Published online before print March 22, 2007, doi: 10.1161/ATVBAHA.107.141515
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© 2007 American Heart Association, Inc.
Thrombosis |
Platelets Recruit Human Dendritic Cells Via Mac-1/JAM-C Interaction and Modulate Dendritic Cell Function In Vitro
From Innere Medizin (H.F.L., K.D., G.B., T.S., A.E.M., K.S., A.B., D.S.-A., P.S., M.G.), Abteilung III, Eberhard Karls University Tuebingen, Germany; Department of Dermatology (M.S., M.R.), Eberhard Karls University Tuebingen, Germany; Internal Medicine I (G.M.S., S.W.), Eberhard Karls University Tuebingen, Germany; Department of Thoracic, Cardiac, and Vascular Surgery (H.P.W., H.A.), Eberhard Karls University Tuebingen, Germany; Institute for Clinical Immunology and Transfusion Medicine (S.S.), Justus-Liebig-University Giessen; Internal Medicine II (P.B.), Eberhard Karls University Tuebingen, Germany.
Correspondence to Harald F. Langer, MD, Medizinische Klinik III, Eberhard Karls Universität Tübingen, Otfried-Müller Str. 10, 72076 Tübingen, Germany. E-mail harald.langer{at}med.uni-tuebingen.de; or to Meinrad Gawaz, MD, Medizinische Klinik III, Universitätsklinikum Tübingen, Otfried-Müllerstr.10, 72076 Tübingen, Germany. E-mail meinrad.gawaz@med.uni-tuebingen.de
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Abstract |
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Objective— Thrombotic events and immunoinflammatory processes take place next to each other during vascular remodeling in atherosclerotic lesions. In this study we investigated the interaction of platelets with dendritic cells (DCs).
Methods and Results— The rolling of DCs on platelets was mediated by PSGL-1. Firm adhesion of DCs was mediated through integrin 
Mβ2 (Mac-1). In vivo, adhesion of DCs to injured carotid arteries in mice was mediated by platelets. Pretreatment with soluble GPVI, which inhibits platelet adhesion to collagen, substantially reduced recruitment of DCs to the injured vessel wall. In addition, preincubation of DCs with sJAM-C significantly reduced their adhesion to platelets. Coincubation of DCs with platelets induced maturation of DCs, as shown by enhanced expression of CD83. In the presence of platelets, DC-induced lymphocyte proliferation was significantly enhanced. Moreover, coincubation of DCs with platelets resulted in platelet phagocytosis by DCs, as verified by different cell phagocytosis assays. Finally, platelet/DC interaction resulted in apoptosis of DCs mediated by a JAM-C–dependent mechanism.
Conclusions— Recruitment of DCs by platelets, which is mediated via CD11b/CD18 (Mac-1) and platelet JAM-C, leads to DC activation and platelet phagocytosis. This process may be of importance for progression of atherosclerotic lesions.
Thrombotic events and immunoinflammatory processes take place next to each other in atherosclerotic lesion formation. We show that recruitment of dendritic cells is mediated by platelets in vitro and in vivo and lead to DC activation and apoptosis. This process may be of importance for atherosclerotic lesion progression.
Key Words: adhesion molecules • cell trafficking • dendritic cells • platelets
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Introduction |
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Beyond their role in hemostasis and thrombosis,1 platelets represent an important linkage between thrombosis, inflammation, and atherogenesis.2 Moreover, there is growing evidence regarding the importance of dendritic cells (DCs) in the pathogenesis of atherosclerosis and of vulnerable coronary plaques.3 In atherosclerotic plaques, the number of DCs is substantially enhanced and DCs preferentially accumulate at rupture-prone regions.4,5 Recently, DCs were shown to accumulate in the intima of atherosclerosis-predisposed regions of the aorta of C57BL/6 mice.6
However, the mechanisms involved in the recruitment of circulating DCs at site of vascular lesions are poorly understood so far.
