Published online before print June 19, 2008, doi: 10.1161/ATVBAHA.107.161174
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© 2008 American Heart Association, Inc.
Brief Reviews |
Chemokines in Atherosclerosis
An Update
From the Institute for Molecular Cardiovascular Research (IMCAR), University Hospital, RWTH Aachen University, Germany.
Correspondence to Christian Weber, MD, Institut für Molekulare Herz-Kreislaufforschung, Universitätsklinikum der RWTH Aachen, Pauwelsstrasse 30, 52074 Aachen, Germany. E-mail cweber{at}ukaachen.de
Series Editor: Christian Weber
ATVB In Focus
Chemokines in Atherosclerosis, Thrombosis, and Vascular Biology
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Abstract |
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Top
Abstract
IntroductionThe fundamental importance of chemokines for atherogenesis, progression, and destabilization of atherosclerotic plaques is now widely appreciated, but the degree of complexity, specificity, and cooperativity harnessed by these signal molecules to govern atherogenic cell recruitment and homeostasis is still being refined. Since the role of chemokines in atherosclerotic vascular disease has been reviewed in this journal, significant progress has been accomplished in defining the regulation of chemokine expression and function in atherosclerosis. In this update, we will highlight these recent developments, in particular the identification of components regulating the transcriptional machinery of the proatherogenic chemokine CCL5, distinct roles of its receptors CCR1 and CCR5 in plaque formation and immunobalance, and differential site- and stage-specific effects of T cell–activating chemokines and their receptors, eg, CXCL10 and CXCR3. The contribution of the transmembrane chemokines CX3CL1 and CXCL16 with their respective receptors CX3CR1 and CXCR6 in the recruitment of T cell and monocyte subsets and shear-mediated plaque modulation will be discussed. Finally, the role of CXCR2 and CXCR4, their respective ligands CXCL1 and CXCL12, and the noncanonical dual agonist MIF in atheroprogression will be dissected. The considerable leap in insight over recent years leads us to anticipate further advances in comprehending the role of chemokines in atherosclerosis, allowing targeted interventions for its prevention and therapy.
Key Words: chemokines • chemokine receptors • atherosclerosis • vascular inflammation
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Introduction |
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Substantial evidence has been accumulated to establish the notion that atherosclerosis is an inflammatory disease. The continuous immigration and infiltration of activated macrophages and T cells into and within atherosclerotic lesions are prominent features in both human and experimental atherosclerotic disease. The recruitment of these cells to lesions is guided by endothelial leukocyte adhesion molecules and chemoattractants. Chemokines belong to a large group of structurally related and secretable, largely basic, chemotactic cytokines, which can be divided into 4 families (CC, CXC, CX3C, XC) based on the position of the first 2 cysteine residues. Chemokines can be located in different vascular cell types, eg, endothelial cells (ECs) but also inflammatory cells and can be detected within atherosclerotic lesions, where they function as messengers to direct leukocytes to sites of inflammation but may also control homeostasis and other activities of emigrated cells.1,2 By signaling through G protein–coupled chemokine receptors, chemokines govern a variety of cell responses including cell activation and transmigration in leukocytes, as well as in nonhematopoietic cells. Several recent studies have addressed the role of chemokines in leukocyte accumulation in atherosclerosis, extending our knowledge and understanding of the complex and cell type–specific functions of chemokines in atherosclerosis (Table 1
). In this update, we will highlight these recent developments and novel aspects, and discuss how these insights will lead us to targeting strategies for the prevention and therapy of atherosclerosis.
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Emerging Role of CCL5 and its Receptors in Atherogenesis |
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The Transcriptional Regulation of Vascular CCL5 Expression
The role of the CC chemokine ligand-5 (CCL5/RANTES) and its receptors CCR1 and CCR5 in atherosclerosis have been addressed in a number of studies. The expression of CCL5 can be detected in atherosclerotic plaques and in monocyte/macrophages is regulated by the Rel proteins p50 and p65 belonging to the NF-
B family. In addition, the Krüppel-like factor 13 (KLF13), originally designated RANTES factor of late activated T lymphocytes-1 (RFLAT-1), has been identified as a new transcription factor regulating the expression of CCL5 in T lymphocytes.3 In smooth muscle cells (SMCs), the expression of CCL5 has recently been found to be controlled by the transcriptional regulator Y-box binding protein-1 (YB-1).4 The overexpression of YB-1 in arterial SMCs enhanced CCL5 transcriptional activity, CCL5 mRNA and protein expression, and CCL5-mediated monocyte recruitment. CCL5 is known to bind several receptors, including CCR1, CCR3, and CCR5. For instance, CCR1 and CCR5 are expressed on various cell types involved in atherosclerosis, eg, monocytes/macrophages, T lymphocytes, or Th1-type cells, and are specialized in mediating CCL5-triggered arrest and transendothelial diapedesis. Beyond ligand binding and directing leukocyte attraction, these receptors have also been implicated in detrimental effects of emigrated cells at lesion sites.5
