The duality of chemokines in heart failure.

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Expert Review of Clinical Immunology Downloaded from informahealthcare.com by Nanyang Technological University on 04/25/15 For personal use only.

The duality of chemokines in heart failure Expert Rev. Clin. Immunol. 11(4), 523–536 (2015)

Andrew A Jarrah and Sima T Tarzami* Department of Medicine, Division of Cardiovascular Research Center, Mount Sinai School of Medicine, 1 Gustave L Levy Place, Box 1030, New York, NY 10029, USA *Author for correspondence: Tel.: +1 212 241 8228 Fax: +1 212 241 4080 [email protected]

The failing human heart is a bustling network of intra- and inter-cellular signals and related processes attempting to coordinate a repair mechanism for the injured or diseased myocardium. While our understanding of signaling by mode of cytokines is well understood on a systemic level, we are only now coming to elucidate the role of cytokines in cardiac self-regulation. An increasing number of studies are showing now that cardiomyocytes themselves have not only the ability but also the mandate to produce signals, and play direct roles in how these signals are interpreted. One of the families of cytokines employed by distressed cardiac tissue are chemokines. By regulating the movement of pro-inflammatory cell types to sites of injury, we see now how the myocardium responds to stress. Herein we review the participation of these inflammatory mediators and explore the delicate balance between their protective roles and damaging functions. KEYWORDS: anti-cytokine therapies . chemokines . clinical trials . cytokines . heart failure . stem cell-based cytokine therapies

Heart disease is set to break 100 years as the number one killer in the USA and a major cause of death in the industrialized world by the end of the current decade. Each year, roughly three-quarters of a million Americans die from cardiovascular disease [1]. We can only expect a significant increase in the number of patients requiring cardiac care as the American population begins to age [1]. The need to not only mitigate heart disease, but develop penetrating and efficient therapies is an urgent one, and it relies heavily on our ability to effectively seek out targets and manipulate them. Cytokines & heart failure

The hypothesis that proinflammatory cytokines induce left ventricular dysfunction was first deduced from animal [2] and human studies of sepsis [3]. These hypotheses put forward that sepsis-associated cardiac dysfunction was caused by circulating myocardial depressant substances, later identified, in large part, to be inflammatory cytokines (including TNF-1a, IL-1b, IL-6, IL-2 and IFN-g) [4–6]. These ideas were supported from numerous animal [7–9] and in vitro studies [2,4,10]. Cytokine overexpression replicates a heart failure phenotype, and blocking the respective cytokine [11] or its respective receptors ameliorates the phenotype [12–15]. Further correlative studies demonstrate a positive informahealthcare.com

10.1586/1744666X.2015.1024658

relationship between cytokine levels and progressively worsening heart failure [13,16,17]. The substantive body of experimental and clinical observations as well as the obvious translational nature of the animal studies led to a series of multicenter clinical trials (TABLE 1) that used ‘targeted’ approaches to neutralize cytokines, such as TNF-a, in patients with moderate to advanced heart failure. However, these targeted approaches resulted in worsening heart failure, thereby raising a number of important questions about what role, if any, proinflammatory cytokines play in the pathogenesis of heart failure. Chemokines have also been implicated in the pathogenesis of various forms of heart failure where elevated levels have been found in patients with failing hearts [18,19]. Using animal studies, it has been demonstrated that chemokines play important regulatory roles in a myriad of physiological functions such as inflammation, autoimmunity, lymphoid organogenesis, vascular angiogenesis and cell survival [20–24]. Chemokines

Chemokines are a class of cytokines that have chemoattractant properties. They are small glycoproteins that signal through septahelical G protein-coupled receptors, a large and functionally diverse superfamily of cell surface

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Table 1. Anticytokine therapies: TNF-a inhibition. Drug

TNF-a antagonists

Mechanism of action

Clinical trials

Outcome

Ref.

Etanercept

A soluble p75 TNF-a receptor fusion protein

Binds and inactivates TNF-a

RENAISSANCE (USA) study for heart failure

Failed to show any improvements

[11,172]

Etanercept



RECOVER study for heart failure


[169,170,172]

Etanercept



RENEWAL update on (RENAISSANCE + RECOVER) for heart failure


[171,172]

Infliximab

A chimeric (mouse/human) anti-TNF-a Ab

Neutralizes soluble and membrane-bound TNF-a

ATTACH study for heart failure


[168]

Adalimumab

A fully human monoclonal anti-TNF-a Ab


PREMIER study for rheumatoid arthritis

Showed benefit in combination with methotrexate

[173]

Certolizumab pegol

An antigen-binding fragment (Fab’) of a humanized mAb coupled to polyethylene glycol


RAPID1 & 2 study for rheumatoid arthritis

Showed benefit

[174]

Certolizumab pegol

An antigen-binding fragment (Fab’) of a humanized mAb coupled to polyethylene glycol


FAST4WARD study for rheumatoid arthritis

Showed benefit

[175]

Golimumab

A human anti-TNF-a mAb


PURSUITS study for colitis

Showed benefit

[176]

mAb: Monoclonal antibody.