It is well recognized that platelets rapidly adhere to the extracellular matrix of the subendothelium at sites of vascular lesions. If this process is controlled, platelets passivate vascular injury and initiate the healing process.1 However, uncontrolled platelet-mediated thrombus formation leads to acute thrombotic occlusion or plaque progression resulting in, eg, acute coronary syndrome.7
Platelet-mediated cell recruitment to the atherosclerotic plaque plays a central role for vascular repair mechanisms. DCs participate both in the innate and adaptive immune system and represent highly specialized antigen-presenting cells.8 Thereby, they are capable of stimulating naive, memory, and effector T-cells, as well as activating natural killer cells.8 Proteins are internalized by phagocytosis, degraded into short peptides, and presented via the MHC II receptors.9 During maturation, DCs express various adhesion receptors, which enable DCs to interact with other cell types and mediate homing of DCs to target tissues.4,8
The present study evaluates the role of platelets for DC adhesion to vascular lesions and shows that platelets play a critical role for the recruitment and function of DCs.
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Materials and Methods |
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DCs were generated from buffy coats derived from healthy donors and differentiated to immature monocyte-derived DCs or mature DCs (MDCs) (supplemental Figure I, please see http://atvb.ahajournals.org). For blocking experiments, soluble Fc fusion proteins JAM-A-Fc, JAM-C-Fc, GPVI-Fc, and Fc-control were generated. Adhesion of DCs to platelets (all experiments were performed with isolated platelets) was evaluated in vitro using a static adhesion assay, as well as a dynamic flow model simulating arterial shear rates with and without blocking fusion proteins or antibodies. Recruitment of DCs by platelets in vivo was evaluated by intravital microscopy in mice. Transmission electron microscopy was used to analyze platelet phagocytosis by DCs and direct interaction between the 2 cells. Phenotyping of DCs and differentiation of DCs by platelets was evaluated by flow cytometry, activation of DCs by platelets using a mixed lymphocyte reaction assay with and without blocking substances. Platelet phagocytosis by DCs further was visualized by phase contrast microscopy, standard and confocal immunofluorescence microscopy and flow cytometry. Platelet-induced DC apoptosis was measured by propidium iodide staining, the method of Nicoletti et al, and terminal deoxynucleotidyl transferase-catalyzed deoxyuridinephosphate-nick end labeling (terminal deoxynucleotidyl transferase-mediated deoxyuridinephosphate nick end-labeling assay).
For detailed Material and Methods, please see http://atvb.ahajournals.org
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Results |
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Dendritic Cells Adhere to Immobilized Platelets Under Static and Dynamic Flow Conditions
Platelets play a critical role in the recruitment and adhesion of circulating blood leukocytes toward vascular lesions.2 Recently, we could demonstrate that immobilized platelets are able to interact with and to recruit endothelial progenitor cells.10 Besides endothelial progenitor cells, dendritic cells have been postulated to play a role in vascular repair mechanisms and atherosclerosis.3,4 To test whether DCs bind to platelets, isolated platelets (2x108/mL) were allowed to adhere to 96-well plates coated with collagen type I. Subsequently, immature DCs (immature monocyte-derived DCs) or MDCs were added to the wells and adhesion of DCs on platelets was evaluated. Under static conditions, DCs substantially adhered to immobilized platelets compared with immobilized collagen type I alone (n=6; P<0.05; Figure 1A, 1B). Adhesion of DCs to platelets was dependent on the maturation status, as adhesion of MDC onto platelets was significantly enhanced compared with immature monocyte-derived DCs (n=6; P<0.05; Figure 1B). In the control experiment, adhesion of DCs to immobilized fibronectin was run in parallel.11 To further characterize adhesion of DCs to platelets, DCs were coincubated with adherent platelets and evaluated by electron microscopy. We found that platelets attached to DCs via forming pseudopodia, indicating that specific adhesion receptors are involved (Figure 1C). To evaluate, whether DC adhesion to immobilized platelets occurs in vivo, we used a carotid injury model of intravital microscopy as described.12 We found that virtually no adhesion of DCs to the intact carotid vessel wall occurs (Figure 1D). However, after vascular injury adhesion of circulating DCs to the site of injury occurs rapidly (Figure 1D). Both transient and firm adhesion was evident and reached a maximum at 5 minutes and finally reached plateau (Figure 1D). To further analyze the role of platelets for DC recruitment to vascular lesions, mice were pretreated with the soluble collagen receptor GPVI-Fc, which inhibits adhesion of platelets to the injured carotid artery in vivo.13 Pretreatment of mice with soluble collagen receptor GPVI-Fc significantly reduced adhesion of DCs 5 minutes (P<0.005) and 30 minutes (P<0.05) after induction of injury (supplemental Figure II). Thus, adhesion of DCs to platelets occurs in vivo.
