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CHEMOKINES
From the Theodor Kocher Institute, University of Berne,
Berne, Switzerland; and Serono Pharmaceutical Research Institute SA,
Geneva, Switzerland.
Platelets are known to contain platelet factor 4 and
Chemokines (chemotactic cytokines) are small
proteins that induce chemotaxis of cells by interacting with specific
receptors. Chemokines are subdivided into 2 major classes based on the
sequence of the cysteine pair domain near to the NH2
terminus.1 The The major physiologic function of platelets is hemostasis and
maintenance of the vessel wall but, in addition, they are thought to
have roles in inflammation and host defense.7 Platelets were the source of the first-described molecules of the chemokine CXC
class with PF4 and More recently platelets have also been shown to contain other members
of the chemokine family, both of the CXC class, such as IL-8 and
epithelial neutrophil-activating protein 78 (ENA-78),15 and of the C-C class, such as RANTES,16
MIP-1 Recent studies have shown that platelets are activated in patients
infected with human immunodeficiency virus (HIV) and that plasma levels
of RANTES are raised.19,20 It was also shown by using
platelet inhibitors that the plasma levels could be brought back to
normal levels, strongly supporting the idea that the platelets were the
main source of the plasma RANTES in patients infected with
HIV.19 Because chemokine receptors are known to play a major role in infection of T cells and macrophages by the
virus21 and it appeared possible that in HIV-infected
patients the virus may induce platelet activation, we investigated the
expression and function of chemokine receptors on platelets in more
detail. These studies indicate that the CCR1, CCR3, CCR4, and CXCR4
receptors function on platelets, signaling to the platelet interior as
well as activating the fibrinogen receptor,
Chemicals
Antibodies
Platelet preparation Human blood platelets were isolated from buffy coats, within 12 hours after blood collection, obtained from the Central Laboratory of the Blood Transfusion Service of the Swiss Red Cross in Berne. The buffy coats were transferred into one third of their volume of 100 mmol/L sodium citrate, pH 6.5. The platelets were collected by centrifugation at 1500g for 7 minutes and washed twice in 40 mL Tyrode solution pH 6.5 (24.4 mmol/L NaH2PO4, 4.3 mmol/L Na2HPO4, 4.3 mmol/L K2HPO4, 113 mmol/L NaCl, 5.5 mmol/L glucose). The platelets were suspended in 20 mmol/L Hepes, 136 mmol/L NaCl, 4.8 mmol/L KCl, pH 7.4, and stirred at 1000 rpm. Activation studies were performed in the presence of 2 mmol/L CaCl2.Polymerase chain reaction Poly A+ mRNA was isolated from human platelets as described previously.15 Reverse transcriptase reactions were performed on 1 µg poly A+ RNA using an oligo dT primer with the Superscript preamplification system (Gibco-BRL-Life Technologies, Basel, Switzerland) and Amplitaq (PerkinElmer-Cetus, Rotkreuz, Switzerland). One twentieth of the reverse transcriptase reaction mixture was then subjected to 35 cycles of PCR (2 minutes, 94°C; 2 minutes, 55°C; and 2 minutes, 72°C) in a reaction mixture containing 50 pmoles sense and antisense primer pairs for each of the following chemokine receptors: CCR1-9, CXCR1-5, CX3CR1, XCR1, DARC, and GAPDH as a control for the quality of the cDNA used in each PCR reaction, in an MJ Research DNA engine (Waltham, MA). Primers were designed to amplify the full coding sequence (approximately 1.1 kb), based on the receptor sequences obtained from the GenBank database. The predicted size of the GAPDH product was 1 kb. In addition, control PCR reactions were performed with each primer pair on RNA samples that had been incubated in the absence of reverse transcriptase (results not shown). The identity of PCR products migrating at the predicted size was verified following gel purification using a Wizard PCR preps kit (Promega, Wallisellen, Switzerland), by