Distinct Function of the CCL5 Receptors CCR1 and CCR5
The administration of Met-RANTES as a peptidic CCL5 receptor antagonist prevents the CCL5-triggered monocyte arrest, modulates the inflammatory process during atherogenesis,6 and reduces atherosclerotic lesion formation with a more stable plaque phenotype.7 Deficiency in Ccr5 in aplioprotein E–deficient mice (Ccr5–/–Apoe–/–) fed a normal chow did not reduce spontaneous formation of early-stage atherosclerotic lesions.8 However, although not influencing early-atherosclerosis, Ccr5–/–Apoe–/– mice are protected against advanced atherosclerosis as well as age-associated aortic valve thickening correlating with aortic valve sclerosis.9 In contrast, the reconstitution of low-density lipoprotein receptor deficient (Ldlr–/–) mice with Ccr5–/– bone marrow had little effects on lesion size but improved atherosclerotic plaque quality.10 Of note, deficiency in bone marrow Ccr1 did not protect but rather enhanced atheroprogression in Ldlr–/– mice.11 Although the general blockade of CCL5 receptors reduces atherosclerosis, specific roles of CCR1 and CCR5 had not been addressed and unequivocally determined. It could be demonstrated that genetic deletion of Ccr5 reduced the diet-induced but also late native atherosclerotic lesion extent, which was accompanied by a more stable plaque quality with reduced mononuclear cell infiltration and Th1-type immune responses, possibly mediated by increased secretion of interleukin (IL)-10, whereas lack of Ccr1 enhanced atherosclerotic plaque development and exacerbated T cell recruitment.12 Similarly, deficiency in Ccr5 protected against neointima formation after arterial wire injury in Apoe–/– mice, attributable to an upregulation of the antiinflammatory cytokine IL-10 in neointimal SMCs. In contrast, Ccr1 deficiency did not affect neointimal area or cell content but entailed an increase in proinflammatory interferon (IFN)-
in the neointima of Ccr1–/–Apoe–/– mice. Moreover, the blockade of IFN- unmasked a reduction in macrophage recruitment in Ccr1–/– mice, revealing that proinflammatory effects of an altered immune balance counteract deficiencies in cell recruitment and contribute to neointima formation after arterial injury in atherosclerosis-prone mice.13 Notably, knock-down of YB-1 controlling RANTES expression in carotid arteries significantly reduced neointima formation and macrophage content after injury, which was not observed in Apoe–/– mice with deficiency in Ccr5 or after treatment with the CCL5-antagonist Met-RANTES, confirming that effects of YB-1 depend on the CCL5/CCR5 axis.4 In addition to its expression by plaque cells, CCL5 can also be deposited by activated platelets on early atherosclerotic endothelium, where it can trigger the arrest of circulating monocytes.6 This process requires oligomerization and proteoglycan binding of CCL5 on the endothelial surface to bridge to the arrest receptor on circulating mononuclear cells, and can be amplified by heterophilic interactions with the platelet chemokine CXCL4, which can occur as a preformed complex stored in platelet 
-granules.14–16 These studies revealed that engagement of distinct receptors by the same chemokine ligand can produce different functions, further extending the degree of specialization. Thus, therapies aiming at a selective blockade of CCR5 but not CCR1 may be a promising approach to prevent ongoing inflammatory processes sustaining or aggravating atherosclerosis.
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Differential Chemokine Receptor Usage by Distinct Monocyte Subsets |
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In mice and men, circulating monocytes display a remarkable heterogeneity in surface receptors, which is possibly associated with distinct yet unresolved functional contributions to atherogenesis. Monocytes fall into at least 2 phenotypically distinct subsets: in mice, Ly-6Chigh (also termed Gr-1hi) and CCR2+CX3CR1low expressing cells versus Ly-6Clow (Gr-1lo) and CCR2–CX3CR1high monocytes correspond to human CD14++CD16– and CD14+CD16+ monocytes, respectively.17,18 Ly-6Chi cells selectively populate sites of experimentally induced inflammation, whereas their Ly-6Clo counterparts can enter lymphoid and nonlymphoid tissues under homeostatic conditions. The Ly-6Chi monocyte subset was found to dramatically increase in hypercholesterolemic Apoe–/– mice consuming a high-fat diet, with the number of Ly-6Chi cells doubling in blood every month, which is the predominant subtype to adhere to activated endothelium, to infiltrate lesions, and to become lesional macrophages. This hypercholesterolemia-associated monocytosis developed from increased survival, continued cell proliferation, and impaired Ly-6Chi to Ly-6Clo conversion.19 The analysis of migration and differentiation properties of these 2 subsets in Apoe–/– mice further revealed that CCR2+Ly-6Chi monocytes efficiently accumulated in atherosclerotic plaques, whereas CCR2–Ly-6Clo monocytes were rather poorly recruited. Moreover, this study investigated the signaling routes used by the 2 monocyte subsets to enter atherosclerotic plaques. Although CCR5 was selectively upregulated in CCR2–Ly-6Clo monocytes and mediated the accumulation of this subset in atherosclerotic lesions, CX3CR1 although highly expressed in Ly-6Clo monocytes was not required for plaque entry. By contrast, CCR2+Ly-6Chi monocytes used CX3CR1 together with CCR2 and CCR5.20 This finding may offer therapeutic approaches based on antagonists selectively targeting CX3CR1-dependent plaque entry without blocking CCR2-dependent inflammatory responses.