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Next, we analyzed adhesion receptors expressed on DCs that are potentially involved in adhesion to immobilized platelets. We found that both subunits of the β2-integrin Mac-1, CD11b (M-subunit), and CD18 (β2-subunit), are highly expressed on DCs (supplemental Figure III). Moreover, CD29 (β1-subunit), CD49d (4-subunit), and CD162 (PSGL-1) were substantially surface expressed on DCs. Interestingly, surface expression of the β2-chain was further enhanced in DCs cultivated in the presence of MDC compared with immature monocyte-derived DCs (supplemental Figure III).
Next, we evaluated the determinants that mediate DC adhesion to platelets under arterial flow conditions. In a parallel plate flow chamber, DCs cultured in the presence of granulocyte-macrophage colony-stimulating factor/IL-4/CD40L (MDC) were perfused over platelets immobilized on collagen type I at a wall shear rate of 2000 s–1 as described.10 Cell rolling was significantly enhanced on platelets compared with the collagen surface alone (Figure 2A). Preincubation with a blocking monoclonal antibody to CD162, but not with a control antibody (2D1), significantly reduced this cell rolling (Figure 2A). Furthermore, DCs showed enhanced firm adhesion to immobilized platelets compared with immobilized collagen alone (Figure 2B, 2C). When DCs were preincubated with a blocking anti-CD18 mAb (5 µg/mL), firm adhesion of DCs to immobilized platelets was significantly reduced compared with experiments in which an irrelevant mAb (2D1) was used (Figure 2B, 2C). This indicates that the β2-integrin is critically involved in DC/platelet adhesion. In contrast, a blocking mAb directed against CD49d had no effect on DC adhesion onto platelets (Figure 2B, 2C). To identify the platelet counter receptor/ligand for DCs, we evaluated the effect of soluble recombinant JAM-C fusion protein (sJAM-C), which is known as the heterophilic counter-receptor of Mac-1 integrin, on DC/platelet adhesion. For the control experiments, sJAM-A, soluble collagen receptor GPVI-Fc, sGPIb, or Fc was applied. In the presence of sJAM-C, but not sJAM-A, sGPIb, soluble collagen receptor GPVI-Fc (not shown), or Fc, DC–platelet interaction was significantly (P<0.05, n=4 to 8) reduced (Figure 2D, 2E). To identify the distinct β2-integrin involved in the adhesion process, further experiments with blocking monoclonal antibodies were performed. Although there was a certain reduction in adhesion after pre-incubation with an anti-CD11c mAb, an obvious decrease in DC adhesion to platelets could be observed after pre-incubation with an anti-CD11b mAb, which showed statistical significance (P=0.006) only in this group (Figure 2F). Taken together, these data indicate that PSGL-1 mediates an initial contact between DCs and platelets under arterial flow conditions followed by firm adhesion mediated to a substantial part via Mac-1/JAM-C.