receptors mediating a large number of cellular responses to extracellular stimuli [25–27]. There are significant structural and regulatory differences in the functional mechanisms of cytokine receptors such as the TNFR and IL-2R as compared to chemokine receptors. First, cytokines are proinflammatory molecules, induced in infection and immune activation whereas chemokine receptors are expressed either inducibly (inflammatory) or constitutively [28]. Chemokines have been classified into four main subfamilies depending on the spacing of their first two cysteine residues: CXC (or a-chemokines), CC (or b-chemokines), CX3C and XC. All of these proteins exert their effects by binding with G protein-coupled receptors called chemokine receptors that are found on the surfaces of their target cells. In addition to their chemotactic and cell homing properties, both chemokines and their receptors are expressed and have entirely distinct biological functions on many cell types in the body including fibroblasts, endothelial cells, smooth muscle cells, cardiomyocytes, neurons and so on [29–32]. While much of their form and function has been uncovered on the universal level, there are still unresolved questions when put into the context of the heart. In the disease state, the characterization of these receptors and their ligands is ongoing, with the role of chemokines being understood only recently. Chemokines & heart failure

Observational studies have demonstrated the presence of certain chemokines within the dysfunctional heart [33–36]. The work of our laboratory and others has further elucidated chemokine 524

receptors to be members of the CXC and C-C-chemokines [23,37,38]. The pathogenesis of dysfunction stemmed from a variety of etiologies including myocarditis [39,40], as well as dilated and ischemic cardiomyopathies [19,33,41]. In explanted hearts from 10 patients with end-stage heart failure, using RNase protection assays and immunohistochemistry, Dama˚s et al. demonstrated particularly high mRNA levels of CCL2 [37]. A transgenic approach overexpressing CCL2 resulted in a cardiomyopathic phenotype [42]. Conversely, treatment with 7ND, an N-terminal deletion mutant of the human CCL2 gene, improved survival, attenuated left ventricular dilatation and decreased contractile dysfunction compared with controls in a murine ischemic cardiomyopathy model [43]. None of these studies, however, have postulated potential mechanisms for chemokine effects on myocardial function other than to suggest that the infiltration of lymphocytes and monocytes, along with concomitant cytokine production [43], into the failing myocardium may lead to reversible or irreversible damage of the cardiac muscle [20,44]. The duality of chemokines has at times been confounding, yet the ability of the same axis to play opposite roles suggests that the variability in these signals depends on the injury or disease environment in which they are observed in addition to the cell types that are expressed in. By method of example, we take IL-8 or CXCL8, one of the first chemokines implicated in a cardiac disease state, as a quick study. In the setting of ischemic reperfusion (I/R) injury, studies have illustrated that CXCL8 is a major player responsible for the recruitment of neutrophils, which resulted in greater myocardial injury [20]. Expert Rev. Clin. Immunol. 11(4), (2015)


Chemokines in heart failure

Conversely however, our group has shown in vitro that macrophage inflammatory protein-2 (MIP-2 or CXCL2), one of the many murine IL-8 homologues, promoted cell survival by reducing apoptosis [23,24]. The dual nature of these signaling proteins is not segregated to a particular subset; take Regulated on Activation Normal T cell Expressed and Secreted (RANTES or CCL5) and CCL2, which have been shown to play a malignant role in the dysfunction of the myocardium [43,45,46]. However, in experimental animal models of vascular injury, CCL5 exerts proangiogenic effects in vivo and in vitro [47]. Our group and others have also demonstrated that CCL2 is proangiogenic and safeguards cardiomyocytes from hypoxia-induced cell death [22,48], yet those same cardioprotective effects are diminished in the setting of I/R injury where inflammatory cell recruitment was increased [38]. Stromal-cell derived factor-1 (SDF-1 or CXCL12) is yet another prime illustration of the ‘double-edged’ role of cardiac chemokines. In a scenario post-myocardial infarction (MI), CXCL12 has been shown to recruit stem cells and promote neovascularization. Yet Liehn et al. have recently shown that the selective inhibition of CXCL12’s receptor CXCR4 by the antagonist AMD3100 reduced scar formation and enhanced cardiac contractility [49]. The juxtaposition of these findings emphasizes the complexity of these chemokines in disease supporting the notion that we cannot simply separate the various players into the good and the bad, protective or maladaptive. We hope to shed some light on the divisions in this review as we characterize the diverse roles that chemokines play in heart failure. Because we cannot segregate the effects of these chemokines on the heart from other body systems, we will very generally mention the effects of chemokines in a systemic context. Additionally, we will outline the challenges of chemokine/cytokine-based immunotherapies and further discuss their dual function in relation to development of efficient treatment strategies for heart disease. CCL2 (MCP-1)

