Abstract
Platelets, beyond their well-described role in haemostasis and thrombosis, act as inflammatory cells playing an active role in several inflammatory conditions. As observed with other inflammatory cells platelets can migrate in vitro, either randomly or in the direction of a chemotactic agent, and in vivo, into inflammed tissues in response to different stimuli. In this chapter we will summarize the current knowledge about the mechanisms that regulate platelet chemotaxis, the evidence for the ability of platelets to migrate in vitro and in vivo, and the mechanisms by which platelets influence chemotaxis of other cells.
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Keywords
- Lower Compartment
- Human Aortic Endothelial Cell
- Formyl Peptide Receptor
- Chemotactic Agent
- Chemotactic Stimulus
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.
Introduction
It is now well established that platelets act as inflammatory cells and contribute to both innate and adaptive immune response through several mechanisms, like pathogen binding, trapping and killing, direct modulation of leukocyte and endothelial cell activation, leukocyte recruitment, and activation of antigen presenting cells (APC) (Czapiga et al. 2004; Jenne et al. 2013; Semple et al. 2011; Vieira-de-Abreu et al. 2012) (also see Slaba and Kubes 2017). Platelets are therefore the most abundant circulating cell type (150–400,000/μL) with an immune function and participate in host defence against parasites, bacteria and viruses. Moreover, increasing evidence shows that platelets play a pathogenic role in several chronic inflammatory disorders including atherosclerosis, allergic inflammation (asthma, rhinitis and eczema), chronic obstructive pulmonary disease, rheumatoid arthritis and inflammatory bowel disease.
Several structural and biochemical characteristics allow platelets to act as inflammatory cells (Heijnen and Korporaal 2017; Slaba and Kubes 2017), probably because they retain some functions of their phylogenetic ancestor, the amoebocyte, the unique nucleated cell with defensive and haemostatic functions circulating in the haemolymph of invertebrates (Momi and Wiwanitkit 2017).
One of the crucial functions of “bona fide” inflammatory cells is their ability to migrate through tissues. Platelets display a number of attributes compatible with the ability to migrate: they express receptors for adhesive proteins and chemokines, contain and release matrix metalloproteinases (MMPs) required for extracellular matrix (ECM) degradation, and have the cytoskeletal and enzymatic machinery required for cell locomotion.
In this chapter, we will summarize the in vitro and in vivo evidence of platelet migration in response to chemotactic stimuli and of the role of platelets in tissue recruitment of other cells, including leukocytes and cancer cells.
Chemotaxis is the active movement, or migration, of a cell in the direction of a chemotactic gradient. It is a central event in several physiologic processes, such as embryonic development, tissue repair, angiogenesis and immune response, and the abnormal chemotaxis of the cells contributes to many pathologic conditions, like chronic inflammation, autoimmunity and metastasis. Cell locomotion is a complex and multistep process by which an extracellular chemotactic gradient is detected by a specific cell receptor, a signal is translated to the cell's motile apparatus and an intracellular functional and structural asymmetry is generated allowing the cell to move towards the detected chemoattractant. Cell polarization is crucial for chemotaxis and consists of the formation of two cellular compartments, the leading edge at the front and the trailing edge at the rear. At the leading edge the cell extends a protrusion, a lamellipodium or filopodium, in the direction of the chemotactic stimulus, which establishes new adhesion sites with the substratum, while at the trailing edge the cell contracts, adhesion sites detach and the uropod, a protrusion at the rear of the cell, retracts. In each of these steps several proteins and intracellular signaling pathways are involved and a fundamental role is played by the cytoskeleton and its ability to rapidly assemble and disassemble (Fig. 1) (Charest and Firtel 2007; Germena and Hirsch 2013; Jin 2013; Raftopoulou and Hall 2004).
Structural Characteristics Ascribing to Platelets the Ability to Migrate
Platelets possess all the structural characteristics required for chemotaxis. They express on their surface several functional chemokine receptors, such as CCR1, CCR3, CCR4, CXCR1, CXCR4, CXCR6, CXCR7 and CX3CR1 (Abi-Younes et al. 2000, 2001; Borst et al. 2012; Chatterjee et al. 2014; Clemetson et al. 2000; Kowalska et al. 1999, 2000; Postea et al. 2012; Rath et al. 2014; Schafer et al. 2004; Suttitanamongkol and Gear 2001; Wang et al. 1998) and other receptors involved in leukocyte migration, like Toll-like receptor 4 (TLR4) and formyl peptide receptors (FPR) (Andonegui et al. 2005; Cognasse et al. 2005; Czapiga et al. 2005).
Platelets possess the central components of chemotaxis-related intracellular signaling, and in particular phosphatidylinositol 3-kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome 10 (PTEN) that regulate the production and cellular localization of phosphatidylinositol 3,4,5-trisphosphate (PIP3), which is crucial for the generation and maintenance of cell polarity (Van Keymeulen et al. 2006), and the Rho family of small GTPases that activate a plethora of effector molecules modulating actin cytoskeleton dynamics (Germena and Hirsch 2013; Worthylake and Burridge 2001; Yan and Jin 2012).