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Platelets Induce Differentiation of DCs and Enhance Their Capacity to Stimulate Lymphocyte Proliferation
Coincubation of DCs with platelets over several days suggested an induced differentiation of the DCs as evidenced by enhanced expression of CD83 (Figure 3A), which reached a plateau at day 3 as evaluated by coexpression of CD1a/CD83 (Figure 3B). Furthermore, expression of differentiation markers CD1a/CD83, CD54, CD40, and CCR-7 was evaluated in the presence of blocking mAbs to CD40L, CD18, PF-4, or sJAM-C (Figure 3C). Pre-incubation with a blocking mAb to CD18 or sJAM-C reduced coexpression of CD1a/CD83 and expression of CCR-7, but not expression of CD54 and CD40 in the presence of platelets. Pre-incubation with a blocking mAb to platelet factor 4 (anti-PF-4) reduced coexpression of CD1a/CD83, expression of CD54, CD40, and CCR-7 in the presence of platelets; mAb to CD40L, however, had no effect on the expression of these differentiation markers under platelet influence (Figure 3C).
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The ability of the generated DC populations to stimulate allogenic T-cell responses was furthermore analyzed in a mixed lymphocyte reaction.14 DCs coincubated with platelets showed an enhanced T-cell stimulatory capacity, dependent on the maturation stimulus used (Figure 3D). Immature DCs cultivated in the presence of granulocyte-macrophage colony-stimulating factor/IL-4 showed clearly increased T-cell stimulation after exposure to platelets (n=3, P<0.05; Figure 3D), similar to DCs additionally treated with CD40L but without platelets. However, DCs cultivated in the presence of granulocyte-macrophage colony-stimulating factor/IL-4/CD40L (MDC) revealed a further enhanced T-cell stimulatory capacity, when additionally coincubated with platelets (n=3, P<0.05; Figure 3D). Thus, platelets substantially enhance the capacity of DCs to initiate lymphocyte proliferation, a critical step in the initiation of primary immune responses. To further characterize the influence of platelets on DC activation, we performed additional mixed lymphocyte reaction assays with or without blocking monoclonal antibodies. We found that a blocking mAb to CD40L significantly (n=4, P<0.05) reduced lymphocyte proliferation induced by DCs that were exposed to platelets (Figure 3E). A blocking mAb to CD18 or sJAM-C, however, had no effect in this setting (Figure 3E).
Phagocytosis of Platelets by DCs After Prolonged Interaction
To further characterize the interaction of DCs with platelets, we coincubated these 2 cell types for up to 12 days. After 3 to 7 days, platelets started to disappear and after 
10 days of coincubation; virtually none of the platelets could be found extracellularly (Figures 4A and 5
A). In turn, DCs showed brown intracellular granules, probably representing phagocytosed platelets (Figure 4A). To further analyze phagocytosis of platelets by DCs, platelets were labeled with the Fluorochrome Celltracker orange CMTMR and added to DCs. After 7 days, substantial amounts of fluorescent platelets were found within DCs as verified by confocal fluorescence microscopy (Figure 4B). Using transmission electron microscopy, we further visualized the process of platelet phagocytosis (Figure 4C). Platelets initiate the contact with DCs via protrusions (Figures 4C and 1
C). Subsequently, platelets are incorporated and lysed to cell fragments (Figure 4C). To analyze the exact kinetics of platelet uptake by DCs, platelets were labeled with mepacrine and DCs were analyzed by flow cytometry at different days. Hereby, we could show that platelet uptake started after 3 days and reached a maximum at 5 to 7 days (Figure 4D). Similarly, time-lapse experiments showed that platelets are phagocytosed at this time point (supplemental film, please see http://atvb.ahajournals.org).
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), brown vesicles could be observed. B, To verify platelet phagocytosis by dendritic cells, platelets (2x108/mL) were labeled with the Fluorochrome Celltracker orange CMTMR and coincubated with DCs for 7 days in chamber slides. Subsequently, cells were analyzed by standard and confocal fluorescence microscopy. C, Furthermore, transmission electron microscopy was performed as described in Materials and Methods. Hereby, we could clearly visualize an established contact (<) between DCs (
), internalization, and finally lysis of the platelets resulting in intracellular platelet components within DCs (magnification as indicated in photographs). D, Platelets were stained with mepacrine and after coincubation of DCs with these platelets, phagocytosis was analyzed by assessment of mepacrine-positive DCs using flow cytometry from days 1 to 11. DCs alone served as control.