The CCL2/MCP-1 family is a subfamily of the CC chemokines and comprised of four members [50]. CCL2 negotiates a response in the cell by interacting with its main receptor, CCR2. CCR2 and CCR4 are two cell surface receptors that bind CCL2 [51]. CCL2 is located on 17q11.2 in humans and is the gene product of the JE gene in mice [50,52]. The immature peptide is composed of 99 amino acid residues, with a 23-amino acid signal sequence being cleaved to give the mature protein at 76 amino acids in length [50]. CCL2 is both a potent monocyte and activated T-cell chemoattractant as well as a primary activator for macrophages [53,54]. CCL2 is primarily secreted by monocytes, macrophages and dendritic cells. Apart from known cell types, CCL2 is also expressed in a larger panel of other cell types including osteoblasts, neurons, astrocytes, microglia, smooth muscle cells, fibroblasts and cardiomyocytes [23,32,55–57]. Given the fact that these cell types also express CCR2 (a CCL2 receptor) on the cell surface, these cells can both generate and respond to inflammatory responses, in either an autocrine or a paracrine manner. informahealthcare.com

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Published findings have demonstrated the induction of both CCL2 and its receptor CCR2 and implicated them in an assortment of diseases characterized by monocytic infiltrates, such as psoriasis, rheumatoid arthritis and atherosclerosis [58]. There has been a tremendous amount of evidence mounting against CCL2 as one of the main inflammatory cytokines involved in the failure of the heart. Several clinical studies report CCL2 upregulation in patients with diminished cardiac activity and with the infiltration of mononuclear cells marked as the key culprit for cardiac disease development and progression [19,37]. While we are careful not to peg maladaptive to any chemokine in our discussion, CCL2 hyperactivity has been observed in the context of various diseases and injuries. In one study, researchers identified significantly elevated CCL2 levels in the sera of patients 24 h post-MI [59]. The proinflammatory role of CCL2 in congestive heart failure has been well documented [33,60], with several studies concluding that chemokine levels were inversely correlated with left-ventricular ejection fraction, a main determinant of cardiovascular well-being [19]. Additionally, we see clear-cut roles in the pathogenesis of atherosclerosis [61,62], cardiomyopathy [39,63] and myocardial ischemia [64]. However, in addition to pathological effects brought about by the presence of potentially damaging inflammatory cells, that is, monocytes and macrophages, ‘observations suggest that CCL2 was also involved in the repair process.’ CCL2 is shown to act directly on endothelial cells and induce angiogenesis through the induction of VEGF [22]. Moreover, CCL2 expression was reported to protect cardiac myocytes from cell death in vitro and in vivo [23,48]. This protective effect of CCL2 was attributed to its autocrine effect on cardiomyocytes and its paracrine effects on endothelial cells. The systemic effects of CCL2 in disease mechanisms have also been well studied. While the expression of this chemokine in the heart is our primary motivation, we must understand that any expression at all can lead to a global effect. CCL2 has been implicated in a host of various diseases including inflammatory bowel disease [65], rheumatoid arthritis, diabetes [66], HIV-associated, inflammation-mediated neuronal injury [67,68], ischemia-associated neuronal death [69] and tumor angiogenesis [70]. The hallmark of this chemokine indeed is its excellent ability to recruit proinflammatory cell types to an area of injury or act as a maladaptive protagonist and lead to increased cell damage or death during pathogenic processes. Chemokinebinding protein, Evasin-4, has been shown to selectively inhibit CC-chemokine-mediated bioactivities. In the study done by Braunersreuther et al., intraperitoneal injections of Evasin-4 during MI significantly reduced cardiac injury/inflammation and improved survival in mice [71]. However, as was mentioned earlier, CCL2 has been shown, in fact, to act in prosurvival capacities [48]. In studies by Morimoto et al., cardiac CCL2 overexpression under the control of the a-cardiac myosin heavy chain promoter (MHC/CCL2 transgenic mice) was shown to not only prevent cardiomyocyte death in I/R injury [72] but also prevent cardiac dysfunction and remodeling in the context of MI [73]. The fact that CCL2 was exclusively 525


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overexpressed in cardiomyocytes may significantly contribute to observed protective effects. It is widely accepted that the loss of cardiac myocytes is a major contributor in the progression of cardiac remodeling and heart failure. As such, the overexpression of CCL2 exclusively in cardiomyocytes may have emphasized protective effects while limiting its ability to recruit proinflammatory cell types, thus limiting a final, detrimental effect. Although these data suggest CCL2/CCR2 is protective during the development and progression of cardiac disease, they also underscore that axis activation in vivo may result in two contradictory effects in the intact heart: death caused by the recruitment of leukocytes and survival from direct cytoprotection or indirect angiogenesis. The net effect of CCL2/ CCR2 signaling in the intact animal lies on the magnitude of this protection relative to CCR2-mediated chemotaxis of potentially damaging inflammatory cells. This interplay clearly delineates why future studies must accurately characterize the autocrine and paracrine signaling events downstream of CCL2/ CCR2 in cardiac myocytes, neutrophils and other heart residence cells. This may provide a means to selectively activate cytoprotective pathways while inhibiting chemotaxis of potentially damaging inflammatory cells, thereby limiting myocardial damage while improving cardiac function. CCL5 (RANTES)