A recent report revealed that chemokine-mediated signals indeed critically determine monocyte homeostasis in blood and bone marrow under baseline or atherosclerotic conditions. Namely, CCL2-, CX3CR1-, and CCR5-dependent signals differentially affected CD11b+Ly6Chi versus Ly6Clo monocytosis. Combined inhibition of CCL2, CCR5, and CX3CR1 in Apoe–/– mice abrogated bone marrow monocytosis and additively reduced circulating monocytes and atherosclerosis despite persistent hypercholesterolemia. Lesion size correlated with circulating monocyte numbers, particularly the Ly6Clo subset. These chemokine signals together account for most of the macrophage accumulation in atherosclerotic arteries.26
Chemokines and the Intralesional Fate of Monocyte Subpopulations
Although entering plaques less frequently, Ly-6Clo monocytes are predisposed for differentiation into cells expressing the dendritic cell (DC)-associated marker CD11c.20 Although typically regarded as a DC marker, CD11c expressed in atherosclerotic tissues colocalizes with the macrophage marker CD68 to some degree. If these lesional cells are true DCs, they likely arise from monocytes rather than independent DC-precursors.20 Furthermore, these findings indicate that phagocyte heterogeneity in plaques might also be linked to distinct types of invading monocytes. Further characterization of this DC-like cell population will support efforts to scrutinize their distinct role in disease compared to classical CD11c– macrophages. Notably, gene profiling in atherosclerosis revealed an early expression of CCL5 during plaque evolution and expression of CX3CL1 at later time points, possibly corresponding to distinct recruitment patterns and receptor usage for monocyte subsets at different time points.21 The contribution and distinct functions of Ly-6Chi and Ly-6Clo monocytes to atherogenesis still need to be elucidated and refined (Table 2).
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The Relation of Monocyte Subpopulations to Endothelial Progenitor Cells
Endothelial progenitor cells (EPCs) play important roles in the repair-to-injury of arteries, share phenotypic features eg, expression of VEGF and its receptors, with CD14+CD16+ or Ly-6Clo monocytes and circulating EPCs positively correlate with endothelial function, serving as a predictor beyond conventional risk factors.22–24 Like these monocytes,17,18 murine EPCs express CCR5 in a distinct subset of about 13%.25 The deletion of Ccr5 in Apoe–/– mice was associated with increased EPC numbers, as a postulated atheroprotective factor.9 Thus, one possibility is that the loss of a negative regulation after disruption of Ccr5 might account for higher numbers of circulating EPCs in Apoe–/–Ccr5–/– mice. This may be attributable to effects on their mobilization or to impaired incorporation, as seen with Ly-6Clo monocytes. Further studies will be required to provide a causal link between increased EPC numbers and reduced atherosclerotic burden, and possibly, thinner aortic valves detected in Apoe–/–Ccr5–/– mice.9
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The Transmembrane Chemokine CX3CL1 and its Receptor CX3CR1 |
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CX3CL1/fractalkine is (together with CXCL16) the only known chemokine expressed in both a soluble/shed and a membrane-tethered form, thus combining chemoattractant functions and properties as an adhesion molecule for monocytes or T cells. Besides mediating inflammatory cell recruitment (see above), CX3CL1 acts as a mediator of SMC migration.27 Although CX3CL1 and CX3CR1 are both expressed on ECs, foam cells, and coronary artery SMCs in mouse and man in atherosclerosis,28–30 only recently a network of CX3CR1-expressing cells could also be detected in normal vessels and characterized as intimal DCs with an increased and CX3CR1-dependent accumulation in aged and atherosclerotic Apoe–/– aortas.31
Shear Rate-Dependent Functions of CX3CL1
The expression of chemokines in inflamed plaque areas is related to different shear stress conditions. Whereas low shear stress increases lipid and matrix metalloproteinase (MMP) but decreased vascular SMC and collagen content contributing to atherosclerosis in mice, vortices with oscillatory shear stress induced more stable lesions.32 Whereas the expression of CX3CL1 was found in low shear stress regions only, blockade of CX3CL1 inhibited plaque growth and resulted in striking differences in plaque composition in low shear stress regions of carotid arteries.33 In the presence of high-shear stress, firm adhesion of leukocytes to inflamed ECs was reduced by blocking antibodies directed against CX3CL1 or CX3CR1 in Apoe–/– mice, suggesting that this axis is critically involved in leukocyte adhesion to inflamed arterial endothelium. Platelets were required for CX3CL1-induced leukocyte adhesion at high-shear rates and both soluble and membrane-bound CX3CL1 can induce platelet degranulation and subsequent surface expression of P-selectin to promote direct platelet-leukocyte interactions.29 The role of CX3CR1 as a signaling or adhesive receptor on platelets and as a prerequisite for postrecruitment survival of macrophages is currently subject to investigation. Evidence on the role of CX3CL1 has also been obtained in human systems, showing that atherogenic lipids (oxidized LDL and linoleic acid derivatives) induce the adhesion of macrophages/foam cells to human coronary artery SMCs by upregulating CX3CL1 on SMCs via an autocrine feedback loop involving tumor necrosis factor (TNF)- production and NF-B signaling.30
The CX3CL1/CX3CR1 Axis in Atherogenesis