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Platelets Induce Apoptosis of DCs
Recently, platelets have been described to induce apoptosis of endothelial cells.15 We analyzed the importance of platelet/DC interaction for the induction of apoptosis of DCs using propidium iodide staining as described in Materials and Methods. After coincubation of DCs with isolated platelets, vesicles appeared around DCs (Figure 5A), indicating apoptosis of DCs. Using the same coincubation model and the method of Nicoletti et al, induction of apoptosis was significantly enhanced in DCs (immature monocyte-derived DCs and MDCs) treated with platelets compared with control (P<0.05; Figures 5B, IV). Mitomycin C treatment of DCs, which served as positive control, showed similar levels of apoptotic cell death (Figure 5B and supplemental Figure IV). Similarly, using a terminal deoxynucleotidyl transferase-mediated deoxyuridinephosphate nick end-labeling assay, we could show, that platelets induced apoptosis of DCs (P<0.05, n=3; Figure 5C). Analyzing the kinetics of platelet-induced DC apoptosis by propidium iodide staining, we could show that apoptosis starts after 3 to 5 days and reaches a maximum after 7 days (Figure 5D). To further elucidate the mechanisms mediating platelet-induced DC apoptosis, we performed experiments with pre-incubation with blocking antibodies and the method of Nicoletti et al Thereby, we could show, that the presence of sJAM-C or a blocking mAb to CD11b resulted in significantly decreased apoptosis of DCs (Figure 5E), suggesting this to be one of the central responsible mechanisms. Application of a blocking antibody to PDGF-AB showed a slight, yet not significant decrease, whereas inhibition of CD40L revealed virtually no reduction of DC apoptosis (Figure 5E).
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Discussion |
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In this study, we have shown that platelets regulate adhesion and function of DCs in vitro. The major findings are as follows. DCs adhere to immobilized platelets via the CD11b/CD18 complex (
Mβ2, Mac-1) after an initial contact has been established by dendritic cell PSGL-1. Blocking experiments further showed that CD11c and JAM-A play a minor, yet not significant, role. Platelets enhance the capacity of DCs to initiate lymphocyte proliferation. DCs phagocyte platelets and undergo apoptosis, which was mediated by JAM-C. The recruitment of DCs by platelets to injured carotid arteries in vivo, as verified by intravital microscopy, emphasizes the (patho-) physiological relevance of the identified mechanism. Atherosclerosis is a chronic disease that involves thrombotic but also immunoinflammatory mechanisms.16 DCs are found in the intima of atherosclerosis-prone vessel areas and form cell clusters.6,17 During atheroprogression, the number of DCs markedly increases preferentially within plaque shoulders, which represent plaque rupture-prone regions4,5 associated with plaque destabilization,18 indicating that DCs might be involved in the process of atherosclerosis. DCs can originate from CD34+ progenitor cells and DC precursors, which circulate via the bloodstream to reach their target tissues.4,9 However, the mechanisms that regulate DC recruitment toward the atherosclerotic plaque are not understood.
Platelets accumulate within seconds to sites of vascular injury and release a variety of potent chemotactic factors and adhesion receptors onto the platelet surface that induce recruitment of circulating blood cells toward sites of vascular lesions.1 Recently, circulating endothelial progenitor cells have been shown to home at sites of vascular lesions,19 most likely mediated by adherent platelets.10
In the present study, we show that DCs adhere to immobilized platelets under flow conditions similar to arterial shear rates. Our data suggest that PSGL-1, which is surface-expressed on DCs, is able to mediate an initial contact between platelets and DCs. We found that both subunits CD11b/CD18 of the Mβ2 integrin (Mac-1) are highly surface-expressed on DCs and that adhesion of DCs onto platelets is mediated by CD11b/CD18 but not CD49d. Previously it was shown that DCs bind to fibronectin, possibly via β1-integrins.11 Similarly, in our studies immature DCs bound to fibronectin, but obviously weaker to collagen, which is the major constituent of the extracellular matrix of atherosclerotic plaques. However, when platelets adhere to collagen, they are activated and mediate adhesion of DCs via interaction with β2-integrin. In the present study we could show that JAM-C,20 but not GPIb21 or fibrinogen,22 acts as a specific counter receptor, which is required on platelets to mediate DC adhesion under arterial shear rates.