CCL5/RANTES is known to be a very potent chemoattractant for a variety of cell types including T lymphocytes, natural killer cells, monocytes and eosinophils [74,75]. CCL5 is located on human chromosome 17q11.2 and is a more typical ligand in that it binds to multiple receptors, namely CCR1, CCR3, CCR4 and CCR5 [76]. CCL5 is released by many cell types, including astrocytes, endothelial cells, smooth muscle cells, macrophages, activated T cells and platelets [77–80]. CCL5 has been shown to contribute to angiogenesis by stimulating endothelial cell sprouting and tube formation in angiogenesis assays [81]. The incubation of endothelial cells from different organs with CCL5 resulted in a rearrangement of these cells and the formation of pseudo-vessels of human appendix endothelial cells [82]. The duality of CCL5 expression is associated with the ability to induce leukocyte recruitment and activation [83] and may play a role in both chronic inflammation and wound repair [84]. CCL5 has been reported to regulate the inflammatory pathways that promote atherosclerosis; it is highly expressed in human transplant-associated accelerated atherosclerosis [75]. Blocking CCL5-mediated signaling in vivo resulted in a significant reduction of atherosclerosis in animal models tested [75]. Moreover, different genetic polymorphisms of CCL5 are associated with susceptibility to coronary artery disease (CAD) and stent restenosis; these polymorphisms were discovered in the promoter region of CCL5 [85]. CCL5-403A allele polymorphism was associated with the presence and severity of CAD independently of conventional cardiovascular risk factors, eventually leading to clinically significant phenotype alterations. 526

In the context of cardiovascular disease, two fairly recent studies have shown that CCL5 may play a leading role in the death of the injured myocardium. In the murine model of MI used by Montecucco et al., researchers saw that the inhibition of CCL5 using a monoclonal antibody (mAb) resulted in a smaller infarct size 24 h post-MI and increased general survival and cardiac function at the conclusion of the study (21 days) [45]. Braunersreuther et al. observed a similar result in their I/R model; intraperitoneal injection of a CCL5 antagonist leads to an overall decrease in the levels of complimentary chemokines, namely CCL2, and perhaps more importantly oxidative stress and cardiomyocyte death [86]. Thus, the beneficial effect of an anti-CCL5 mAb was associated with reduced chemotaxis of potentially damaging inflammatory cells into the reperfused myocardium, as well as a decrease in the expression of CCL2, oxidative stress and apoptosis [86]. Indeed most of the published data on cardiac disease indicate that CCL5 inhibition may exert cardioprotective effects during early myocardial reperfusion through its anti-inflammatory properties. Interestingly, the prosurvival roles of CCL5 are also reported in brain development; CCL5 promotes the growth and survival of human first-trimester forebrain astrocytes [87]. Moreover, IFN-g, a cytokine that is critical for innate and adaptive immunity, was required for CCL5 effects because blocking IFN-g with an antibody reversed the effects of CCL5. These findings yet again serve as another example of how intertwined the cytokine/chemokine networks can be. Chemokines and their receptors can function directly on some cell types but they can also indirectly affect cell fates through the activation of other cytokines expression, that is, IFN-g. CXCL2 (MIP-2)

CXCL2/MIP-2 was first characterized in 1989 by Cerami et al.; CXCL2 was shown to be a functional murine homologue of human CXCL8, a close relative of CXCL1 and a chemokine that is a primary activator for polymorphonuclear leukocytes [88]. Further studies have shown that monocytes and macrophages are the main sources of CXCL2, which is chemotactic for hematopoietic stem cells in addition to polymorphonuclear leukocytes [89,90]. CXCL2 is located on human chromosome 4q21.1 and associates with its only known receptor, CXCR2 [76]. We note that functional and structural similarities exist between CXCL2 and other a-chemokines such as CXCL1, -5, -6 and -8. CXCL2 belongs to the group of CXCchemokines that have a specific amino acid sequence of glutamic acid-leucine-arginine (abbr. ELR) immediately before the first cysteine of the CXC-motif (ELR+). ELR+ CXCchemokines specifically induce the migration of neutrophils, and the presence of this motif is associated with a proangiogenic function [91]. As we should suspect, CXCL2 has been implicated in a number of systemic diseases. Wu et al. demonstrated the increased expression of CXCL2, as regulated by the differential expression of microRNAs in a swath of gastrointestinal diseases including ulcerative colitis and Crohn’s disease [92], CAD [93] Expert Rev. Clin. Immunol. 11(4), (2015)