direct sequencing using the same primers as for the PCR reaction, in an ABI 377 DNA sequencer (PerkinElmer, Hünenberg, Switzerland).Intracellular Ca++ measurements Washed platelets (108/mL) were loaded with 2 µm fura-2/AM (Fluka, Buchs, Switzerland) for 20 minutes, washed once with Hepes buffer, pH 7.4, and resuspended in Hepes buffer, pH 7.4, containing 2 mmol/L Ca++. Fluorescence of fura-2/Ca++ complex in platelets was measured in a multichannel fluorimeter. Ca++ measurements were standardized using ionomycin (1 µmol/L) and Mn++ (5 mmol/L) to give maximum and minimum levels, respectively. Platelet activation by ADP (10 µmol/L) and thrombin (0.05 U/mL) was used to control platelet viability.Immunoblotting Aliquots (5 µL or 20 µL, 5 × 108 platelets/mL) of control, resting platelets as well as activated platelets were solubilized in sodium dodecyl sulfate (SDS) electrophoresis buffer containing 1 mmol/L PMSF, 5 mmol/L EDTA, 2 mmol/L N-ethylmaleimide, 2 mmol/L benzamidine, and 2 mmol/L sodium orthovanadate and separated by polyacrylamide gel electrophoresis (PAGE) on 7% to 20% acrylamide gels using the Laemmli method. Proteins were blotted to PVDF membranes using a semidry technique. Proteins were then detected by staining the membranes using specific antibodies, polyclonal or monoclonal, followed by chemiluminescence using peroxidase-coupled second antibody, luminol-enhancer substrate, and autoradiography or using a phosphatase-coupled second antibody, then 5-bromo-4-chloro-3-indolyl phosphate plus nitroblue tetrazolium.Immunoprecipitation Aliquots (700 µL, 5 × 108/µL) of control, resting as well as activated platelets were solubilized in phosphate-buffered saline containing either 1% Triton X-100, 0.5% sodium deoxycholate, and 0.1% SDS (RIPA) or 1% Triton X-100 with 1 mmol/L PMSF, 5 mmol/L EDTA, 2 mmol/L N-ethylmaleimide, 2 mmol/L benzamidine, and 2 mmol/L sodium orthovanadate. After platelet solubilization, the lysates were left for 30 minutes on ice, centrifuged for 30 minutes at 10 000g, in most cases cleared with 10 µL Protein A-Sepharose and then agitated for 2 hours with specific antibodies before adding 20 µL Protein A-Sepharose followed by a 6- to 8- hour incubation. The Protein A-Sepharose pellets were washed 4 times in the platelet solubilizing buffer, boiled in Laemmli buffer, and the supernatants collected. The immunoprecipitated or affinity-precipitated proteins were separated by gel electrophoresis, transferred to PVDF membranes, and incubated with specific antibodies. They were detected by chemiluminescence. Before reprobing with another antibody the membranes were stripped for 30 minutes at 60°C in 62.5 mmol/L Tris-HCl, pH 7.0, 2% SDS, and 100 mmol/L -mercaptoethanol.
Detection of platelet chemokine receptors Evidence for the presence of platelet chemokine receptors was obtained by several methods. PCR of platelet mRNA with specific primers for CCR1-9 and CXCR1-5 showed the presence of mRNA for CCR1, CCR3, CCR4, CXCR1, and, weakly, CXCR4 (Figure 1). Flow cytometry with specific antibodies showed the presence of a clear signal for CXCR4 and weaker signals for CCR1 and CCR3, whereas CXCR1, CXCR2, CXCR3, and CCR5 were all negative (Figure 2). Immunoprecipitation and Western blotting with polyclonal antibodies to cytoplasmic peptides clearly showed the presence of CCR1 and CCR4 in platelets in comparable amounts to monocytes and CCR4 transfected cells, respectively (Figure 3).
Chemokines induce a Ca++ response in platelets To determine whether chemokine receptors on platelets are functional, we tested several chemokines on platelets to assess their ability to induce Ca++ responses. Of those tested, IL-8 and MCP-3 had essentially no effect (a very marginal effect was seen with 100 nmol/L IL-8). MCP-1, MIP-1 , eotaxin, RANTES, TARC, MDC,
and SDF-1 all induced a rapid, dose-dependent (10-100 nmol/L) rise in
[Ca++]i. Figure
4 shows results with 100 nmol/L amounts.
