthermore
endogenous anti-inflammatory cytokines such as IL-2 and IL-10
have proved to protect the myocardium against injury induced
by ischemia and reperfusion
[64]. It has been shown that G-CSF
activates the JAK/STAT pathway in cardiomyocytes thus protecting
against cardiac remodeling by reducing apoptosis post infarction
[40]. Rapid activation of potassium channels and protein kinases
by EPO reportedly represents a central new mechanism for increased
cardioprotection. Another recent study suggests that EPO has
cardioprotective effects by preventing cardiomyocyte apoptosis
[63]. EPO seems to instigate the immediate protection of the
heart through multiple signal transduction pathways, among which
the JAK/STAT is one of them
[65]. Additional experiments have
revealed that the rapid cardioprotective effect of EPO is associated
with ATP preservation in the ischemic myocardium
[66]. In view
of the existing knowledge on the biological effects of cytokines
on the heart, anti-cytokine therapy is likely to provide a new
direction for management of heart failure. Even though a cytokine-mediated
response initially may be beneficial, it might become deleterious
when sustained. In addition, the same therapeutic approach has
the potential of acting differently in a given patient depending
on the disease state. Consequently future therapies likely need
to aim at intracellular goals to inactivate signaling systems
responsible for injurious effect in cardiac disease and heart
failure
[67].
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6. Cardiac antimicrobial peptides
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Antimicrobial peptides (AMPs) are "multi-tasking natural antibiotics"
and ancient molecules of innate immunity with functions extending
far beyond that of simple antibiotics – including anti-tumor
and mitogenic activity, as well as immunomodulation and signal
transduction characteristics
[68]. The term antimicrobial is
used because these peptides have extraordinary broad spectra
of activity, including an ability to kill or neutralize Gram-negative
and Gram-positive bacteria, fungi, yeast, cancer cells and some
enveloped viruses
[69]. The overall effectiveness of an innate
immunity based host defense is shown by the clearly successful
survival of plants and invertebrates, organisms which completely
lack adaptive immunity. Defensins (including
-, β- and
-defensins) and cathelicidins constitute the two major groups
of AMPs in the majority of mammalian species
[70]. Mammalian
defensins are endogenous cysteine-rich peptide molecules classically
produced by epithelial cells of the external and internal surfaces
or by circulating cells, including granulocytes and macrophages.
β-defensins are small (3.5–4.5 kDa) highly basic
cationic peptides, structurally defined by a conserved cysteine-rich
motif forming three disulphide bonds, which stabilize a β-sheet
formation
[71]. Their folding pattern is determined by the amphipathicity
of these molecules, which is also believed to govern their antimicrobial
effect. The mechanism of action is thought to rely on permeabilization
of the microbial membrane and lysis of invading organisms, which
is explained in theory by the Shai–Matsuzaki–Huang
(SMH) model
[72]. Epithelial β-defensins consequently represent
a rapidly mobilized local defense against microbial intruders
at the epithelial and mucosal surfaces, and several studies
have shown induction of these defensins at sites of inflammation,
injury, infection as well as other types of disease processes
[73]. β-defensins are either constitutive or inducible,
and their production can be elicited by ligands such as bacterial
LPS through TLRs using the NF-kB pathway (
Fig. 2A)
[74]. Other
pathways, including MAPK and JAK/STAT signaling, seem to be
involved in β-defensin regulation
[75]. β-Defensins
have recently been identified in what may be considered as non-traditional
tissue such as the heart; including HBD-3 (human beta-defensin
3) expression in adult human heart
[76], pBD1 (porcine beta-defensin
1) in pigs
[77], eBD1 (equine beta-defensin 1) in the horse
[78], Defb1 (murine beta-defensin 1) in mice
[79], and rBD1
(rat beta-defensin 1) in the rat
[73]. Our laboratory has furthermore
recently documented that at least seven different beta-defensins
(i.e. rBD1/3/10/11/15/18 and 33) are expressed in the adult
rat heart (unpublished data). These findings suggest that AMPs
might participate as effector molecules of the innate immune
system in the heart as in other types of tissue, but information
on cardiac AMPs is still sparse and further research is needed
to elucidate the actual role played by AMPs in heart disease
and health.
