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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Arterioscler Thromb Vasc Biol. Author manuscript; available in PMC May 1, 2009.
Published in final edited form as:
PMCID: PMC2657037
NIHMSID: NIHMS96590

Platelet chemokines in vascular disease

Abstract

Platelets are a rich source of different chemokines and express chemokine receptors. CXCL4 is highly abundant in platelets and involved in promoting monocyte arrest from rolling and monocyte differentiation to macrophages. CXCL4 can also associate with CCL5 and amplify its effect on monocytes. The megakaryocyte CXCL7 gene product is proteolytically cleaved into the strong neutrophil chemoattractant, NAP-2, which has also been implicated in repair cell homing to vascular lesions. Platelet adhesion can induce release of CCL2 and CXCL8 from endothelial cells. Conversely, the chemokines CCL17, CCL22 and CXCL12 made by other cells amplify platelet activation. Platelet chemokines enhance recruitment of various hematopoietic cells to the vascular wall, fostering processes such as neointima formation, atherosclerosis, and thrombosis but also vessel repair and regeneration after vascular injury.

The response-to-injury hypothesis of atherosclerosis emphasized a central role of endothelial denudation 1 and was later replaced by the view that atherosclerosis is an inflammatory disease 2. The complex composition of the cellular infiltrate in the arterial wall clearly implicates the immune system to be involved in atherogenesis 3. Numerous findings reflecting the inflammatory and immune modulatory capacity of platelets have increased our knowledge about their function in vascular disease 4, 5. A role for platelets and platelet-derived factors in atherosclerosis beyond their role in the hemostastic system has been suggested for a long time 6. Especially, platelet-derived chemokines have been demonstrated to be important in the pathogenesis of atherosclerotic disease including neointima formation and thrombosis 7, 8.

Platelets are anuclear cellular fragments derived from megakaryocytes in the bone marrow that play an important role in hemostasis 9, 10. Among various soluble factors, chemokines constitute a significant portion of α-granule contents which are released within seconds after platelet activation 11, 12. Chemokines are chemotactic cytokines that, depending on the position of cysteine residues within their structure, can be classified into different families (CXCL, CCL and the exceptions CX3CL1 and XCL1/2) 13, 14. Most chemokines signal through 7-transmembrane G-protein coupled receptors (GPCRs), of the Gi type that can be inhibited by pertussis toxin (PTX) derived from bordetella pertussis. The classification of chemokines into the CC- and CXC-type reflects the dogma that CC-chemokines are restricted to bind CC-chemokine receptors and the same holds true for the CXC-system. Within each family, binding of chemokines to chemokine receptors is highly promiscuous. Thus, a given chemokine receptor may bind several different chemokines and vice versa 13.

Platelets may be activated by chemokines, induce chemokine expression in other cell types 4 and release chemokines quickly upon their own activation. In the latter group, CXCL4 (platelet factor 4, PF4) and the chemokine CXCL7, which is processed from platelet basic protein through connective tissue-activating peptide-III and β thromboglobulin to its active form neutrophil-activating peptide-2 are the most abundant. Both CXCL4 and CXCL7 are found in high micromolar concentrations in the α-granule releasate 15. A number of other chemokines has been identified in platelets, even tough platelets may not represent their major source 4. Accordingly, this review will discuss the interactions between platelets and chemokines in the context of vascular disease, focusing on chemokines that activate platelets, platelet-induced chemokine activation or secretion a by other cells, secretion and deposition of chemokines by activated platelets and platelet chemokines that induce cell differentiation.

Chemokines that activate platelets

Platelets express a number of chemokine receptors including CCR1, CCR3, CCR4, CXCR4, and CX3CR1 16, 17. Accordingly, several chemokines have been demonstrated to activate platelets inducing calcium signaling, aggregation and release of biologically active substances. CCL17 (thymus and activation-regulated chemokine, TARC), CCL22 (macrophage-derived chemokine, MDC), and CXCL12 (stromal cell-derived factor-1α, SDF-1α) have been shown to activate platelets and amplify their aggregation via CXCR4 and CCR4, respectively 18, 19. CCL22 and CXCL12 are able to induce platelet P-selectin expression 19, stimulate platelet adhesion to immobilized collagen and fibrinogen under flow 19, and induce release of various platelet chemokines 4. P-selectin is an adhesion molecule stored in platelet α-granules and is expressed on the platelet surface upon degranulation 20. P-selectin induction was also demonstrated in platelets after stimulation with recombinant CXC3CL1 via CX3CR1, an effect which was inhibited by PTX 16. Circumstantial evidence suggests that these chemokine effects may be important in atherosclerotic disease: CXCL12 and CX3CL1 are expressed in atherosclerotic lesionsa 16, 21 and elevated serum levels of CCL18 (pulmonary and activation-regulated, PARC) and regulated upon activation and normal T cell expressed and secreted (regulated upon activation, normally T-expressed, and presumably secreted, RANTES, CCL5) have been found in patients with unstable angina 22.