and I/R injury [94]. It has become apparent over the past years that many chemokine receptors display marked promiscuity of ligand binding, which greatly complicates studying their potential roles in a disease. For example, CXCR2 also binds to the cytokine macrophage migration inhibitory factor (MIF), which plays a critical role in inflammatory diseases and atherogenesis. Abrogation of MIF binding, but not CXCL2, the canonical ligand of CXCR2, resulted in a significant reduction of atherosclerosis and reduced monocyte infiltrate in the plaques of animal models tested [93], implicating that atherogenic or inflammatory monocyte recruitment induced by CXCR2 relies not only on CXCL2 binding but also on MIF binding. In I/R injury, post-ischemic inflammatory reaction is a major determinant of the extent of cardiac injury and CXCL2 is considered an important mediator involved in I/R injury through modulating neutrophil recruitment [95]. Neutrophil release of proteolytic enzymes, reactive oxygen species and inflammatory cytokines have been identified as the main culprits in mediating organ damage in early phases of reperfusion [95]. Selectively neutralizing CXC-chemokine bioactivity, for example, CXCL2, using chemokine-binding protein (Evasin-3) during MI, significantly reduced the infarct size by preventing neutrophil recruitment and reactive oxygen species production in myocardial I/R [95]. In contrast however, our laboratory and others have shown that CXCL2 has protective effects in the setting of ischemia/hypoxia injury [23,96]. CXCL2 is suggested as an effective preconditioning therapy against increasingly severe ischemic episodes [96]. CXCL2 overexpression inhibits myocyte apoptosis in vitro, but opposite effects are also observed in vivo; protection seems to have been masked by infiltrating inflammatory cells [23]. The fact that CXCL2 is expressed in cardiac cells and can differentially regulate cardiac cell survival but simultaneously recruit inflammatory cells that may potentially cause cardiac injury post-reperfusion reiterates the point that cardiomyocytespecific overexpression of CXCL2 might be advantageous as it would bypass potential inflammatory roles. CXCL12 (SDF-1)

CXCL12, along with one of its receptors CXCR4, is one of the most studied ligand–receptor pairs [97]. While technically a CXC-chemokine due to an intervening cysteine residue at the N-terminus, typical of CXC’s, the primary structure of CXCL12 appears to be equally related to C-C chemokines [98,99]. CXCL12 is located on human chromosome 10q11.21. Even though CXCL12 is an ELR-chemokine, and is expected to have angiostatic properties, it is well known that CXCL12 is angiogenic [100]. This chemokine is critical to fetal development given that deletion of either the ligand [101] or receptor [102] results in an embryonic lethal mutation resulting from cardiovascular septal and gastrointestinal vascular defects; deficiencies in hematopoiesis and myelopoiesis and deficiencies in neutrophil and B-cell production. This finding coupled with the phenotypic similarity of CXCL12- or CXCR4-deficient mice suggests that this axis comprises a monogamous signaling unit in vivo [103], which is a marked contrast to the typically informahealthcare.com

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promiscuous chemokine axes. We should note here however that recent studies have shown that CXCR7, previously believed to be an orphan receptor, is now known to associate with CXCL12 and has thus been dubbed the CXCL12 alternative receptor [104]. Furthermore, CXCR7 has been shown to heterodimerize with CXCR4, suggesting that CXCR7 may act as a modulator of this axis’ signal in various cell types and capacities [105]. CXCL12 is constitutively produced by stromal, dendritic, myocardial and endothelial cells [30,106,107]; the highest concentrations of this chemokine are found in bone marrow, spleen red pulp and lymph node medulla [108]. Various cell types ubiquitously express CXCR4, including endothelial cells, smooth muscle cells, neurons and cardiomyocytes [30,109–111]. Both CXCR4 and CXCL12 are expressed by and function in cardiomyocytes. Increased expression of this axis has been observed in the myocardium of patients with heart failure, suggesting that there may be cardiomodulatory functions [37,111]. Recently published findings support that CXCR4 may impact b-adrenergic processes such as heart failure progression. Data have shown that this chemokine negatively regulates acute activation of b-adrenergic receptor signaling in vitro inhibiting isoproterenolinduced L-type calcium channel activity, negates phospholamban phosphorylation and limits peak calcium transients and myocyte contraction [111]. These data suggest CXCR4 may impact b-adrenergic processes such as heart failure progression. The broad expression pattern of both receptor and ligand make tight control of receptor responsiveness necessary to maintain signaling specificity. CXCL12/CXCR4 plays an important role post-acute MI yielding a potent chemotactic signal for recruiting circulating CXCR4+ progenitor cells to the damaged myocardium. However, the increased CXCL12 signal is transient, lasting approximately 24 h post-MI [37,112]. Even though the CXCL12/CXCR4 axis has been shown to recruit stem cells and promote neovascularization post-MI, it was also reported that the selective inhibition of its receptor, CXCR4, by the antagonist AMD3100, reduced scar formation and enhanced cardiac contractility [49]. Yet Dai et al. recently reported that long-term AMD3100 (CXCR4 specific antagonist) administration leads to increased scar size and adverse ventricular remodeling in murine models of chronic MI, further implicating the beneficial effect of the CXCR4 axis post-MI [113]. Finally, adenoviral overexpression of CXCR4 exacerbated cardiac dysfunction in a rat model of I/R injury through augmentation of TNF-a expression and inflammation [114]. Given the keen interest in using CXCL12 as a therapeutic target in cardiovascular disease [115,116], in order to better understand the protective versus maladaptive effects of CXCL12 and CXCR4 in cardiac injury models, it is essential to determine the direct effects of CXCL12 and its receptor, CXCR4, on myocardial function at the cellular level. As we further define the role of the CXCL12/CXCR4 in the heart, we should note that the axis is also well studied in the context of HIV infection. HIV utilizes CXCR4 as a co-receptor with CCR5 [117,118]. Heart muscle disease is the most important 527