Figure 5 shows a dose-dependent response
with lower amounts of ligands typical for 3 receptors. To clarify which
receptors respond and the ligand specificity, cross-desensitization was
carried out between these chemokines. The known CCR4 ligands showed
cross-desensitization; however, SDF-1, which is a CXCR4-specific
ligand, also showed cross-desensitization with MCP-1, MIP-1, RANTES,
TARC, and MDC. All of these chemokines also showed a desensitized
response to a second dose of the same chemokine.
ADP and ADP receptor inhibitor induced effects on chemokine signals Unlike most cells on which chemokines have been tested, platelets show rapid positive feedback responses to many agonists, via release of storage granule contents or by thromboxane generation. ADP is a major component of dense granules and also causes a rapid rise in [Ca++]i when used as agonist. To check if ADP release in response to chemokines might be responsible for some desensitization, we tested both ADP as a desensitization agent as well as the ADP receptor inhibitor (AR-C66096). ADP as first agonist gave a signal and partially desensitized the response to the chemokines. ADP receptor inhibitor or, alternatively, apyrase to destroy released ADP both reduced, but did not eliminate, the Ca++ signal in response to the chemokines (Figure 6).
Thrombin receptor peptide causes desensitization of chemokine responses Platelets gave a strong Ca++ elevation in response to SFLLRN (TRAP) but a following challenge by MCP-1, MIP-1, RANTES,
TARC, MDC, and SDF-1 was partially desensitized (Figure 6). In reverse order, following a challenge by these chemokines, the
[Ca++]i signal induced by TRAP was also
reduced compared to when it was given as first agonist. Similarly, a
first challenge by a chemokine reduced somewhat the Ca++
response to thrombin (Figure 6).
Chemokines signal synergistically via Ca++ and signals are inhibited by specific receptor antibodies When platelets were treated with a mixture of low amounts of 2 chemokines acting on different receptors, the calcium signal obtained was much higher than when they were treated with the same amounts of each chemokine subsequently (eg, eotaxin and TARC, Figure 7A) or with double the amount of each chemokine (compare with Figure 5). The platelets nevertheless still responded well to thrombin. A synergistic aggregation response to mixed chemokines was also detected (see below).
To demonstrate that signals were specific to a given ligand/receptor a
blocking antibody against CCR3 (MAB155) was used (Figure 7B). This
antibody caused a calcium signal by itself, which could be eliminated
by pretreating the platelets with Fab fragments of the anti-Fc Chemokines induce platelet aggregation Platelet suspensions (500 µL, 5 × 108 platelets/mL) were treated with chemokines in an aggregometer. TARC, RANTES, and MDC gave rapid aggregation responses that were slowly and partly reversible. SDF-1 gave a lower but still clear response (Figure 8), as did MCP-1 and MIP-1 (data not
shown). Following an aggregation response to TARC or SDF-1, platelets
were still capable of responding to RANTES (data not shown).
Combinations of TARC and SDF-1 or RANTES and TARC gave an additive
aggregation response when given simultaneously (Figure 8) but not when
added successively (not shown).
Chemokine-induced platelet aggregation is dependent on ADP release and ADP receptor engagement Platelet suspensions (500 µL, 5 × 108 platelets/mL) were pretreated with either AR-C66096 ADP receptor inhibitor or apyrase in an aggregometer. After 2 minutes, RANTES, TARC, MDC, or SDF-1 was added. Aggregation was inhibited in a dose-dependent way with complete inhibition at above 100 nmol/L ADP receptor inhibitor or 2 U/mL apyrase. Figure 8 shows the results obtained with TARC and with RANTES in the presence of apyrase.Heparin and low-molecular-weight heparin inhibit the platelet response to chemokines in a dose-dependent way Addition of 1 U/mL heparin to a suspension of washed platelets reduced the aggregation response to TARC by 50% (Figure 9). Amounts greater than 7 U/mL essentially prevented platelet aggregation in response to TARC. Similar results were obtained with the other chemokines. Use of low-molecular-weight heparin (Fragmin) in place of unfractionated heparin gave similar results (Figure 9).