The role of CX3CL1 was examined in 2 murine models of atherosclerosis. Whereas Cx3cl–/–Apoe–/– mice displayed decreased atherosclerotic lesion formation in the brachiocephalic artery but not the aortic root, Cx3cl–/–Ldlr–/– mice had less atherosclerosis at both sites, with fewer lesional macrophages in both cases.34 Taking the recently appreciated role of neutrophils and endothelial dysfunction into account,35 beyond a direct function in monocyte recruitment, CX3CL1 shed from ECs after hypoxia/reoxygenation can act through CX3CR1 on ECs to promote intercellular adhesion molecule-1 (ICAM-1) expression and neutrophil adhesion by activating the Jak-Stat5 pathway.36 Moreover, CX3CL1 contributes to vascular dysfunction by stimulating the release of vascular reactive oxygen species and reducing NO bioavailability in isolated rat aortas.37
The function of the fractalkine receptor CX3CR1 had been focus of 2 independent studies. In both studies, Cx3cl1–/–Apoe–/– mice displayed a significant reduction in macrophage recruitment to the vessel wall and decreased atherosclerotic lesion formation.38,39 Recently, triple-knockout mice further showed that the combined genetic deletion of CCR2 and CX3CL1 leads to a dramatic reduction of atherosclerotic lesions in Cx3cl1–/–Ccr2–/–Apoe–/–mice providing the first in vivo evidence for independent roles for CX3CL1 and CCR2 in direct monocyte recruitment to atherosclerotic lesions.40 Moreover, the inhibition of CCL2, CX3CR1, and CCR5 in Apoe–/– mice was associated with a marked and additive 90% reduction in atherosclerosis, providing additional insights into the role of monocyte chemokines in atherogenesis and suggesting that CX3CR1-, CCL2-, and CCR5-mediated signals play independent and additive roles in atherogenesis.26
CX3CR1 Polymorphisms in Humans
The expression of CX3CR1 was also revealed in patients with coronary artery disease (CAD) and related to INF-.41 In addition, enhanced surface expression of CX3CR1 on expanded CD4+/CD28+ T cells in patients with rheumatoid arthritis correlated with accelerated atherosclerotic damage.42 The importance of CX3CRL/CX3CR1 in human atherosclerosis was corroborated by 2 common coding polymorphisms, V249I and T280M, which were associated with interindividual differences in susceptibility to atherosclerosis. However, whereas 1 study identified the polymorphism in CX3CR1 (V249I) to be associated with a lower risk of CAD, suggesting an implication of this receptor in cardiovascular disease, another study failed to unravel an association of the V249I or T280M polymorphism with CAD, but revealed protective effects of the T280M polymorphism during acute coronary syndromes.43,44,45 In addition, the presence of T280M is associated with a decreased common carotid artery intima-media thickness, whereas the presence of the V249I polymorphism did not play a major role in the progression of carotid artery atherosclerosis.46 Conversely, an epidemiological study conducted in 365 patients undergoing coronary stenting revealed a link between CX3CR1 polymorphisms and elevated risk of restenosis.45
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CXCL16 as a Multi-Functional Chemokine Player |
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The transmembrane chemokine CXCL16/SR-PSOX (scavenger receptor for phosphatidyl-serine and oxidized lipoprotein) is expressed by macrophages, DCs, T cells, and cytokine-stimulated SMCs and ECs. It is known that the disintegrin and metalloproteinase ADAM10 is involved in CXCL16 cleavage from the cell membrane, leading to the release of a soluble protein functioning as a chemoattractant for CXCR6+ cells. In addition to its properties as a chemokine, CXCL16 also acts as a scavenger receptor for apoptotic cells, phosphatidylserine, and oxidized LDL.27 The roles of CXCL16 in vivo are not well understood but CXCL16 was shown to be present in both human and murine atherosclerotic lesions and upregulated by IFN-
47 and a clinical study showed that low plasma levels of CXCL16 are associated with CAD.48 Interestingly, Cxcl16–/–Ldlr–/– mice display accelerated atherosclerosis, an enhanced macrophage recruitment, and elevated CCL2 and TNF- mRNA levels.49 Because deleting CXCL16 entails a loss of its scavenging and chemotactic activity, these 2 functions had not been discriminated in atherosclerosis. CXCL16 is the only known ligand for CXCR6, which is expressed on a subset of CD4+ effector memory T cells, on NKT cells, and a Foxp3+ subset (CD69+CD45RO+) of regulatory T cells in man. In mice, interstitial lymphocytes, NKT cells, monocytes, DCs, and memory subsets of CD8+ or CD4+ T cells express CXCR6, which is upregulated by IL-2 and IL-15.27 Moreover, endotoxin-induced toll-like receptor 4-dependent CXCR6 expression has been shown in aortic SMCs.50 Mice deficient in Cxcr6 displayed reduced atherosclerosis associated by a lower content of CXCR6+ T cells and CD11b+CD68+ macrophages in the aorta. The decrease in CXCR6+ T cells was associated with a diminished production of IFN-.51 Although CXCL16 binding to CXCR6 is pivotal in leukocyte recruitment and thus proatherogenic, the scavenger function of CXCL16 may convey atheroprotection. |
CXCR2 Ligands in Atherosclerosis |
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The CXC chemokine receptor CXCR252 has several ligands defined by an N-terminal ELR motif, including CXCL8/IL-8, CXCL1/KC (keratinocyte-derived chemokine), or its human ortholog GRO (growth-regulated oncogene)-
.53 Both arterial CXCL1 and leukocyte-specific CXCR2 expression are central to macrophage accumulation in established fatty streak lesions with major impact on lesion progression and macrophage accumulation in advanced lesions.53 The repopulation of atherosclerosis-prone Ldlr–/– mice with bone marrow deficient in CXCR2 resulted in a substantial reduction of advanced atherosclerosis.52 Because a deficiency in CXCL1 exerted a less pronounced inhibition, it has been suggested that alternative CXCR2 ligands are involved in the proatherogenic effects.53 Furthermore, this study revealed that CXCL1 and CXCR2 may not play an essential role for monocyte influx into early atherosclerotic lesions.