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cardiovascular manifestation of HIV infection [119,120]. This may take the form of either a dilated cardiomyopathy [121,122] or isolated left or right ventricular dysfunction, is associated with a poor prognosis, and results in symptomatic heart failure in up to 5% of HIV patients [119,123]. Autopsy studies have shown that up to 25% of HIV-infected adults have dilated cardiomyopathy and up to 52% have myocarditis [123]. WHIM syndrome is the first disease identified in humans due to a mutation in a chemokine receptor [124]. The acronym WHIM syndrome was coined to describe an unusual form of congenital neutropenia characterized by warts, hypogammaglobulinemia, immunodeficiency and myelokathexis (the apparent retention of mature neutrophils in the bone marrow) [125]. WHIM syndrome is caused by heterozygous truncating mutations in the cytoplasmic tail domain of the gene encoding CXCR4 [126]. The CXCR4 WHIM mutant fails to internalize upon CXCL12 binding. This constitutive signaling event results in increased retention of neutrophils in the bone marrow and enhanced migration towards CXCL12 [127–129]. Family members of WHIM patients have not undergone systematic cardiac evaluations. There is, however, a 10% incidence of cardiac abnormalities, the most common of which are ventricular septal defects, pulmonary atresia and tetralogy of Fallot [124,130]. The overwhelming majority of aforementioned studies have focused on chemokine expression as a prominent feature of the post-infarction inflammatory response and therefore solely on chemokines’ role in inflammatory leukocyte recruitment [131]. These studies have not addressed the possibility of an autocrine/paracrine effect wherein the chemokine receptors, present on the cardiomyocytes surface, modulate functional responses to stress. During the past decade, a number of studies have elucidated some of the mechanisms by which inflammatory mediators cause heart dysfunction. Their works, regardless of whether cytokines or chemokines were questioned as the mediators of negative inotropy, have suggested paracrine pathways. As we delve deeper, the roles of cytokines and chemokines in scores of clinical conditions will continue to be clarified. These targets could have profound implications in disease management and treatment; which has however been a difficult problem to address in humans due to an apparent lack of genetic abnormalities involving chemokines and their receptors. Stem cells & stem cell-based cytokine therapies

While there is still much unknown, within the past 20 years, there has been a tremendous effort from all walks of the scientific community to characterize and mitigate diseases of the human heart. As a strategy for repairing damaged cardiac tissue following MI, one potentially promising approach involves the use of cell therapy [132–136] to prevent or reverse heart failure (FIGURE 1) [137]. Work began with committed cells such as skeletal myoblasts [138], but recently the field has expanded to explore a wider range of cell types. Most types of stem cells that have been implemented in clinical practice are bone marrowmononuclear cells, BM-MSCs (bone-marrow-derived mesenchymal stem cells), adipose-derived stem cells and endothelial 528

progenitor cells. However, these stem cells yield a very modest improvement in cardiac function [133,139–145]. Endogenous cardiac stem or progenitor cells have also been considered important targets to explore, and three clinical trials (SCIPIO [146], CADUCEUS [147] and ALCADIA [148]) have been conducted to test the therapeutic efficacy of these cells for ischemic heart disease. Even with encouraging initial results, however, controversy still exists regarding the ability of these cells to acquire cardiac cell lineages, promote myocardial regeneration and reconstitute the amount of mass lost after infarction. Interestingly, there are multiple studies in the literature which demonstrate that the effect of adult cell therapy is enacted by the release of paracrine factors that promote repair by mobilizing endogenous progenitors, that is, cytokines, chemokines and growth factors [112,149–152]. One such example is the study by Marba´n et al. which demonstrated that cardiosphere-derived cells are capable of secreting large amounts of angiopoietin-2, bFGF, HGF, IGF-1, VEGF and CXCL12. These findings suggest that upside effects seen in the CADUCEUS trial, which utilized cardiosphere-derived cells, may be due to the secretion of the paracrine factors which in turn stimulated cardiac repair post-MI [152]. The question still remains however: “should we administer cells or cell products to promote cardiac repair and/or mobilize endogenous cardiac precursors?” This has led to a recent clinical trial (ACRX-100) in which researchers attempted to mobilize a patients’ own cardiac stem cells using CXCL12 gene therapy as a homing signal [153]. In this study, researchers used the CXCL12 to draw stem cells to the site of injury and enhance the body’s stem cell-based repair process [154]. This study was different from other cell therapies that typically involve extracting and expanding the number of cells, then delivering them back to the subject. Even though the results of ACRX-100 seemed promising, there are some concerns regarding the results: they had a very small group of participants; and there was no placebo group. Although this approach could be promising for patients with ischemic heart disease, the potential benefits of these findings must be accepted with caution. We should note that current research is now focused on using stem cell technology/transplantation to explore possible tissue regeneration capabilities. A major hurdle in the stem cell therapy is the optimization of such techniques; therapies are not yet able to safely transplant a significant number of cells into the myocardium at the site of injury or infarct. There are many animal models that are currently being used in preclinical experimental models, however, limitations have been identified in all. The main approaches currently being used to deliver these immune mediators, (stem-) cells and/or vectors, in preclinical animal studies of acute MI, include intramyocardial injections, epicardial deposition and intracoronary or transvascular application. Published data comparing intravenous, intracoronary and endocardial delivery of MSCs immediately following infarction in a paracrine model suggests that intracoronary delivery of MSCs was associated with a significantly greater number of engrafted MSCs compared to either Expert Rev. Clin. Immunol. 11(4), (2015)