Heparinases and chondroitinases reduce the platelet aggregation response to chemokines A suspension of washed platelets, which was incubated at 37°C for 30 minutes with heparinases I and III (5 U/mL) or chondroitinases ABC (5 U/mL), showed a reduced aggregation response to TARC (Figure 9), SDF-1, and RANTES (not shown) chemokines. Incubation with a mixture of heparinases and chondroitinases (each 5 U/mL) was more effective than either alone but still did not completely prevent platelet aggregation.Chemokines induce tyrosine kinase signaling in platelets Platelets (700 µL, 5 × 108/mL) were treated with chemokines as for aggregation; aliquots were taken at 0, 30, 60, 90, 120, and 300 seconds and dissolved in 1% SDS, 1 mmol/L N-ethylmaleimide, 1 mmol/L EDTA, and 2 mmol/L sodium orthovanadate. After separation by SDS-PAGE (7%-20% acrylamide gradient) and transfer to PVDF membranes, the proteins were incubated with the antiphosphotyrosine antibody 4G10 before detection by a peroxidase-linked second antibody and chemiluminescence (Figure 10). Clear dose-related responses to chemokines were detected, which showed some distinct differences from signals induced by ADP. The results shown are those obtained with different doses of 2 different agonists, in one case 100 nmol/L RANTES and, in the other, 40 nmol/L TARC. However, similar results were also obtained with different doses of the same agonist. The lower dose of agonist caused a rapid, transient tyrosine phosphorylation of several typical components, including p72SYK and Fc . The higher
dose also caused a rapid increase in tyrosine phosphorylation of these
components but they remained phosphorylated and were only slowly
dephosphorylated. Comparison with the pattern of tyrosine
phosphorylation obtained under the same conditions using ADP or
thrombin as agonists showed some similarities but also differences.
Chemokines induce tyrosine phosphorylation of Fc although to a
lesser degree. Although the ADP-activated platelets showed a similar
dose-dependent increase in phosphorylation of p72SYK, the
Fc was not detectably phosphorylated. In addition, a band at 36 to
38 kd corresponding to Linker for Activation of
T cells (LAT) was also phosphorylated in a dose-dependent
way that was not detectable in the ADP-activated platelets.
Immunoprecipitation showed a time-dependent increase in tyrosine
phosphorylation of PLC2 (Figure 10B), a major downstream enzyme
target of these pathways responsible for calcium release and protein
kinase C (PKC) activation. Thus, chemokine-activated platelets
showed an increase in tyrosine phosphorylation of some components
independent of the effects of ADP alone.
Chemokine family proteins were first detected stored in platelet
Desensitization of the signal from a second stimulus was also observed,
whether the same chemokine was used twice or followed by another, which
was active as a first stimulus. Normally, this is a classic method for
testing for G-protein-linked receptor specificity because only ligands
that interact with the same receptor mutually desensitize the response.
It was therefore surprising to observe desensitization occurring
between chemokines such as TARC, specific for CCR4, and SDF-1, specific
for CXCR4. However, platelets are different from many other cells where
chemokine receptors have been studied because of the many rapid
feedback mechanisms that operate. Further experiments showed that,
following platelet activation by ADP or TRAP, derived from the protease activated receptor 1 (PAR-1) thrombin receptor, the platelet
Ca++ response to chemokines was also partially
down-regulated. Chemokines as first stimulus also influenced the
platelet response to ADP as well as that to TRAP (which causes ADP
release). This suggested that the desensitization effect could be due
to ADP release from platelet-dense granules caused by the first agonist
feeding back to ADP receptors and desensitizing these to ADP released
by the second agonist. To test this hypothesis we used either the ADP receptor inhibitor, AR-C66096, to prevent feedback to the ADP receptor
involved in activating the fibrinogen receptor
When small amounts of 2 chemokines were mixed before adding to
platelets they gave a much stronger effect, whether Ca++
signal or aggregation response, than when the same reagents were added
sequentially (Figures 7 and 10). This suggests a synergistic effect due to simultaneous activation of G In addition to a Ca++ signal chemokines also induce
platelet aggregation but weakly compared to normal amounts of classic
reagents such as thrombin and collagen, although within the range found with ADP. TARC and RANTES gave the strongest signals among the CCR
ligands and SDF-1 gave a slightly weaker signal as a CXCR4 agonist.