Hagihara et al23 demonstrated that activated platelets induce IL-10–producing MDCs in vitro derived from mononuclear cells. Similar to the study by Hagihara et al, our data indicate that platelets induce a differentiation of DCs, as shown by enhanced coexpression of CD1a/CD83, which started already after 1 day and peaked at days 2 to 3 of coincubation. Furthermore, we could show that platelets enhance the capacity of DCs to initiate lymphocyte proliferation. Thus, once adherent to platelets, DCs are stimulated to regulate immunoinflammatory responses. Activated platelets release a variety of potent inflammatory compounds, including IL-1, CD40 ligand, or growth factors, that might stimulate maturation and function of DCs. Thus, it is tempting to speculate that in the microenvironment of adherent platelets, immature DCs adhere and mature through stimulation of platelet-derived compounds.23 Because of our experiments, CD40L as one of these candidate substances is involved in platelet-mediated DC activation, as a blocking mAb to CD40L could reduce the effect of platelets on DCs in a mixed lymphocyte reaction.
Once homed to target tissues, DCs continuously and efficiently sample the antigenic content of their microenvironment by phagocytosis.8 We found that platelets are substantially internalized into DCs. As platelets and DCs were coincubated over several days, the platelets presumably were activated. When platelets were coincubated for up to 12 days with DCs, a complete uptake of platelets was obvious. Because platelet-containing DCs changed their morphology significantly, we asked whether they undergo apoptosis. We found that platelet phagocytosis induces apoptosis of DCs as measured by the generation of hypodiploid apoptotic nuclei and terminal deoxynucleotidyl transferase-mediated deoxyuridinephosphate nick end-labeling assay. Interestingly, platelet phagocytosis and DC apoptosis occurred at parallel time points, possibly implying that the one may be linked to the other process. By experiments with blocking proteins, we could show that JAM-C/CD11b is of importance for this process. Our experimental data are strengthened by recent clinical data, which indicate that DCs may be involved in atherosclerosis.3,5,24 For example, application of statins leads to lower numbers of DCs in atherosclerotic plaques.5 An interaction between platelets and dendritic cells thus may be one of the critical cellular links between atherosclerosis and immunologic processes.
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Acknowledgments |
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We acknowledge the excellent technical assistance of Sarah Gehring, Iris Schäfer, Alexandra Gauβ, Heike Runge, Sylvia Stephan, Solveig Daecke and Birgit Fehrenbacher.
Sources of Funding
The study was supported by grants of the Deutsche Forschungsgemeinschaft (GRK1302 to S.W., SFB 685 to P.B. and S.W., We 1801/2-4 to S.W., and Graduiertenkolleg MA2186/3-1 "Zellbiologische Mechanismen immunassoziierter Prozesse," GK 794, and Nr. 2186/3-1 to M.G.), the Bundesministerium für Bildung, Wissenschaft, Forschung und Technologie (Center for Interdisciplinary Clinical Research, IZKF; Fö. 01KS9602 to S.W.), SFB 685 (M.R.), and the Karl und Lore Klein Stiftung and the Sandersstiftung (Nr. 2003.0601 to M.G.), the fortüne program of the UKT, and the Novartis foundation (H.F.L. and M.G.).
Disclosures
None.
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Footnotes |
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P.B. and M.G. contributed equally to this work and both should be considered first authors.
Original received September 24, 2006; final version accepted February 21, 2007.
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References |
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