Platelets contain a cytoskeletal framework that allows cell movement. The discoid shape of platelets is maintained by a membrane skeleton that coats internally the plasma membrane, composed by a network of actin filaments, spectrin, adducin, and actin-associated proteins, and by a rigid cytoplasmic scaffold made of actin and filamin A. Actin-associated proteins and filamin A link the platelet cytoskeleton to integrins. Platelet activation induces changes in the cytoskeletal organization with the formation of focal adhesion complexes, dynamic structures linking integrins to the actin cytoskeleton and which together with stress fibres contribute to a contractile response (Goggs et al. 2015; Hartwig 2006).
Platelets contain, and release upon activation, several MMPs, including MMP-1, -2, -3, and -14 (Seizer and May 2013; Busti et al. 2010), which may accomplish the extracellular matrix degradation required for the passage of migrating cells through the basement membrane (Fig. 2).
Platelet Migration: Studies In Vitro
The first in vitro observations on the ability of platelets to migrate date back to the early 70s. Before then, platelets were considered cell fragments passively drifting in the circulation until a contact with an area of damaged endothelium stopped them. The motion of platelets occasionally observed under a light microscope was considered as passive diffusion or Brownian movements, i.e. a temperature-dependent, erratic, not directional movement of particles smaller than 4–5 μm observed in colloidal suspensions (Chamot and Mason 1947).
The first studies on platelet migration in vitro assessed the optimal conditions to study platelet movement showing that several factors, such as temperature, pH, anticoagulant, platelet concentration and buffer composition, influence this process (Lowenhaupt et al. 1977; Nathan 1973; Valone et al. 1974) (Table 1).
Methods
Lowenhaupt and Valone were the first to study platelet migration (Lowenhaupt et al. 1973, 1977; Lowenhaupt 1978; Valone et al. 1974). Lowenhaupt adapted the capillary tube migration chamber previously described by George and Vaughan for the study of macrophage migration (George and Vaughan 1962). This consisted of an incubation chamber with a capillary tube immobilized at the bottom. The incubation chamber was composed of a stainless steel slide (75 × 25 × 3 mm) with a center hole 20 mm in diameter and one side sealed by a siliconized glass slide to form a dish and two small channels connecting it to the edge of the slide (Fig. 3a). A siliconized micro-hematocrit capillary tube, fire-sealed at one end, was filled with platelet-rich plasma (PRP) (300,000 platelets/μL) and centrifuged for 5 min. The capillary tube was then cut at the meniscus between platelet poor plasma (PPP) and the platelet pellet and secured to the bottom of the incubation chamber. The chamber was then filled with autologous PPP, covered with a siliconized cover glass and incubated at 22 °C for 18 h in a CO2 incubator in order to maintain pH between 7.2 and 7.4. To investigate platelet chemotaxis, in the same incubation chamber, a thread-like piece of collagen or a fine-collagen-packed capillary tube was placed at a distance of about 5–6 mm from the platelet-packed capillary tube. The end point was the area of platelet migration out of the capillary tube visible by a stereomicroscope and measured with a planimeter (Lowenhaupt et al. 1973).
Valone instead studied platelet migration by adapting the Boyden chamber initially developed for the study of leukocyte chemotaxis (Boyden 1962) (Fig. 3b). This is a perspex chamber composed of two compartments separated by a filter membrane 100 μm thick with pores of 8 μm size. A platelet suspension in standard buffer (0.005 M KH2PO4, 0.005 M Na2HPO4, 0.1 M NaCl, 0.2 g/100 mL glucose and 0.5 g/mL gelatin) (100,000/μL) was placed in the upper compartment and buffer medium in the lower compartment. After 3 h of incubation the filter was removed, washed, fixed in 10 % formalin, stained, cleared and mounted on a glass slide. Platelets migrated into the filter were counted in 10 high-power fields by phase-contrast microscopy at a fixed level (40–70 μm from the top of the filter) (Valone et al. 1974).
Directional migration of platelets towards a chemotactic gradient was also studied with the micromaze method (Lowenhaupt 1978) or the 7-compartment chamber using indium111-oxine-labeled platelets (Lowenhaupt et al. 1982). The micromaze is a chamber formed by four compartments connected by thin slits to permit cell passage between compartments; collagen was placed in compartment 4 (Fig. 4a). Platelet movement was visualized by an inverted phase-contrast microscope by following the leading edge of the platelet mass or by viewing the passage of individual platelets between compartments through the slits: time-lapse image sequences were taken at fixed intervals (Lowenhaupt 1978). The 7-compartment chamber consists of seven identical compartments linearly connected and separated by Nucleopore or Millipore filters of different pore size (III and IV 3 μm, II and V 1 μm, I and VI 0.45 μm); collagen was placed in compartment G (Fig. 4b). Gel-filtered platelets were labeled with 111In-oxine, resuspended in autologous platelet-free plasma (PFP) and filtered through two sterile nylon mesh filters to remove aggregates. Platelet chemotaxis was expressed as a ratio of the radioactive counts of the two-end compartments (Lowenhaupt et al. 1982).