Prevention of ADP receptor activation by either the ADP receptor
inhibitor or by apyrase resulted in a complete inhibition of platelet
aggregation demonstrating that the aggregation response is completely
dependent on feedback of released ADP to the ADP receptor(s). Thus,
activation of platelets by chemokines causes release of ADP from dense
granules and ADP feedback is a prerequisite for aggregation in common
with plasma from patients with heparin-induced thrombocytopenia22 and collagen as agonists, which suggests common mechanisms for all these agonists. A possible explanation may
lie in studies that showed that simultaneous activation via G Both TARC and RANTES induce tyrosine phosphorylation of signaling
proteins, including p72SYK, Fc It was shown earlier that cell surface proteoglycans play a role in the activation of endothelial cells by chemokines, either by enhancing binding to the cell surface or by multiplying interactions with receptors or both.31 Similarly, the interactions between SDF-1 and cell-bound glycosaminoglycans were suggested to enhance SDF-1 interactions with CXCR4 on epithelial cells, possibly by presenting the chemokine to its receptor in a more concentrated form.32 It has also been shown previously that platelet surface proteoglycans are involved in interactions between certain platelet agonists and the platelet surface. These include human group II PLA2, which uses a glycophosphatidylinositol-anchored heparan sulfate proteoglycan to interact with the platelet surface,33 as well as the PF4-heparin antibody complex involved in heparin-induced thrombocytopenia, which requires surface proteoglycans for effective platelet activation and also acts via released ADP.22 Because of these observations various heparinases and chondroitinases were tested to see if they affected platelet activation by chemokines. All of those tested reduced platelet aggregation by typical chemokines by 20% to 30%. A mixture of glycosaminoglycanases reduced platelet aggregation response by 60% to 70%, as had been noted earlier for endothelial cells, suggesting that the glycosaminoglycans involved belong to different classes that are not all cleaved off when single-specificity enzymes were used. This interpretation was strengthened by the effect of heparin and low-molecular-weight heparin (Fragmin) on platelet activation by chemokines. In both cases a dose-dependent inhibition was observed, and at the higher concentrations platelet aggregation was completely inhibited. It has been suggested that those chemokine receptors present on platelets are simply carried over from megakaryocytes and have no direct function in platelet physiology. CXCR4 receptors expressed on mature polyploid megakaryocytes responded to SDF-1 and caused chemotaxis, proplatelet formation, and transmigration through bone marrow endothelial cells.34 The proplatelets and platelet-like particles that were formed expressed CXCR4. The results described here show clearly that platelets express functional CCR4 and CXCR4 receptors that are capable of signaling, inducing release of storage granules, and causing aggregation, albeit at a low level. The demonstration of the presence of functional CCR4 suggests that chemokines that are ligands for this receptor might also function in megakaryocyte maturation and platelet formation. Platelets themselves contain some of the chemokines that are ligands for CCR1 and CCR3, such as RANTES, so that one role may be in feeding back to receptors on the same or other platelets to amplify response in an aggregatory situation. Recently, vascular endothelial cells35 as well as smooth muscle cells36 have been shown to express several chemokine receptors. In addition several cells associated with atherosclerotic plaque were found to express RANTES, which was absent in normal vascular tissue. Raised levels of RANTES as well as other CC chemokines were found in patients with congestive heart failure,37 and a role for both platelets and monocytes was suggested.38 Recent studies found elevated levels of RANTES in plasma from patients with HIV-1 infections. This was demonstrated to come predominantly from activation of platelets because platelet activation inhibitors reduced plasma levels considerably.19,20 In patients on antiretroviral therapy higher maintained levels of RANTES were associated with nonprogressors, suggesting that RANTES had a beneficial effect.39 Patients with asymptomatic HIV infections have thrombocytopenia in about 10% of cases, which has not yet been satisfactorily explained, although several hypotheses have been proposed.40 Shortened platelet lifetime is certainly one reason. Activation of platelets