Importance of CXCR2 in Endothelial Regeneration
Although chemokines are not only important in orchestrating the influx of inflammatory cells, they may also mediate vascular wound healing by recruiting EPCs.54 Regenerating ECs express CXCR2 in vivo, and CXCL1 has been shown to enhance endothelial recovery via CXCR2 in vitro and in vivo in a model of arterial injury.55 In addition, CXCR2 appears to be important in recruiting EPCs, in particular CD14+ cells, to injured vessels thus enhancing endothelial recovery and reducing neointimal hyperplasia.23 Beyond inflammatory cell recruitment, plaque macrophages secreting CXCL1 may contribute also to endothelial regeneration, which may be vasoprotective. To better understand the role of human CXCR2 in atherosclerosis, a hCXCR2+/+Ldlr–/– mouse model was proposed, which—given the cross-reactivity of murine ligands with hCXCR22—would allow for testing novel pharmaceuticals designed to antagonize hCXCR2.56
Numerous studies found that inflammatory biomarkers help to identify patients with stable CAD and acute coronary syndromes and is predictive for the development of CAD in high-risk patients. The role of chemokines as candidates for cardiovascular risk prediction has been appreciated, although it has not been validated in large clinical trials.57 Interestingly, among apparently healthy men and women, elevated IL-8 levels are associated with increased risk of future CAD.58 Moreover, CAD patients display raised levels of IL-8 in an long-term clinical outcome study.59 CXCL1 is one of most differentially overexpressed transcripts in circulating mononuclear cells of CAD patients with stable or unstable angina versus healthy controls.60 This hints at a role of IL-8–triggered EPC homing in plaque destabilization in a chronic context.
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Chemokine-Like Functions of Macrophage Migration Inhibitory Factor |
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Migration inhibitory factor (MIF) has emerged as a key factor in vascular processes giving rise to atherosclerosis.61 Its expression is upregulated in response to proatherogenic stimuli such as oxidized LDL in ECs, SMCs, and macrophages during the development of atherosclerotic lesions in humans, rabbits, and mice.62 After vascular injury, blocking MIF was found to diminish neointimal infiltration with macrophages in Apoe–/– mice, whereas SMC and collagen content were increased, reflecting a more stable plaque composition.63 In a model of diet-induced atherogenesis in Ldlr–/– mice, genetic deletion of MIF decreased intimal thickening, lipid deposition, and protease expression.64 Similarly, treatment with a blocking anti-MIF antibody in apoe–/– mice led to a reduction of a various inflammatory mediators typically associated with atherosclerosis including circulating levels of fibrinogen and IL-6. Importantly, local aortic expression levels of inflammatory mediators and transcription factors were reduced by MIF blockade.65 These results are complemented by a study examining leukocyte recruitment in postcapillary venules in vivo. Antibodies against the monocyte-selective chemokine CCL2 and its receptor CCR2 but not CCL3 and CXCL2, significantly inhibited the MIF-induced monocyte adhesion and transmigration. Moreover, Ccl2–/– mice displayed a similar reduction in MIF-induced recruitment, indicating a critical role of CCL2 in the MIF-induced response.66 Despite a strong reduction in inflammatory parameters by anti-MIF treatment, only a small reduction in aortic plaque area was observed. However, the intimal accumulation of macrophages was markedly reduced in Apoe–/– mice under MIF blockade.65 Thus, actions of MIF may not be directly linked to initial plaque expansion but rather to intimal inflammation during spontaneous atherogenesis. Although it was previously unclear whether MIF can induce leukocyte recruitment independently of additional inflammatory stimuli, this study showed that MIF is capable of inducing leukocyte adhesion and transmigration into tissues in vivo.