More recently platelet chemotaxis has been studied using several further modifications of the original Boyden chamber, namely:
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1.
The NeuroProbe 96-well ChemoTx microplate, with the upper and lower compartments separated by a 2 μm pores filter. After 2 h of incubation, platelets migrated into the lower compartment were counted by light microscopy (Czapiga et al. 2005).
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2.
The Nucleopore single wells, with the upper and lower compartments separated by a 3 μm pore size filter, loaded with murine or human PRP. After 1.5 or 3 h incubation, respectively, filters were stained and platelets were counted at various depths below the filter surface (0–100 μm for murine and 40–70 μm for human platelets) (Pitchford et al. 2008).
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3.
The transwell inserts, with a polyethylene terephthalate (PET) membrane with 0.4 μm pores. Platelets were added in the upper compartment, allowed to migrate for 8 h and then counted in the lower compartment by flow cytometry (Kraemer et al. 2010).
Horizontal migration of platelets has been studied in a delta T culture dish placed on a microscope with a heated stage and platelet movements were recordedbefore and during the addition of either fMLP or PBS (as a control) every 5 s for 15 min (Czapiga et al. 2005), or in a migration chamber consisting of a fibrinogen-coated slide with a central spot of low-melting agarose containing the chemotactic agent and platelet movement were recorded using a polarization microscope for 3 h (Kraemer et al. 2010).
The assays used to study platelet migration are summarized in Table 1.
Chemotactic Agents
Platelets can detect an extracellular chemotactic gradient and move along this gradient. The first platelet chemotactic agent to be described has been collagen. Various types of collagen (bovine, equine, human from skin or from achilles tendon) elicit platelet chemotaxis, although with different potency. Only native collagen, and not heat-denatured or dinitrofluorobenzene-treated collagen, induces platelet chemotaxis. Interestingly, the structural features of collagen required for platelet aggregation, i.e. the fibrillar structure, are not required for chemotaxis. Collagen-induced platelet chemotaxis does not require a direct contact with platelets, given that migration was still observed when a filter impermeable to the large polymerized collagen molecules was interposed between platelets and the stimulus. Thus, the generation of “chemotaxins”, low molecular weight substances produced by the interaction between collagen and plasma, was postulated (Lowenhaupt 1982). Platelets migrated in the direction of collagen for a long distance (3000 times their diameter, i.e. 6 mm) in a very short time (15 min) (Lowenhaupt 1978).
Formyl peptides, cleavage products of bacterial and mitochondrial proteins, induce platelet chemotaxis via binding to formyl peptide receptors (FPR), seven transmembrane receptors coupled to Gαi stored in α-granules and expressed on the platelet surface after activation (Czapiga et al. 2005). Platelet movement towards fMLP at a velocity of 13.07 ± 1.10 μm/min has also been recorded in time-lapse (Czapiga et al. 2005).
Recently, platelet chemotaxis towards a conventional chemokine of the CXC family, CXCL12 or stromal cell-derived factor-1α (SDF-1α), has been shown (Kraemer et al. 2010). This chemokine induced platelet migration upon binding to its specific receptor CXCR4 expressed on platelets, given that the CXCR4-receptor antagonist AMD3100 inhibits it. Platelets also trans-migrate through an IL-1β-activated layer of human umbilical vein endothelial cells (HUVEC) in the direction of SDF-1α (Kraemer et al. 2010). In time-lapse studies platelets accumulated around the source of SDF-1α after 3 h, with a speed of migration variable depending on the number of focal adhesion contacts. In the early stages of migration (fast migration: 200 μm/3 h) platelets have only few focal adhesion contacts, while their number increases as migration speed slows down (Kraemer et al. 2010).
Molecular Mechanisms Regulating Platelet Migration
Platelet migration is an active, energy-consuming process that requires viable and metabolically intact platelets. Infact, fixation with formalin or pre-treatment with iodoacetic acid (IAA) and sodium fluoride (NaF), which interfere with the glycolytic pathway, with 2,4-dinitrophenol (DNP), which uncouples oxidative phosphorylation, and with 6-aminonicotinamide, which suppresses the hexose monophosphate shunt, blocks platelet migration (Valone et al. 1974; Lowenhaupt et al. 1977). As expected cytochalasin B, which disrupts actin filaments, inhibited migration, while colchicine, which interferes with the polymerization of microtubules, did not (Lowenhaupt et al. 1977).