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Stem cell renewal


3) Cardiac differentiation

Cardiac stem cells

CXCL12

BM-derived stem cells

Cardiac myocytes

Myocardial regeneration Exogenous chemokines/ growth factors and/or stem cells

Damaged myocardium 2) Cardiac stem cells mobilization CXCL12

Acute MI: Endogenous CXCL12 released from heart 1) BM-derived stem cells mobilization

Figure 1. Stem cell-based cytokine therapy: in acute myocardial ischemia (MI), cardiac repair involves stem cell mobilization, retention, and trans-differentiation into functional cardiomyocytes. Upregulation of CXCL12 can act as a homing signal to further assist the recruitment of these stem cells.

percutaneous endocardial delivery or intravenous delivery. Nevertheless, the percentage of retained/engrafted cells was low in all three groups [155,156]. The biggest advantage of using direct injection is that it helps to localize implanted cells into the infarct region and improves graft retention. However, successful chemokine protein deliveries are affected by barriers including the rapid diffusion of chemokines and proteolytic cleavage of chemokines by proteases that are activated in injured tissues [157]. To circumvent this drawback, the epicardium and pericardial sac may offer a less invasive approach for intrapericardial delivery. The pericardium encloses the whole heart, creating a small fluidfilled compartment; this offers an ideal environment for local delivery of (stem-) cells and/or vectors to the heart. However, migration of cells across the visceral pericardium into the myocardium is necessary for the success of this approach. Moreover, there is little known about the efficiency and efficacy of cells delivered via this approach. The molecular mechanisms for stem cell mobilization have not been identified. It has been assumed that stem cells migrate similarly to leukocytes, even though, there has been little evidence supporting it. Future studies will be needed to optimize a proper transmigration and informahealthcare.com

subsequent cross-talk between the engrafted cells and the host myocardium. For patients presenting an acute MI, the intracoronary delivery approach will be the less invasive approach and can be accomplished easily following catheter intervention to reestablish coronary flow. The results of preclinical animal studies for intrapericardial delivery have been very promising; in particular, using cytokine/chemokine seeded biomaterials for intrapericardial delivery. This approach allows for a time-controlled release of these proteins using biodegradable hydrogels which presents a potential advantage [158]. Cytokine-based immunotherapy: anti-cytokine therapies

Cytokine-based immunotherapies are widely used in cancer treatment, where the immune system is harnessed to eradicate cancer [159,160]. Animal studies have shown that cytokines have broad antitumor activity; a cytokine-coordinated response to a target antigen has been well translated into a number of cytokine-based immunotherapy approaches for cancer [161,162]. In spite of this, there is overwhelming evidence to support that the immune mediators (inflammatory cytokines and 529


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chemokines) can contribute to cardiac dysfunction and the progression of heart failure by promoting cardiac hypertrophy, cell death and/or fibrosis. As such, cytokine-based immunotherapies haven not been yet successful in the treatment of heart failure. This may be partially due to the fact that chronic heart failure is a multifactorial disease; in addition to the immune system, there are implications in a variety of body mechanisms including the neurohormonal system, which are known to activate in response to the heart failure state. Moreover, activation of the neurohormonal systems in response to cardiac injury can have deleterious effects on the heart, which ultimately causes the disease to progress [163,164]. Since the cytokine network is compromised of both inflammatory and anti-inflammatory immune mediators, any inflammation associated with aforementioned diseases might be the result of an imbalance of the two opposing arms of the cytokine network: an increase in inflammatory cytokines and/or a decrease of anti-inflammatory cytokines. Therefore, to create an equilibrium, immunotherapies for heart failure have to target inflammatory mechanisms in a way that decreases the relative ratio of inflammatory cytokines to anti-inflammatory cytokines. Based on this premise, the ACCLAIM trial (Celacade immunotherapy) was designed using a novel non-drug treatment strategy to specifically downregulate proinflammatory cytokines and increase anti-inflammatory cytokines in heart failure patients [165]. The trial was reported safe and well tolerated and seemed to show promise in reducing risk of mortality or morbidity. This trial is a marked contrast from the majority of current efforts, given that inflammatory cytokines are believed to negatively influence contractility and remodeling processes during progression of chronic heart failure. To date, most researchers are more interested in anti-cytokine therapy to improve myocardial performance and which is reflected in the design of past clinical trials (TABLE 1). As we previously mentioned, increased circulating levels of proinflammatory cytokines, that is, TNF-a, IL-1 and IL-6, have been reported within the failing myocardium [16,18,19,33,37,166,167]; among these factors, TNF-a has received the most attention. TNF-a is elevated in the serum of patients with heart failure, and the magnitude of the increase is directly correlated with the severity of disease [16]. Indeed, overproduction of TNF-a by cardiomyocytes is sufficient enough to cause pathological changes in the myocardium consistent with heart failure, including ventricular remodeling, interstitial fibrosis and cardiomyocyte apoptosis [8]. Thus, it was postulated that inhibition of TNF-a might favorably modify the progression of heart failure; however, the ATTACH (Anti-TNF-a Therapy Against Congestive Heart failure) [168] trial failed to show any improvements in patients with moderate-to-severe heart failure. Results of this study were followed up by unfavorable outcomes of other antiTNF-a clinical trials such as the Randomized Etanercept North American Strategy to Study Antagonism of Cytokine (RENASSANCE), the Research into Etanercept: Cytokine Antagonism in Ventricular function (RECOVER) and RENEWAL (combine analysis on RENASSANCE + RECOVER) [11,169–172]. One 530