Platelets induce activation and chemokine secretion from other cells

Activated platelets have been described to promote cell activation and chemokine expression in several cell types relevant in atherogenesis including endothelial cells, monocytes, and smooth muscle cells. In endothelial cells, platelets may induce CCL2 (monocyte chemotactic protein-1, MCP-1) or CXCL8 (interleukin 8, IL-8) as well as the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) leading to subsequent recruitment of leukocytes 20, 23. This process is dependent on the cell surface receptor CD40 interacting with platelet CD40 ligand (CD40L or CD154) 23. The potential in vivo relevance of this mechanism is underlined by the finding that disrupting CD40 signaling significantly reduces atherosclerotic lesions in the two most commonly used mouse models of atherosclerosis, rotic lesions in the two most commonly used mouse models of atherosclerosis, the LDL receptor-deficient mice (Ldlr-/-) and the apolipoprotein E knockout mice (Apoe-/-). Ldlr-/- mice treated with anti-CD40L antibodies and Apoe-/- mice deficient for CD40L are both protected from atherosclerosis 24, 25. CXCL1 (keratinocyte-derived chemokine, KC) is secreted by platelets and induces increased oxidative stress and downregulation of eNOS in porcine endothelial cells 26. CXCL4 was the fist chemokine to be discovered 27 and is one of the two most abundant platelet proteins. CXCL4 can activate endothelial cells and induce E-selectin expression in human umbilical vein endothelial cells 28. This effect depends on the nuclear factor of kappa B (NFκB) and lipoprotein-related protein (LRP). The genetic absence of CXCL4 reduces lesion size in Apoe-/- mice 29.

In human monocytes, CXCL4 induces a respiratory burst, which is the increased oxygen consumption associated with activation of NADPH oxidase, and expression of several cytokines including CCL3, CCL4 and CXCL8 30. Two distinct pathways have been shown: Phosphatidylinositol-3-kinase (PI3K), spleen tyrosine kinase (Syk) and p38 mitogen-activated protein kinase (MAPK) for induction of respiratory burst, and name (JNK and the MAPK Erk for CXCL4-induced cell differentiation 30. Recently, monocytes treated with CXCL4 were shown to become cytotoxic for endothelial, but not epithelial cells 31. This effect was shown to be mediated by β2 integrin, the most abundant integrins on monocytes, interacting with ICAM-1 and depended on generation of reactive oxygen species in monocytes 31. In vascular smooth muscle cells in vitro, activated platelets have been demonstrated to induce CCL2 in an interleukin (IL)-1-dependent manner 32.

Activated platelets present, secrete and deposit chemokines and thereby induce recruitment of other cells

A defining feature of chemokines is their chemotactic activity towards specific cell types. This activity may be achieved by presentation, secretion or deposition of chemokines by platelets.

CXCL7

The most abundant platelet chemokine is CXCL7 15. In contrast to other chemokines, there are several known molecular variants of CXCL7 including platelet basic protein (PBP), connective tissue-activating peptide III (CTAP-III), β thromboglobulin (β-TG), and neutrophil-activating peptide-2 (NAP-2) (see Figure 1) 15. These CXCL7 variants are proteolytically derived from a precursor molecule (pre-platelet basic protein (pre-PBP)) encoded by the CXCL7 gene. Proteolytic processing of CXCL7 can be accomplished by neutrophil-derived cathepsin G 33 and is inhibited by interaction of CXCL7 with CXCL4 34. The relative proportions of precursor and truncated forms of CXCL7 change during maturation from high levels of pre-PBP in megakaryocytes to high levels of CTAP-III released upon platelet activation 35. The only CXCL7 variant actually displaying chemotactic activity is NAP-2 36. The other variants may be considered precursors of NAP-2 even though they also have other specific biological activities as discussed below 37.

Figure 1
Amino acid sequences of the differentially truncated peptide forms of CXCL7. Starting with pro-PBP in megakaryocytes, sequential proteolytic modification (bold arrows) generates different CXCL7 peptides with different biological functions which are indicated ...