Platelet migration triggered by SDF-1α is mediated by PI3K, given that the PI3K inhibitors wortmannin and LY294002 significantly inhibited it. PI3K phosphorylates Wiskott-Aldrich syndrome protein (WASP) that induces the rearrangement of the actin cytoskeleton (Kraemer et al. 2010). Downstream signaling linking PI3K to platelet migration involves the serum- and glucocorticoid-inducible kinase 1 (SGK1), known to be involved in endothelial cell and monocyte/macrophage migration (Borst et al. 2015; Zarrinpashneh et al. 2013). The importance of SGK1 in platelet migration seems to be connected to its ability to regulate the actin cytoskeletal architecture in fact WASP and vinculin, two proteins interacting with actin, are SGK1-sensitive. WASP activates the Arp 2/3 complex that binds actin, thus inducing its polymerization, and vinculin is an actin-binding protein that, when phosphorylated, stabilizes the focal adhesions (Kraemer et al. 2010; Schmidt et al. 2012). SGK1-deficient platelets show impaired migration, reduced WASP activation and enhanced vinculin phosphorylation (Schmidt et al. 2012).
Platelet migration is dependent on the increase of intracellular Ca2+ via the Ca2+ channel Orai1, the pore forming unit of the store-operated Ca2+ entry (SOCE) channel, and on K+ efflux via the Ca2+-activated K+ channel SK4 (Schmidt et al. 2011).
Platelets adhering to a fibrinogen-coated surface and then exposed to high shear conditions (1500 s−1) undergo polarization, cytoskeletal reorganization with increased WASP phosphorylation and redistribution of intracellular focal adhesion kinases (FAK) to areas of dynamic focal adhesions, and migration in the direction of flow at a speed of approximately 10 μm/h (Kraemer et al. 2011).
Platelet Migration in Disease
Platelet migration has also been studied in disease conditions and/or in response to various pathologic stimuli. Duquesnoy in 1975 described a platelet migration inhibition (PMI) assay to detect antibodies in serum directed against the human leukocyte antigen (HLA) and the platelet-specific antigen Pl-A1 (Duquesnoy et al. 1975), or alloantibodies against platelets in platelet-transfused patients (Levine and Brubaker 1983). This assay was a modification of the capillary tube chemotaxis chamber used by Lowenhaupt et al. (1973) and it tested the capacity of antibodies to inhibit platelet migration by mixing control PRP with patient’s serum. The sensitivity of the PMI test was reported to be comparable or even greater to that of several other methods used for the detection of platelet antibodies, such as the platelet lysis assay, complement fixation, platelet aggregometry and platelet factor-3 release (Duquesnoy et al. 1975; Levine and Brubaker 1983).
Platelets from allergic asthmatic subjects, but not from healthy donors, concentration-dependently migrated in vitro in response to the specific sensitizing allergen and in response to a monoclonal anti-human IgE antibody. In asthmatic subjects allergen-specific IgEs, produced upon previous contact with the allergen and bound to the platelet high-affinity receptor for IgE, FcεRI, bind the allergen inducing the cross-linking of contiguous receptors thus triggering platelet chemotaxis (Pitchford et al. 2008). The same phenomenon is triggered by an anti-IgE antibody that, binding to contiguous Fc portions of FcεRI-bound IgEs, induces the cross-linking of the receptors. The crosslinking of IgE receptors on platelets was previously shown to trigger other platelet functional activities, such as cytotoxicity (Polack et al. 1991), oxygen radical formation (Vargas et al. 1999) and release of chemokines (Hasegawa et al. 2001; Klouche et al. 1997). Migration of platelets from ovalbumin (OVA)-immunized mice in response to the sensitizing allergen was also demonstrated (Pitchford et al. 2008).
Platelet Chemotaxis: Studies in Animal Models
Studies in animal models confirm the ability of platelets to migrate into inflammed tissues. Extravascular accumulation of platelets in bronchial tissue and in lungs, associated with bronchospasm, has been observed by electron microscopy or by the accumulation of 111In-oxine-labelled platelets in guinea pigs and baboons after intravenous challenge with platelet-activating factor (PAF) and other platelet agonists, like ADP or collagen. The penetration of platelets in tissue was not the consequence of blood extravasation, as no other blood cells were concomitantly found (Arnoux et al. 1988; Lellouch-Tubiana et al. 1985; Page et al. 1984; Robertson and Page 1987). The presence of platelets in skin accompanied by neutrophils was also described after the intradermal injection of PAF in rats (Pirotzky et al. 1984).
Platelets have also been detected in bronchoalveolar lavage (BAL) fluid of mice with chronic allergic airway inflammation (Pitchford et al. 2004) and from rabbits with experimental asthma, following allergen-challenge (Coyle et al. 1990).
Platelets from OVA-immunized mice were observed to migrate out of blood vessels after allergen inhalation and to localize in lung parenchima, directly underneath the airways (Fig. 5). Platelet influx in tissue preceded leukocytes and was largely independent of the latter (Pitchford et al. 2003, 2005). Platelet migration into inflammed lung was shown to be mediated by the binding of allergen to FcεRIγ-bound allergen-specific IgEs on the platelet surface (Pitchford et al. 2008), a phenomenon previously described for other inflammatory cells such as eosinophils, basophils and mast cells (Ishizuka et al. 2001; Orida et al. 1983; Svensson et al. 2004).