MIF Acts as a Functional Ligand of CXCR2 and CXCR4
Whereas MIF is known to bind cell surface CD74 (invariant chain), it has only recently been demonstrated to directly bind to CXCR2 and CXCR4.67 The MIF-induced monocyte recruitment to the arterial wall not only relied on CXCR2 binding but also involved the MIF-binding protein CD74, which colocalized with CXCR2, suggesting that MIF signals via a functional CXCR/CD74 complex. Using a peritonitis model and intravital microscopy in postcapillary venules and in carotid arteries with early atherosclerosis, a functional involvement of CXCR2 in MIF-triggered monocyte recruitment was observed in vivo. Importantly, blocking MIF (as a dual CXCR agonist) but not the cognate ligands CXCL1 and CXCL12 resulted in a regression of preexisting atherosclerotic plaques in Apoe–/– mice, accompanied by a decrease in both macrophage and T-cell content, resulting in more stable plaques. Moreover, blockade of MIF impaired the CXCR4-mediated T cell recruitment, also important for driving lesion development.67 As genetic deletion of CXCL1 in Ldlr–/– mice53 reduces atherosclerosis to a lesser extent than bone marrow CXCR2 deficiency in Ldlr–/– mice with effects on macrophage accumulation in established rather than early lesions, these findings support the notion that MIF as a CXCR2 ligand may partially compensate for a lack of CXCL1. Thus, targeting MIF may represent a promising approach to initiate therapeutic regression and to stabilize advanced atherosclerosis. The specific components of its dual receptor agonism and options for their selective inhibition are currently under investigation.
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Immune-Regulatory Chemokines CCL19 and CCL21 in Vascular Disease |
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The chemokines CCL19 and CCL21 bind the receptor CCR7 to direct the migration of T cells and DCs into lymph nodes, where these cells are instrumental in the initiation of the immune response.68,69 A possible role for these chemokines and their receptor CCR7 in atherosclerosis has recently been addressed in 3 separate studies with contradictory findings. Compared to healthy controls, both CCL19 and CCL21 were increased in plasma and within carotid atherosclerotic lesions of patients with stable angina and even further in those with unstable CAD and in plaques of Apoe–/– mice. Whereas circulating T cells from CAD patients displayed decreased CCR7 expression, lesional T cells expressed high levels of CCR7 and its ligands promoted an inflammatory phenotype in T cells, inducing increased macrophage MMP and tissue factor levels.70 These chemokines may thus contribute to atherogenesis and plaque destabilization by recruiting T cells and promoting an inflammatory response in T cells and a matrix-degrading, prothrombotic, and inflammatory phenotype in macrophages. By contrast, some studies have shown that sustained application of soluble or immobilized CCL19 and CCL21 elicits an inhibitory program in T cells attributable to specifically interfering with cell proliferation and IL-2 secretion of CCR7+ human and murine T cells, not observed in T cells from Ccr7–/– mice.71 The role of CCR7 was also investigated in a mouse model of atherosclerosis regression, where the aortic arch of Apoe–/– mice with established atherosclerotic lesions was transplanted into wild-type recipients. Whereas CCR7 expression levels increased in regressing lesions after transfer, combined blockade of CCL19 and CCL21 inhibited plaque regression and also preserved foam cell content.72 Although the underlying mechanisms remain unclear, a complex interplay of the immune system and inflammation with an importance of CCL19/CCL21/CCR7 in plaque regression was deduced. Taken together, expression levels of CCL19/CCL21 may reflect immune stimulatory functions but also compensatory mechanisms counteracting atherosclerotic disease progression.
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Atheroprotective Functions of the CXCR4/CXCL12 Axis |
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The essential role of the homeostatic CXCL12 in hematopoiesis, stem cell mobilization, bone marrow engraftment, organ development, and angiogenesis is well documented. Its role in neointima formation and atherosclerosis has only recently been addressed. In a model of transplant arteriosclerosis, the neutralization of CXCL12 inhibited the mobilization of blood-borne stem cells giving rise to lesional SMCs and thereby attenuated neointimal formation.72 CXCL12 has been found to be induced in medial SMCs in the context of apoptosis after arterial wire-injury, and increases in the circulation to mobilize and recruit PDGFR-β+lineage–sca-1+ progenitor cells from the bone marrow to the neointima,73,74 where they accumulate, give rise to neointimal SMCs, and contribute to neointimal hyperplasia.74 After arterial denudation, CXCL12 is also secreted and presented by activated platelets adhering to the site of injury to recruit lineage–sca-1+c-kit+ or CD34+ progenitor cells74,75 and promotes EPC differentiation during withdrawal of mitogenic cytokines, eg, PDGF-β, and formation of vascular structures under conditions of ischemia.76 Platelets are also major storage and deployment vehicles for other angiogenic growth factors, which orchestrate the recruitment and differentiation of circulating bone marrow–derived cells but also of other immune cells,77 which may accentuate the balance toward SMC progeny. Nevertheless, CXCL12 is of fundamental importance in vascular repair and remodeling. Within atherosclerotic plaques, CXCL12 can be detected in SMCs and ECs, and plasma levels of CXCL12 are decreased in patients with stable and unstable angina compared with healthy control subjects so that CXCL12 was suggested to mediate antiinflammatory and plaque-stabilizing effects in unstable angina.78 The function of CXCL12 and its receptor CXCR4 in diet-induced primary atherosclerosis has only recently been addressed owing to the embryonic lethality of deficient mice. Interfering with the CXCL12/CXCR4 axis by a potent small-molecule antagonist, genetic CXCR4 deficiency or lentiviral transduction with CXCR4 degrakine in bone marrow chimeras aggravated diet-induced atherosclerosis in Apoe–/– or Ldlr–/– mice. The chronic blockade of CXCR4 caused leukocytosis with an expansion of more immature yet functional neutrophils in the circulation and increased neutrophil content associated with apoptosis and a proinflammatory phenotype in the plaques. Whereas circulating neutrophils were recruited to atherosclerotic lesions, depletion of neutrophils reduced plaque formation and prevented its exacerbation after blocking CXCR4. Thus, the CXCL12/CXCR4 axis was clearly shown to be atheroprotective and to reveal the important contribution of neutrophils to atherogenesis in mice via maintaining a antiinflammatory leukocyte homeostasis.35 These effects favor therapeutic strategies that enhance CXCL12 activity in CAD78 but warrant caution during interventions associated with vascular injury.