Proteolytic products of CXCL7 down to the size of NAP-2 have been demonstrated to bind to CXCR1 and CXCR2 4. Further truncation, however, impaired binding to these receptors, most likely due to loss of the glutamic acid - leucine - arginine (ELR) sequence 37. NAP-2 itself may downregulate CXCR2 in neutrophils which may represent a negative feedback mechanism and may reduce neutrophil sensitivity towards other chemokines binding to this receptor 33, 38. As the affinity of NAP-2 to CXCR2 is much higher than to CXCR1, NAP-2 may attract neutrophils over a wide range of concentrations39.

CTAP-III and more strongly NAP-2 have been demonstrated to dose-dependently induce neutrophil adhesion to monolayers of HUVEC in vitro over a concentration range broader than CXCL8 40. Beginning at nanomolar concentrations, NAP-2, but not CTAP-III, induced neutrophil transendothelial migration. So far, it is not known whether CXCL7 gets immobilized on the endothelium as has been described for CCL5 and CXCL4 41, 42.

There is little direct evidence for a pro-atherogenic role for platelet-derived CXCL7. Recently, the presence of CXCL7 has been demonstrated in mouse carotid arteries after wire injury 43, 44. CXCL7 has been shown to induce adhesion of endothelial progenitor cells (EPC) under flow and after arterial injury in vivo through its receptor CXCR2 43. Thus, platelet-derived CXCL7 may not only be important for creating an inflammatory environment, but also for regenerating vascular integrity after injury.

CCL5

CCL5 is secreted by lymphocytes, but platelets also represent an important source 45. CCL5 binds to CCR1, CCR3, and CCR5 4 and induces adhesion and transmigration of monocytes and T lymphocytes in a manner that depends on integrins and adhesion molecules like ICAM-1 and VCAM-1 46, 47. In mice, platelets have been demonstrated to deliver CCL5 (and CXCL4) to the monocyte surface and the endothelium resulting in increased leukocyte adhesion to the vascular wall 41. Furthermore, it has been shown that the combination of CXCL4 and CCL5 promotes monocyte adhesion to activated human umbilical vein endothelial cells under flow in a greater number than each of the chemokines alone 42. It is thought that CXCL4 may form heterodimers with CCL5 and thereby promote CCL5 binding to monocytes. Dimerization of CXCL4 with CCL5 may also induce heterodimerization of chemokine receptors, which might modulate intracellular signaling, but direct evidence for this process is lacking.

CXCL4 and CXCL4L1

CXCL4 is stored in the platelet’s α-granules and released into the plasma in concentrations ranging from 0.4-1.9 μM 15. It is the only platelet-derived CXCL chemokine lacking the ELR amino acid sequence at its amino terminus that mediates binding to CXCR1 and CXCR2 4.

CXCL4 binds a 200 kDa chondroitin sulfate proteogylcan on the surface of human neutrophils, which is most likely attached to an unidentified core protein 48. CXCL4 binding was abolished when cells were pretreated with chondroitinase A. In human microvascular endothelial cells, CXCL4 has been shown to bind to CXCR3B, a splice variant of CXCR3, but not to CXCR3A, which is the receptor for the T helper-1 chemokines CXCL9, 10 and 11 49. CXCL4 signaling through CXCR3B was not PTX-sensitive, suggesting an unusual signaling mechanism. A recent report demonstrated that chemotactic activity of CXCL4 towards human T lymphocytes is mediated by both CXCR3 splice variants (CXCR3B>CXCR3A) in a PTX-sensitive manner 50. Human neutrophil adhesion in response to CXCL4 has been shown to require src kinases, because it is blocked after treatment with a src kinase inhibitor 51. Furthermore, blocking studies demonstrate a functional role for Syk, RAS and JNK in the adhesion process 51. Neutrophil exocytosis as determined by lactoferrin release induced by a combination of TNFα and CXCL4 required p38 MAPK and PI3K 30. Taken together, these findings suggest that CXCL4 triggers more than one signalling pathway.

Chemotactic activity of CXCL4 has been controversial. Early reports suggested that CXCL4 exerts chemotactic activity towards neutrophils and monocytes 52. However, these findings were not confirmed and may have been caused by contamination with other chemokines like CCL5 53-55.

A role for CXCL4 in atherosclerosis had been suggested a quarter century ago 56. Both platelets and CXCL4 are present in atherosclerotic lesions and correlate with severity of atherosclerotic lesions and clinical parameters 57. Recently, a causal role of CXCL4 in atherogenesis was suggested by reduced lesion sizes in CXCL4-deficient Apoe-/- mice 29. As discussed above, this may be due to reduced platelet-dependent deposition of CXCL4 and CCL5 on endothelial cells and thus reduced monocyte recruitment 41.