by HIV envelope glycoprotein 120 (gp120) or by herpesvirus proteins41 as well as feedback through RANTES release from their granules or from neighboring platelets could be contributory factors. Following activation, platelets aggregate via plasma proteins such as fibrinogen and the aggregates are removed by the spleen leading to thrombocytopenia. Thrombotic microangiopathy is also increased in patients with acquired immunodeficiency syndrome and HIV infections.42 Platelets were recently shown to be able to take up and transport HIV, and the platelets containing virus were activated.43 Several studies have been made of signal transduction via chemokine receptors.44 HIV gp120 induced signal transduction in cells expressing CXCR4 or CCR5 in addition to CD4.45 An important question is what activates the platelets in patients infected with HIV-1. Because platelets do not express CD4 but do express CXCR4 and CCR4, which are or can be coreceptors, a possibility exists that another molecule can replace CD4. Recently, it was shown that gp120 from HIV can activate human neuronal tera (hNT) neuronal cell lines directly via CXCR4 without a requirement for CD446 so that a direct mechanism may also exist for platelets. Taken together, these results suggest that RANTES release from platelets could be a defense mechanism in HIV infections by blocking or down-regulating CCR3 or CCR5 receptors on immune cells with RANTES and that chemokine receptors on platelets may be involved in feedback mechanisms. Because of the inhibitory effects of both ADP receptor inhibitors as well as heparin and low-molecular-weight heparin on the platelet response, it should be borne in mind that antithrombotic treatment of patients with these classes of inhibitors could affect the development of the disease in HIV-infected patients and that other types of treatment such as GPIIb-IIIa or thrombin inhibitors should also be considered. It was recently shown that soluble complexes of RANTES and glycosaminoglycans could suppress HIV-1 infection of monocytes but did not induce calcium signaling,47 suggesting that, as in platelets, binding to glycosaminoglycan-carrying macromolecules on the cell surface may supply a critical component of the signal response. It was recently shown that the platelet CXC chemokine PF4 promotes monocyte survival and induces monocyte differentiation into macrophages.48 Activated platelets cause monocytes to release chemokines49 so that mutual activation by specific chemokines could be an important mechanism for interaction between these cells under a variety of physiologically relevant conditions. After this manuscript was submitted Abi-Younes and coworkers50 demonstrated that SDF-1 induces platelet aggregation and calcium signaling and that human atheroma is rich in SDF-1. It is likely that atheroma is also enriched in other platelet-active chemokines, supporting a role for platelet-chemokine interactions in atherosclerosis. Release of RANTES from platelets with a role in accumulation of eosinophils has been implicated in asthma.51 Here again platelets may have a role in amplifying this response. Platelets do not contain either CCR4 (MDC, TARC) or CXCR4 (SDF-1) agonists. Therefore, the role of these receptors may be to involve platelets in situations where these agonists are provided by other cells. In general, the part that platelets play in many inflammatory and allergic responses has not yet been carefully examined. The availability of clinically approved, efficient inhibitors of platelet aggregation as well as those that affect platelet release should allow the role of platelet activation to be tested in a variety of diseases other than those directly related to thrombosis.
We thank the Central Laboratory of the Swiss Red Cross Blood Transfusion Service for the supply of buffy coats.
Submitted January 27, 2000; accepted August 17, 2000.
Work at the Theodor Kocher Institute was supported by Swiss National Science Foundation grant 31-52396.97 to K.J.C. and 31-055996.98 to M.B.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Kenneth J. Clemetson, Theodor Kocher Institute, University of Berne, Freiestrasse 1 CH-3012, Berne, Switzerland; e-mail: clemetson{at}tki.unibe.ch.
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T. Youssefian, A. Drouin, J.-M. Masse, J. Guichard, and E. M. Cramer Host defense role of platelets: engulfment of HIV and Staphylococcus aureus occurs in a specific subcellular compartment and is enhanced by platelet activation Blood, May 13, 2002; 99(11): 4021 - 4029. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
possible role of platelets and
monocytes. Cardiovasc Res. 45:428-436.