Transendothelial migration of platelets into the skin of guinea pigs induced by the subcutaneous injection of fMLP was demonstrated by serial electron-microscopy of thin tissue sections (Feng et al. 1998b). In that study it was shown that platelets crossed endothelial cells not at the level of interendothelial cell junctions, which remained closed. However, platelets have been demonstrated to extend pseudopods suggesting active diapedesis. Moreover, single platelets enclosed within endothelial cytoplasmic vacuoles, generally located close to interendothelial cell junctions, were observed and the platelet-containing vacuoles were observed to open to the abluminal surface whereupon platelets were discharged into the underlying basal lamina. Following transmigration across the basal lamina, platelets were found free in dermal connective tissue, together with neutrophils and other white cells. Interestingly, migrating platelets did not display the ultrastructural features of a release reaction, suggesting that conventional platelet activation is not required for platelet migration (Feng et al. 1998b).
The mechanism of transmigration observed in this model, i.e. that platelets cross undamaged endothelium by a process similar to pinocytosis, has been previously described for neutrophils (Feng et al. 1998a). This mechanism does not necessarily apply to all stimuli-inducing diapedesis and active migration through interendothelial cell junctions may also take place (Laitinen 1993; Marchesi 1966).
Platelet translocation into the Disse spaces of the liver and their active penetration into hepatocytes have been reported by immunostaining for 5-hydroxytryptamine (5-HT), a sensitive method to detect platelets in tissue as platelets contain large amounts of 5-HT, and by electron microscopy (Nakamura et al. 1998). Platelets in the Disse spaces of lipopolysaccharide (LPS)-treated mice were in contact with Kupffer cells (hepatic macrophages) (Nakamura et al. 1998; Yamaguchi et al. 2006). This process seems to involve biochemical pathways different from those involved in aggregation, given that anti-platelet agents, including aspirin, did not prevent hepatic platelet accumulation (Nakamura et al. 1998).
In a murine model of corneal abrasion, diapedesis of platelets out of vessels was demonstrated with accumulation of platelets in the limbus where they actively contribute to corneal nerve regeneration. The accumulation of platelets was mediated by P-selectin (Li et al. 2011), an adhesion molecule that also plays a role in the accumulation of platelets in glomeruli in a murine model of glomerulonephritis (Zachem et al. 1997). Activated platelets, alone or together with neutrophils, were found by immunofluorescence within glomeruli of rats with nephritis induced by the selective perfusion of the renal artery with the lectin concanavalin A (Zachem et al. 1997).
In a model of ligation of intestinal arteries in mice, green fluorescent protein (GFP)-labeled platelets were observed in areas of post-ischemic inflamed tissue, where they could function as pilot cells that guide the invasion of other inflammatory cells. This mechanism was mediated by SDF-1α involving signalling through PI3K and activation of SGK-1 (Kraemer et al. 2010). Furthermore, SGK-1−/−mice showed decreased platelet transmigration into the ischemic intestinal vascular wall (Schmidt et al. 2012).
Platelet Chemotaxis: Studies in Humans
Despite the difficulty in detecting platelets in tissue using histology with conventional staining techniques, due to the small dimensions and the lack of a nucleus, observations using electron microscopy and/or immunological staining confirm the ability of platelets to transmigrate into tissues in humans with inflammatory conditions.
Platelets were found in BAL of patients with allergic asthma following allergen challenge without the concomitant presence of erythrocytes, confirming active diapedesis and not passive transfer due to blood extravasation, with some degranulated platelets and free granules in the lavage (Metzger et al. 1985, 1987). Platelet aggregates have also been observed in the lamina propria of the microvasculature of lungs of asthmatic subjects by transmission electron microscopy during late-onset airways obstruction following allergen provocation, in apposition to areas of bronchial smooth muscle, underneath the epithelium, and in areas of eosinophil infiltration (Beasley et al. 1989).
Extravascular platelets, colocalized with leukocytes, have been detected by immunofluorescence in surgically excised nasal polyps from patients with aspirin-exacerbated respiratory disease (AERD), a chronic inflammatory disorder characterized by nasal polyposis and asthma triggered by the ingestion of aspirin (Laidlaw and Boyce 2012).
Platelets were also identified by immunohistochemistry in brain tissue sections from patients with multiple sclerosis with active demyelinating plaques and by confocal immunofluorescent microscopy in a chronic active type 1 lesion (active inflammation and demyelination) (Langer et al. 2012).