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7. The heart as an immunological organ
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The heart possesses a gene-encoded intrinsic or innate stress
system, which is activated in response to different types of
injury (
Fig. 3)
[80]. This local innate stress response plays
a key role in instigating and coordinating homeostatic responses
in the heart, while the released inflammatory mediators at the
same time possess the potential of producing cardiac decompensation
if expressed at sufficiently high concentrations
[80]. The quintessential
feature of this innate immune system is that it serves as an
immediate warning system thus constituting a first-line-of-defense
allowing the host to discriminate self from non-self
[80]. The
"Danger Model of Immunity" suggests that cell damage rather
than foreignness is what prompts an immune response (
Fig. 3)
[81], and current research also suggests that chronic heart
failure in fact is a state of chronic inflammation, thus stressing
the importance of a functionally intact innate immune system
in the heart. Pro-inflammatory cytokines appear to play a central
role in the orchestration and timing of the intrinsic cardiac
stress response providing instantaneous anti-apoptotic cytoprotective
signals, as well as delayed signals facilitating tissue repair
and/or remodeling. The protective response may occur at the
cost of unwanted injurious effects occurring when cytokines
are elaborately expressed for sustained time intervals or at
pathologic/supra-physiologic levels contributing to cardiac
remodeling through different mechanisms involving cardiomyocytes
as well as non-cardiomyocytes
[80]. As in the case with TNF
,
NF-
B and AP1 (activator protein 1) have been suggested as potential
therapeutic targets, since these proteins are activated in heart
failure patients
[16]. Not only has NF-
B proved to play a key
role in muscle wasting and cardiac cachexia in heart disease,
but its activation also seems to play a role in proliferation
of vascular smooth muscle cells and intimal hyperplasia in atherosclerosis
[82]. Furthermore, NF-
B is both necessary and sufficient to
elicit a hypertrophic response in isolated rat cardiomyocytes
[83], and TNF
-induced hypertrophy is reported as being dependent
on NF-
B activation
[84]. The activities of NF-
B-dependent genes
can in fact explain many of the actions of TNF
on the heart
[27]. Results from studies involving transgenic mice show that
TNF
over-expression can cause development of severe dilated
cardiomyopathy with rapid progression to heart failure
[85].
Interestingly, the cardiac-specific TNF
expression in these
transgenic mice can lead to not only heart failure through activation
of pro-apoptotic signaling pathways, but also cardioprotection
through activation of anti-apoptotic proteins
[86]. NF-
B-signaling
is therefore likely a mixture of pro- and anti-apoptotic activity,
as well as other effects such as inflammation and infiltration,
as well as effects on Ca
2+ handling and NO (nitric oxide) production
etc.
[27]. Moreover, cross-talk seems to exist between NF-
B
and other signaling pathways
[27]. Apoptosis has been implicated
in different aspects of cardiac pathology, including cardiomyopathy,
myocardial infarction and heart failure
[87], thus making regulation
of pro- and anti-apoptotic signaling a quite central topic when
addressing heart disease. Apoptosis and necrosis differentially
contribute to myocardial injury. Still, the extent to which
apoptosis versus necrosis is mechanistically accountable for
cell death in the intact heart post infarction/reperfusion is
somewhat controversial
[27]. Apoptosis appears to be the predominant
mechanism for at least the first 24 h post infarction,
whereas necrosis seems to be more predominant in the developing
infarct
[88]. Modification of TLR expression may prove another
important therapeutic target. TLR1, 2 and 4 expressions are
all enhanced in human atherosclerotic plaques
[89], and studies
in knock-out mice have shown that inhibitors of TLR4 may be
helpful in treatment of atherosclerosis
[90]. Studies have shown
that inhibition of TLR2 may be advantageous after myocardial
infarction since this TLR seems to play an important role in
ventricular remodeling
[91]. Much attention has clearly been
paid to non-pathogenic insult affecting the heart, while infections
with viruses, protozoa, fungi or bacteria clearly also can be
associated with heart disease and thus responsible for eliciting
an innate immune response and inflammation. The most common
virus infection type identified in the human heart are due to
the Coxsackie B group viruses, which can be detected in up to
50% of patients with dilated cardiomyopathy
[92] – work
which, however, remains controversial. As such one of the main
etiological factors in DCM is persistence of cardiotrophic viruses
(including enterovirus, adenovirus, human cytomegalovirus, parvovirus
B19, and influenza virus). The significance of viral injury