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The Chemokine CXCL10 and the T Cell Connection |
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CXCL10 or IP-10 (IFN-
–induced protein of 10 kDa) is a T cell chemokine and constitutively expressed at low levels in thymic, splenic, and lymph node stroma; however, expression can strongly be upregulated by IFN- in monocytes, macrophages, ECs, and SMCs.79,80 CXCL10 and 2 functionally related CXC chemokines, monokine induced by IFN- (MIG/CXCL9) and IFN-–inducible T cell -chemoattractant (ITAC/CXCL11), are highly expressed in human atheromas throughout all stages of plaque development.81 Among the CXCR3 ligands, CXCL10 is unique in that its promoter has 2 functional NF-B binding sites, whereas the CXCL9 and CXCL11 promoters have none.82 Increased expression of IFN- and CXCL10 has been detected in patients with CAD,83 and higher levels of plasma CXCL10 correlate directly with restenosis after percutaneous coronary interventions.84 CXCR3 is a marker of activated T helper type 1 lymphocytes and common receptor for CXCL10, CXCL9, and CXCL11. The deletion of CXCR3 has been shown to affect early lesion formation in Apoe–/– mice with an upregulation of the antiinflammatory molecules IL-10, IL-18BP, and endothelial nitric oxide synthase and an increased number of regulatory T lymphocytes within atherosclerotic lesions.85 Treatment of Ldlr–/– with the HIV entry inhibitor TAK-779, an antagonist for CCR5 and CXCR3, dramatically reduced atherosclerotic plaque area, T cell number and IFN- content.86 A recent study confirmed that treatment with a CXCR3 specific antagonist NBI-74330 attenuates atherosclerotic lesion formation by interfering directly with the recruitment of CXCR3+ effector T cells and macrophages into plaques but also by modulating the local inflammatory response with an enhancement of markers for regulatory T cells in Ldlr–/– mice. Moreover, lymph nodes draining from the aortic arch were smaller and enriched in regulatory T cells and contained fewer activated T cells after treatment.87 Evidence for a functional role of CXCL10 in lesion formation in altering of the local balance of effector and regulatory immune mechanisms has been provided subsequently. Genetic absence of CXCL10 conferred a 2-fold reduction in early aortic lesion formation with a marked reduction in CD4+ and CXCR3+ T cells. Although overall T cell accumulation was diminished, an enhancement of regulatory T cell numbers and activity with increased expression of IL-10 and transforming growth factor (TGF)-β1 was observed, and the aortas of Cxl10–/–Apoe–/– mice displayed increased levels of CCL17, CCL22, CCR4, and CCR8, chemokine-receptor pairs involved in regulatory T cell trafficking.88 Thus, the CXCR3/CXCL10 axis is pivotal in dysbalancing T cell responses during atherogenesis. |
The "Oldest" Chemokine CXCL4 as an Important Functional Modulator |
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The mechanisms of platelets and in particular platelet chemokines cooperate as partners incriminated in atherogenesis and neointima formation have recently been discussed.89 Among the chemokines present in platelets, CXCL4/PF4 (platelet factor 4) stands out by being abundantly expressed and sharing several, including angiostatic, activities with CXCL9, CXCL10, and CXCL11. CXCL4 is a lysine-rich chemokine belonging to the CXC subfamily, is synthesized mainly by megakaryocytes, and exists as a tetramer in
-granules of platelets in micromolar concentrations. It comprises 2% to 3% of the total of released proteins of mature platelets and is secreted in high concentrations on activation. CXCL4 binds avidly to glycosaminoglycans but only few high affinity protein receptors, LDLR90 and a splice variant of CXCR3 named CXCR3B, have been identified to date.91 CXCL4 is localized in fatty streaks and atherosclerotic lesion in humans,92 and lesional CXCL4 expression correlates with histological and clinical severity of disease, indicating its role in human atherosclerosis. A recent study indeed confirmed a significant decrease in atherosclerotic lesion formation in the absence of CXCL4 in 2 different murine models of atherosclerosis, providing direct evidence that this platelet chemokine is proatherogenic.93
CXCL4 and CXCL4L1—Two Homologous but Functionally Distinct Genes
The human CXCL4 gene appears to be duplicated. A second highly homologous gene named PF4alt or PF4-Var1 has been identified.94,95 The protein product of the PF4alt gene was isolated from thrombin-stimulated human platelets, renamed as CXCL4L1.96 Compared with CXCL4, CXCL4L1 is a 30-fold more potent inhibitor of EC chemotaxis in vitro and has more profound effects in blocking angiogenesis in vivo.96 CXCL4L1 shows only 4.3% amino acid divergence in the mature protein, containing 3 amino acid substitutions in the C terminus, a region known to be critical for CXCL4-heparin interaction.96 However, CXCL4 and CXCL4L1 exhibit a 38% amino acid divergence in the signal peptide region. Previous studies hypothesized that this implies a difference in the cell type in which CXCL4L1 is expressed or different modes of secretion.95 By introducing plasmids encoding CXCL4 or CXCL4L1 in heterologous cell systems, CXCL4 was revealed to be stored within the cytoplasm and secreted via a regulated pathway in response to protein kinase C activation, whereas CXCL4L1 was continuously secreted through a constitutive pathway. Accordingly, human T cells, which preferentially expressed CXCL4, released only low levels of this chemokine under basal conditions but on stimulation immediately secreted high amounts of CXCL4. Human VSMCs almost exclusively expressed and constitutively released CXCL4L1, which was unresponsive to PMA stimulation. These results suggest a distinct role for CXCL4 and CXCL4L1 in inflammatory or homeostatic processes, respectively,97 given the versatile role of platelets in atherosclerosis, vascular biology and immune regulation.77,89,98