Electron microscopy of the synovium of patients with rheumatoid arthritis (RA) showed platelet thrombi obliterating the lumen of vessels and platelets were observed in the vicinity of gaps between endothelial cells of the joint vasculature (Schumacher 1975). Positive staining for αIIbβ3 outside the vasculature was detected using immunohistochemistry of the synovium from patients with RA, representing either platelets or platelet-derived microparticles (PMPs) (Konttinen et al. 1989; Palmer et al. 1986). Moreover, platelets, platelet aggregates and platelet-leukocytes complexes have been shown in the synovial fluid of patients with RA suggesting active migration into extravascular sites (Endresen 1981; Endresen and Forre 1992; Farr et al. 1984; Ginsberg et al. 1978; Yaron and Djaldetti 1978).
Platelet Contribution to the Chemotaxis of Other Cells
Platelets influence the migration of other cells by releasing soluble chemotactic mediators, by liberating PMPs, or by direct contact with the involved cells (Fig. 6).
Platelet lysates enhanced cell migration of several hepatocellular carcinoma cell lines (Carr et al. 2014) and fibroblasts (Carducci et al. 2016; Senior et al. 1983), and adherent activated platelets stimulated the migration of murine embryonic endothelial progenitor cells (EPC) (Langer et al. 2006).
Platelets contain and release upon activation several soluble mediators influencing cell migration (Table 2). Among them chemokines, which represent a significant fraction of the platelet α-granules content, are released upon platelet activation and mediate the recruitment of several cells to sites of inflammation, including leukocytes, cancer cells and hematopoietic cells, thus favouring neointima formation and atherosclerosis, vessel repair and regeneration after vascular injury (Gleissner et al. 2008). CXCL4/platelet factor 4 (CXCL4/PF4), the first member of the chemokine family discovered in platelets and the most abundant platelet chemokine (Deuel et al. 1977), and CXCL7/neutrophil-activating peptide-2 (CXCL7/NAP-2) purified from supernatants of thrombin-stimulated platelets induce neutrophils to undergo firm adhesion on an endothelial cells monolayer in a concentration-dependent manner. CXCL7 also stimulates neutrophil transendothelial migration (Petersen et al. 1999; Schenk et al. 2002). Furthermore, CXCL7 and CXCL5/epithelial neutrophil-activating protein 78 (ENA-78), secreted by activated platelets upon contact with tumor cells, induce granulocyte migration and guide the formation of the early metastatic niche (Labelle et al. 2014). Activated platelets are a major source of CXCL12/SDF-1α (Chatterjee and Gawaz 2013). Platelet-derived CXCL12 supports adhesion of CD34+ human progenitor cells (PCs) under static conditions and facilitates the rolling and firm adhesion of CD34+ cells onto platelets adhered to a layer of human aortic endothelial cells (HAEC) under high shear rate in vitro and in vivo (Stellos et al. 2008). Platelet-derived CXCL12 also enhances the adhesion and migration of bone marrow progenitor cells to sites of vascular injury thereby promoting repair (Massberg et al. 2006). Furthermore, CXCL12 released by activated platelets induces monocyte chemotaxis by acting on CXCR4 and monocyte adhesion under static and dynamic arterial flow conditions by acting on CXCR7 (Chatterjee et al. 2015). CCL5/regulated on activation normal T cell expressed and secreted (CCL5/RANTES) secreted by activated platelets and immobilized on the inflamed/activated endothelium of atherosclerotic arteries induces adhesion of monocytes (Mause et al. 2005; Schober et al. 2002; von Hundelshausen et al. 2001). Platelets under shear flow deposit CXCL4 and CCL5 on atherosclerotic or IL-1β-activated HAEC, enhancing the recruitment of monocytes to the endothelium (Baltus et al. 2005; Huo et al. 2003). Moreover, platelet-derived macrophage migration inhibitory factor (MIF) stimulates monocyte arrest on endothelium and chemotaxis (Wirtz et al. 2015).
Platelet-derived IL-1β induces the secretion of CCL2/monocyte chemottractant protein-1 (MCP-1) and increases the expression of intracellular adhesion molecule-1 (ICAM-1) by endothelial cells, promoting the adhesion of monocytes to the endothelium and their chemotaxis; in fact MCP-1 is a potent chemotactic factor for monocytes (Gawaz et al. 2000). Platelet-derived IL-1 induces the release of CXCL1 and CXCL8 from endothelium, which in turn induces neutrophil recruitment (Page and Pitchford 2013; Kaplanski et al. 1993; Thornton et al. 2010).
Platelet dense-granules contain serotonin, a vasoactive inflammatory mediator that can induce vascular permeability and promotes the recruitment of neutrophils into lung and peritoneum, after intraperitoneal and intratracheal LPS administration, and in aseptic skin wounds (Duerschmied et al. 2013), and the recruitment of T cells into the liver during viral hepatitis-induced hepatic injury (Lang et al. 2008). Platelet-derived ATP promotes tumor cell transendothelial migration and metastasis via stimulation of P2Y2 receptors (Schumacher et al. 2013).