and inflammation in the etiology of certain cardiomyopathies
is further recognized by the most recent WHO/WHF definition
of inflammatory cardiomyopathy (DCMi) as a distinct entity adding
to the already existing five major forms of cardiomyopathies
[93,94]. Naturally occurring, as well as experimentally induced,
cardiovascular disorders have been associated with a range of
different causative pathogens
[95]. It is worth keeping in mind
that cardiovascular organs may also become "casualties" of inflammatory
processes that have a focus outside the heart
[2]. In sepsis,
TNF
has also been implicated as a key factor in development
of myocardial dysfunction
[24]. The canine and human cardiovascular
profile is remarkably similar in sepsis, and the sphingomyelin
pathway is believed to play a central role in TNF
-induced myocardial
depression in both species. In addition, these highly specialized
immune processes are not surprisingly of outmost interest in
thoracic surgery, as a systemic inflammatory response syndrome
(SIRS) due to cellular and humoral defense reactions are activated
in cardiac surgery using cardiopulmonary bypass
[96]. A line
of research has focused on the innate immune response associated
with open heart surgery and cardiac transplantation. One study
found that activation of an innate immune response through TLR4
contributes to development of chronic rejection after heart
transplantation
[97]. In children with congenital heart disease,
cardiopulmonary bypass elicits a prominent innate immune response,
and cardiac operations are associated with increased oxidative
stress, leukocyte activation and increased production of pro-
and anti-inflammatory cytokines
[98]. TLR2 and 4 are suggested
as putative signaling receptors for heat shock proteins (HSP)
in mediating synthesis of inflammatory cytokines in cardiac
surgery
[99]. In conclusion, evidence is rapidly accumulating
that the effector-molecules and signaling pathways of the innate
immune response have a marked impact on the heart in different
types of cardiac diseases. Ultimately, the myocardium's ability
to adapt to environmental stress determines if it will maintain
health or decompensate and fail
[80]. Still, further research
aimed at elucidating the molecular mechanisms behind potential
injurious and protective effects caused by the innate immune
response is pivotal toward gaining a better understanding of
many types of cardiovascular pathology.
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|
Fig. 3 Schematic danger model of intrinsic cardiac immunity illustrating factors which may initiate an innate immune response within the heart, leading to activation of intrinsic signaling pathways and production of certain immune mediators, which may have either protective or deleterious effects – ultimately resulting in cardiac stabilization or failure. Abbreviations – AMPs = antimicrobial peptides; JAK/STAT = Janus-kinase/signal transducer and activator of transcription; NF-B = nuclear factor kappa B; TLRs = toll-like receptors.
|
|
|
8. Summary
|
|---|
Inflammation underlies the pathogenesis of a range of the most
common cardiovascular diseases. Recent development and use of
genetically manipulated murine models such as transgenic/knock-out
mice have created an opportunity to pinpoint specific signaling
pathways underlying heart disease as well as evaluate therapeutic
strategies of candidates for clinical development. When formulating
treatment strategies in inflammatory processes in any organ
it is essential to understand tissue-specific pathways that
may either intensify or dampen cells and mediators of the inflammatory
system
[100]. It is important to recognize that amplification
and/or damping of the inflammatory reaction is likely to vary
between organs, and that the primary cellular composition of
an organ, as well as the matrix and mediators released by specialized
cells will govern the overall inflammatory reaction
[100]. Immunomodulatory
therapy has emerged as a possible new treatment modality in
CHF, as traditional cardiovascular drugs seem to have little
if any effect on the overall cytokine network. Selective gene
targeting to identify which PRRs play a central role in the
heart secondary to injury will likely be one obvious area for
future discovery. Overall, relatively little is still known
about how the innate immunity response is modulated in the heart
and it is therefore most likely that the learning curve will
remain rather steep in the most immediate future
[80]. In all
considerations it is pivotal to keep in mind the "Janus Face"
of innate immunity and inflammation as a system that aims to
heal but holds the capacity to destroy.
|
Notes
|
|---|
Time for primary review 27 days
1 Polypeptide sequences enriched in proline (P), glutamate (E), serine (S), and threonine (T) that are proposed to expedite protein degradation [101]. 
2 http://people.bu.edu/gilmore/nf-kb/lab/index.html.
|
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Abstract
1. Innate immunity and...