Synergy of CCL5 and CXCL4 in Monocyte Recruitment
It is notable that the platelet chemokines CCL5 and CXCL4 exert additive effects by triggering monocyte arrest on atherosclerotic endothelium in concert.16 Importantly, this finely-tuned regulation of leukocyte responses to platelet chemokines has been refined by demonstrating that blood cell–derived CCL5 and CXCL4 associate to form CC-type mixed heterodimers, possibly preformed in platelet granules as key mediators in atheroprogression. The notion that platelets drive atherogenesis through combined delivery of CCL5 and CXCL4 to sites of vascular inflammation can be validated in mice reconstituted with bone marrow deficient in CCL5 or CXCL4, which display a significant decrease in atherosclerotic lesion formation associated with reduced macrophage infiltration (R. Koenen & C.W., unpublished data, 2008).99 This reduction in plaque area and macrophage content attributable to deletion of either CCL5 or CXCL4 may be attributable to a lack of CCL5–CXCL4 heteromers intensifying monocyte arrest. The functional relevance of CCL5 and CXCL4 in aggravating atherogenesis combined with their propensity to engage in functional heteromerization highlights this chemokine pair as an attractive target for therapeutic intervention. Indeed, a synthetic peptide disrupting CXCL4–CCL5 interactions attenuated plaque formation in Apoe–/– mice and atherogenic monocyte recruitment, establishing that selective inhibition of CCL5–CXCL4 heteromer formation may represent a feasible strategy to counteract atheroprogression (R. Koenen & C.W., unpublished data, 2008).99 Likewise, interference with chemokine oligomerization and heparin interactions with a 44AANA47-CCL5 variant is an effective approach that inhibits progression of established atherosclerosis. The treatment with CCL5 carrying a mutation in its principal proteoglycan binding site limits progression of advanced atherosclerotic plaques and inhibits leukocyte recruitment into atherosclerotic lesions in Ldlr–/– mice.100 These findings further support the concept of a functional "interactome,"99 constituted by a variety of homophilic and heterophilic chemokine interactions in defined microenvironments, which explains how signals conferred by various chemokines are integrated for the combinatorial control of leukocyte responses.
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Conclusions |
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Research in recent years has further enhanced our understanding of chemokines as highly elaborate and specialized molecules that also cooperate in distinct steps of cell recruitment. Moreover, chemokines are now established to be of paramount importance for maintaining the delicate leukocyte homeostasis with changes in cell mobilization, differentiation, influx, proliferation, and apoptosis or survival to contribute to atherogenesis and neointima formation rather than solely effecting leukocyte recruitment. Importantly, chemokines are beginning to emerge as instrumental mediators of atherosclerotic plaque regression and modulators of the immune system. Of note, remarkable differences in presentation and functional involvement of chemokines and their receptors in leukocytic cell recruitment have been observed between native atherogenesis and neointima formation after injury, possibly also related to the evolving differences in their pathogeneses and contribution of different mononuclear subsets and precursors of vascular cell types (see Figure for summary). In particular, CCR5 and CCR2 together with CX3CR1 control the recruitment of Ly-6Clo versus Ly-6Chi monocyte subsets, respectively, whereas their combined action leads to a proatherogenic monocytosis. The peripheral blood homeostasis and homing of neutrophils and vascular progenitor cells with relevance to atherosclerosis is controlled by CXCR2 and CXCR4 and their ligands. The recruitment of activated T cells of a predominant Th1-type appears to be driven by CXCR3 but also by CCR7 or CXCR6 and their ligands. Finally, the chemokine-like cytokine MIF as a dual CXCR2 and CXCR4 agonist increases the plaque content of both monocytes and T cells. Moreover, functional interactions between different chemokines in atherogenesis need to be taken into consideration. For instance, effects of platelet-derived CCL5 can be synergistically enhanced by CXCL4. A framework for such a highly elaborated and specialized division of labor is summarized in Table 1. This warrants extensive studies into the effects of chemokines on vascular cell homeostasis beyond the recruitment process which are currently underway.
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Acknowledgments |
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Sources of Funding
This work was supported by Deutsche Forschung Sgemeinsdraft (IOR809) and Interdisciplinary Centre for Clinical Research BIOMAT.
Disclosures
None.
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Footnotes |
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Original received April 22, 2008; final version accepted June 4, 2008.
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