interpretation of the failure of these anti-cytokine approaches in comparison to other clinical trials [24,173–176] is that the disease is multifactorial in nature; targeting a single component of the inflammatory cascade without regard to the cellular origin or the mechanism underlying the chronic expression is not a sufficient approach. Conclusion

The focus here though has been to describe the parallel process in the intact heart in which the activity of these chemokines/ cytokines can be both protective and detrimental. Summarized are the rather elusive roles of these proteins and how characterizing these receptor–ligand axes are of critical importance if we are to translate their noted success in cancer treatment and produce efficient cardiac therapies. As of yet, our characterizations cannot do much beyond describe these cytokines/chemokines as both protective and detrimental. Aside from the potential in stem cells to promote cardiac repair, current therapies have failed to address autocrine/paracrine effects in this process. Although both views (stem cell-based cytokine therapy and anti-cytokine therapy) have merit in using cytokines/ chemokines as new targets for therapy in myocardial failure, the results of these past clinical trials suggest that we simply have not targeted these mediators with the proper modes when considering the context of heart failure. The question remains unanswered: “Are the previous targets, namely anti-cytokine therapies, still relevant or should we look for novel targets?” We believe that increased attention should be given to how proinflammatory mediators are modulated and what is the underlying cell network that serves both as an important source and effector target for cytokines in order to develop more specific immunomodulating agents to combat chronic heart failure. Furthermore, stem cell-based cytokine therapy may play a pivotal role in cardiac repair, and regardless even of its shortcomings, is a promising approach for patients with acute MI. Drawbacks stem from the fact that stem cell-based therapies are at an early stage and much needs to be done to optimize stem cell mobilization, retention and engraftment into the failing heart. With further research and tuning, however, this approach may hold promise. Expert commentary

The jury is still out on whether or not the future of non-invasive, chemokine-dependent therapies is a rich one; further development and refinement of current strategies may one day lead to impressive and powerful techniques to combat cardiac disease. However, the complexity of these targets leads us to believe that therapies will need to be highly specific, thus posing the question of whether or not pursing such non-general treatments is appropriate. The coming years will be a pivotal point in the progression or expulsion of these treatments. Five-year view

Findings from numerous studies support the feasibility of cardiac repair using stem cell mobilization to the infarcted heart Expert Rev. Clin. Immunol. 11(4), (2015)



with factors such as cytokines/chemokines; however, these factors have additional direct effects on the recruitment of inflammatory cells into the injured heart, and it is difficult to determine the beneficial contribution of chemokines in stem cell mobilization from those associated with inflammatorymediated injuries. Since many chemokines subfamilies are expressed on cardiac cells, it is hoped that their respective autocrine/paracrine signals in the heart, and more importantly the injured heart, will be characterized in the near future.

Review

This will allow for the development of more adept therapeutic remedies. Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Key issues .

The present review provides a critical overview of the clinical status of immunotherapy in patients with a failing heart.

.

The duality of chemokines has been at times confounding, yet the ability of the same axis to play opposite roles suggests that these signals operate differently depending on the injury or disease environment.

.

A related strategy for cardiac repair involves stem cell mobilization with factors such as cytokines/chemokines (stem cell-based cytokine therapies).

.

There has been an interest in anti-cytokine therapy to improve myocardial performance; however, past clinical trials have failed to show any clinical benefits.

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Heart failure: chapter 3. Underlying pathology in heart failure 'Failure of the circulation versus failure of the heart'

Targeting the duality of cancer.

The duality of teleost gonadotropins.

It takes two to tango: monocyte and macrophage duality in the infarcted heart.

Duality in retinocerebellar projections in the rabbit.

[Perioperative heart failure - acute intraoperative heart failure].

The kidney in heart failure.

Heart failure in the elderly.

On the duality of resilience and privacy†.

Heart failure: another new PARADIGM in treatment for heart failure?

Heart failure: chapter 8. Education and counselling of heart failure patients: the role of a heart failure clinic.

The role of echocardiography in heart failure.

Heart failure: chapter 6. Pharmacological treatment of chronic heart failure.

Benefits of an integrated heart failure service at critical periods in the heart failure disease trajectory.

Dopamine in the treatment of heart failure.

Heart failure: chapter 8. Treatment of end-stage heart failure.

Heart failure. BMD a predictor of incident heart failure.

Skeletal muscle failure in heart failure.

Troponins in heart failure.

Potassium in heart failure.

Antithrombotics in heart failure.

Biomarkers in heart failure.

Potassium in heart failure.

Frailty in heart failure.