CXCL4L1 (initially called PF4alt), the transcript of a gene highly homologous to CXCL4 58, has also been demonstrated to be present in human platelets. CXCL4L1 differs from CXCL4 by substitution of three amino acids in the C-terminal alpha helix 59. Both CXCL1 and CXCL4L1 have similar homology to the rodent gene for CXCL4, thus it seems likely that the gene was duplicated after the divergence of the two species 58. The functional characteristics of CXCL4L1 are different from those of CXCL4, most strikingly, CXCL4L1 has been demonstrated to be a much stronger inhibitor of endothelial cell chemotaxis than CXCL4 59. So far, no receptor for CXCL4L1 has been identified.

CXCL1

CXCL1 expression has been demonstrated in platelets 13, but it is also expressed by endothelial cells 60, neutrophils, monocytes and macrophages. Thus, platelets may not represent the major source of CXCL1. CXCL1 binds to CXCR2 and with lesser affinity to CXCR1 61. CXCL1 has been demonstrated to support arrest of human monocytic cell lines and primary monocytes under flow conditions 62. This effect is mediated through CXCR2 signaling which was shown to be Gαi-mediated and may play an important role in monocyte recruitment to atherosclerotic lesions 62. Bovine aortic as well as human umbilical vein endothelial cells have been demonstrated to express CXCL1 when exposed to increased shear stress 60, which may promote monocyte arrest under flow 62. It remains unclear as to what extent platelet-derived CXCL1 is involved in these events. Global absence of CXCL1 in Cxcl1-/- mice crossed with Ldlr-/- atherosclerosis-prone mice 26 resulted in smaller lesion size after 16 weeks of Western diet although serum lipids remained unchanged. Interestingly, chimeric Ldlr-/- mice that received bone marrow from mice lacking CXCL1 did not show this reduction suggesting that chemokine expression within the aortic wall rather than in blood leukocytes is the determining factor 26. Similarly, a role for leukocyte CXCR2 expression could be demonstrated, as Ldlr-/- mice repopulated with bone marrow from Cxcr2-/- mice displayed smaller lesion size than those reconstituted with Cxcr2+/+ bone marrow 26.

Other chemokines

CCL2 is abundantly present in atherosclerotic lesions 63. In vivo, the importance of CCL2 has been shown by knocking out either its receptor CCR2 64 or CCL2 itself in mouse models of atherosclerosis (Apoe-/- or Ldlr-/-) resulting in reduced atherosclerotic lesion size 65-67. In the vasculature CCL2 is mostly produced by endothelial cells and smooth muscle cells, but CCL2 presentation by platelets has been demonstrated to support monocyte adhesion in vitro and neointima formation in vivo 68.

CCL3 (macrophage inflammatory protein-1α, MIP-1α) has been shown to be expressed in human atherosclerotic plaques 69. It binds to CCR1 and CCR5 4. CCL3 has been detected in the shoulder region of plaques, and its blood levels are elevated levels during acute myocardial infarction, suggesting a role for this chemokines in plaque destabilization 69.

CXCL5 (encoding a neutrophil chemoattractant peptide, ENA-78) has been cloned from human platelets 70. Having high structural similarity with other chemokines like NAP-2 or CTAP-III, CXCL5 was demonstrated to attract neutrophils 70. By contrast, other than CCL5 or CXCL4, pre-incubation of human microvascular endothelial cells with CXCL5 did not enhance in monocyte arrest under flow 71. The relevance of this chemokine in atherogenesis remains unclear.

CXCL12 is present in atherosclerotic lesions 21. CXCL12 is expressed in platelets, but also in endothelial cells, smooth muscle cells and macrophages 4, 18. Apart from its potential function in platelet activation, CXCL12 seems to plays an important role in neointima formation after arterial injury as it has been demonstrated to attract bone marrow-derived smooth muscle cell progenitors in Apoe-/-72 mice after wire injury. CXCL12 expression was increased on activated platelets, where it induced adherence of CD34+ progenitor cells in vitro under static conditions and under flow. CXCL12- mediated neointima formation was shown to depend on hypoxia-induced factor-1α (HIF-1α) as demonstrated by knock-down experiments in wire-injured Apoe-/- mice 15.