Platelet release lysosomal enzymes, such as cathepsin, β-hexosoaminidase and heparinase, in vivo in humans at a localized site of vessel wall damage (Ciferri et al. 2000; Vlodavsky et al. 1992), and these may participate in cell diapedesis due to their tissue-degrading activity and by remodelling the inflammed tissues, a role already demonstrated to be involved in the migration of fibroblasts, cancer and endothelial cells (Mohamed and Sloane 2006; Palka et al. 1997; Schraufstatter et al. 2003)
PMPs play an important role in tissue recruitment of inflammatory cells by the interaction between P-selectin expressed on their surface and P-selectin glycoprotein ligand-1 (PSGL-1) on neutrophils (Forlow et al. 2000) and simultaneously by their adhesion to the subendothelial matrix through integrin αIIbβ3 (Merten et al. 1999). PMPs stimulate monocyte adhesion also by inducing endothelial cells (ECs) to express ICAM-1 and by delivering chemokines, such as RANTES, to the endothelium (Barry et al. 1998; Mause et al. 2005). In addition, PMPs transport cytokines (e.g. IL-1β) that stimulate polymorphonuclear cells (PMNs) adhesion to ECs and miRNAs that may modify the phenotype of endothelial cells (Gidlof et al. 2013) and macrophages (Laffon et al. 2016). PMPs enhance the chemotaxis of invasive breast and lung cancer cells and stimulate their invasion across Matrigel by inducing MMPs production. Furthermore, PMPs act as chemotactic agent for hematopoietic stem/progenitor (CD34+) cells as well as for various myeloid and lymphoid cells (Baj-Krzyworzeka et al. 2002; Janowska-Wieczorek et al. 2005, 2006).
Platelets express upon activation a number of surface proteins involved in heterotypic interactions with endothelial cells and leukocytes, mediating the rolling and adhesion of leukocytes to the endothelium and the subsequent trans-migration into inflammed tissue (Gawaz et al. 2005; Weyrich and Zimmerman 2004). The formation of platelet-neutrophil and platelet-monocyte complexes, the subsequent neutrophil and monocyte adhesion to the endothelium and recruitment into the inflammed tissue is dependent on platelet P-selectin (Page and Pitchford 2013), mediated by its binding to the high affinity counter ligand PSGL-1 (Hamburger and McEver 1990; Moore et al. 1995; Kuijper et al. 1998). High-resolution videomicroscopy has revealed the existence of membrane tethers involving P-selectin/PSGL-1 bonds that regulate neutrophil rolling on platelets (Schmidtke and Diamond 2000). The importance of platelet P-selectin/PSGL-1 axis has been determined by the use of P-selectin-deficient mice, by the blockade of P-selectin or with PSGL-1 antibodies (Abdulla et al. 2012; Diacovo et al. 1996; Mayadas et al. 1993; Pitchford et al. 2005).
Platelet CD40 ligand (CD40L/CD154) binds CD40 on endothelial cells and enhances the release of IL-8 and MCP-1, the expression of E-selectin (CD62-E), Vascular Cell Adhesion Protein-1 (VCAM-1) and ICAM-1, and the release of matrix metalloproteinases (e.g., MMP-1, -2, -3, and -9). Furthermore CD40L-positive T cells activate platelets through a CD40-dependent pathway resulting in CCL5 release and T cell recruitment (Danese et al. 2004; Henn et al. 1998; Giannini et al. 2011).
Platelet Junctional Adhesion Molecule (JAM-A) can support homophilic interactions with endothelial-cell JAM-A, mediating platelet adhesion to the endothelium (Babinska et al. 2002), thus facilitating the deposition on endothelium of platelet CCL5/RANTES (Zernecke et al. 2006). Platelet JAM-C functions as a counter-receptor for the β2-integrin Mac-1 on neutrophils mediating firm adhesion of leukocytes to adherent platelets (Santoso et al. 2002).
Conclusions
Among the functions that characterize platelets as inflammatory cells, one which is little considered but is probably crucial is the ability to migrate into tissue in the direction of a chemotactic stimulus. This allows platelets to actively participate in the tissue inflammatory process by releasing stored or newly synthesized mediators acting both on other platelets and/or on other cell types. Furthermore, platelets influence and sometimes are essential for the migration of other inflammatory cells, including leukocytes and cancer cells.
This “non-classical” platelet activity is an example of the existence of a dichotomy in platelet function, i.e. the ability of platelets to display an inflammatory or a haemostatic/thrombotic response depending on the stimulus and on the environment, recently elegantly demonstrated investigating the role of different purinergic receptor subtypes on platelets (Amison et al. 2015).
Further investigation into the mechanisms regulating platelet migration, and in general the characterization of the mechanisms regulating this dichotomy of platelet function, may be crucial for the discovery of new therapeutic approaches to inflammatory diseases by the development of drugs able to interfere with the inflammatory but not with the haemostatic function of platelets.