Platelet chemokines induce differentiation of other cells

CXCL4

Several platelet chemokines including CXCL4 have been described to induce differentiation of other cell types 12, 37. Apart from its potential role in conjunction with CCL5 in monocyte recruitment to the vascular wall 42, CXCL4 may promote monocyte differentiation to macrophages 73 or specialized antigen-presenting cells (in the presence of IL-4 and/or GM-CSF) 74, 75. CXCL4-driven macrophages differ from their untreated counterparts by lack of HLA-DR and high CD86 surface expression 55. Furthermore, CXCL4 induces higher phagocytic capacity as compared to GM-CSF induced macrophages 30. Accordingly, CXCL4 may increase atherogenesis by promoting differentiation of monocytes into macrophages and foam cells 73, 76. In murine atherosclerotic plaque, CXCL4 is found close to foam cells 29. Macrophages and foam cells differentiated from monocytes under the influence of CXCL4 are phenotypically different from those differentiated in the presence of M-CSF 76. CXCL4 was demonstrated to inhibit binding and uptake of low density lipoprotein (LDL) through the LDL receptor which may enhance oxidation of LDL and be related to a 10-fold increase in the amount of esterified oxidized (ox)LDL in macrophages, which would be expected to promote foam cell formation in atherosclerotic lesions 77, 78.

Apart from its effects on monocytes, CXCL4 also exerts effects on other cell types including inhibition of cell proliferation and angiogenesis in endothelial cells 59, 79. CXCL4 inhibits proliferation and cytokine release from activated T cells in vitro 54. T cells exposed to CXCL4 show an inhibition of cell proliferation, and deviation towards a T helper (Th)2 phenotype 80. CXCL4 suppresses megakaryopoiesis in vitro and in vivo 81.

CXCL7

Apart from their chemotactic activity, some CXCL7 variants may influence differentiation and behavior of other cells. Thus, CXCL7 variants may promote synthesis of matrix components such as hyaluronic acid or glycosaminoglycanes by fibroblasts 37. Interestingly, CXCL7 variants with a truncated C terminus (thrombocidins) have antimicrobial activity 82, 83.

CXCL12

CXCL12 plays an important role in neointima formation after arterial injury 84. Apart from its role in recruiting progenitor cells to the site of vascular injury 44, it has also been demonstrated to promote differentiation of CD34+ progenitor cells to endothelial cells in vitro and in vivo 84. Thus, upregulation of the endothelial differentiation marker CD146 was inhibited in CD34+ progenitor cells if treated with antibodies against CXCL12 or its receptor CXCR4 85.

Conclusions

Platelets and platelet-derived chemokines play an important role in atherogenesis. In contrast to chemokines synthesized upon certain stimuli, they are stored within the platelets’ α-granules and can be quickly released upon platelet activation. Most chemokines are able to attract specific leukocyte subsets to the lesion site, but they also influence proliferation, differentiation and degranulation of various cell types. Alone or as heterodimers with other chemokines, they may exert their effects via different G-protein coupled receptors expressed in their target cells, some of which remain to be identified. Finally, some chemokines may regulate expression or processing of precursors of other chemokines illustrating that there is a finely tuned chemokines network exerting its effects.

Recent studies have illustrated the clinical importance of gene polymorphisms 86 or serum levels of circulating chemokines to predict clinically significant atherosclerosis 85 or even acute cardiovascular events 22. These findings emphasize the importance of a good understanding of chemokine function in atherosclerosis. Some platelet-derived chemokines such as CXCL4 may represent interesting therapeutic targets as they promote several steps in the development of atherosclerotic lesions. Anti-platelet therapy has been a valuable tool to treat patients with atherosclerosis and has clearly been shown to prevent adverse events. Combining anti-hemostatic with anti-inflammatory treatments targeting platelet-derived chemokines may improve long-term prognosis in patients with cardiovascular disease.

Footnotes

Publisher's Disclaimer: The manuscript and its contents are confidential, intended for journal review purposes only, and not to be further disclosed. This is an un-copyedited author manuscript that was accepted for publication in Arteriosclerosis, Thrombosis, and Vascular Biology, copyright The American Heart Association. This may not be duplicated or reproduced, other than for personal use or within the “Fair Use of Copyrighted Materials” (section 107, title 17, U.S. Code) without prior permission of the copyright owner, The American Heart Association. The final copyedited article, which is the version of record, can be found at Arteriosclerosis, Thrombosis, and Vascular Biology. The American Heart Association disclaims any responsibility or liability for errors or omissions in this version of the manuscript or in any version derived from it by the National Institutes of Health or other parties.

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