Take Home Messages
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Platelets possess several characteristics that allow them to migrate: the expression of receptors for chemokines and for other chemotactic agents, the presence of all the signaling pathways responsible for the transduction of the extracellular chemotactic signal to the motile apparatus, a dynamic cytoskeleton and the relase of several enzymes (MMPs, cathepsins, β-hexosoaminidase, heparinase) responsible for ECM degradation.
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The ability of platelets to migrate in vitro, both randomly and in the direction of a chemotactic stimulus, such as collagen, fMLP, SDF-1α, IgE and allergens, has been confirmed using different assays.
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The penetration of platelets in inflammed tissues has been described in several animal models and in human disease conditions.
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Platelets can induce the migration of other cell types by several mechanisms, including the shedding of PMPs, release of granular materials (chemokines, cytokines, growth factors, ATP, enzymes), and the expression of surface receptors involved in platelet heterotypic interactions with leukocytes, endothelial and cancer cells.
References
Abdulla A, Awla D, Hartman H, Weiber H, Jeppsson B, Regner S, Thorlacius H (2012) Platelets regulate P-selectin expression and leukocyte rolling in inflamed venules of the pancreas. Eur J Pharmacol 682(1-3):153–160
Abi-Younes S, Sauty A, Mach F, Sukhova GK, Libby P, Luster AD (2000) The stromal cell-derived factor-1 chemokine is a potent platelet agonist highly expressed in atherosclerotic plaques. Circ Res 86(2):131–138
Abi-Younes S, Si-Tahar M, Luster AD (2001) The CC chemokines MDC and TARC induce platelet activation via CCR4. Thromb Res 101(4):279–289
Amison RT, Momi S, Morris A, Manni G, Keir S, Gresele P, Page CP, Pitchford SC (2015) RhoA signaling through platelet P2Y(1) receptor controls leukocyte recruitment in allergic mice. J Allergy Clin Immunol 135(2):528–538
Andonegui G, Kerfoot SM, McNagny K, Ebbert KV, Patel KD, Kubes P (2005) Platelets express functional Toll-like receptor-4. Blood 106(7):2417–2423
Arnoux B, Denjean A, Page CP, Nolibe D, Morley J, Benveniste J (1988) Accumulation of platelets and eosinophils in baboon lung after paf-acether challenge. Inhibition by ketotifen. Am Rev Respir Dis 137(4):855–860
Babinska A, Kedees MH, Athar H, Ahmed T, Batuman O, Ehrlich YH, Hussain MM, Kornecki E (2002) F11-receptor (F11R/JAM) mediates platelet adhesion to endothelial cells: role in inflammatory thrombosis. Thromb Haemost 88(5):843–850
Baj-Krzyworzeka M, Majka M, Pratico D, Ratajczak J, Vilaire G, Kijowski J, Reca R, Janowska-Wieczorek A, Ratajczak MZ (2002) Platelet-derived microparticles stimulate proliferation, survival, adhesion, and chemotaxis of hematopoietic cells. Exp Hematol 30(5):450–459
Baltus T, von Hundelshausen P, Mause SF, Buhre W, Rossaint R, Weber C (2005) Differential and additive effects of platelet-derived chemokines on monocyte arrest on inflamed endothelium under flow conditions. J Leukoc Biol 78(2):435–441
Barry OP, Pratico D, Savani RC, FitzGerald GA (1998) Modulation of monocyte-endothelial cell interactions by platelet microparticles. J Clin Invest 102(1):136–144
Beasley R, Roche WR, Roberts JA, Holgate ST (1989) Cellular events in the bronchi in mild asthma and after bronchial provocation. Am Rev Respir Dis 139(3):806–817
Borst O, Münzer P, Gatidis S, Schmidt EM, Schönberger T, Schmid E, Towhid ST, Stellos K, Seizer P, May AE, Lang F, Gawaz M (2012) The inflammatory chemokine CXC motif ligand 16 triggers platelet activation and adhesion via CXC motif receptor 6-dependent phosphatidylinositide 3-kinase/Akt signaling. Circ Res 111:1297–307
Borst O, Schaub M, Walker B, Schmid E, Munzer P, Voelkl J, Alesutan I, Rodriguez JM, Vogel S, Schoenberger T, Metzger K, Rath D, Umbach A, Kuhl D, Muller II, Seizer P, Geisler T, Gawaz M, Lang F (2015) Pivotal role of serum- and glucocorticoid-inducible kinase 1 in vascular inflammation and atherogenesis. Arterioscler Thromb Vasc Biol 35(3):547–557
Boyden S (1962) The chemotactic effect of mixtures of antibody and antigen on polymorphonuclear leucocytes. J Exp Med 115:453–466
Busti C, Falcinelli E, Momi S, Gresele P (2010) Matrix metalloproteinases and peripheral arterial disease. Intern Emerg Med 5(1):13–25
Carducci A, Scafetta G, Siciliano C, Carnevale R, Rosa P, Coccia A, Mangino G, Bordin A, Vingolo EM, Pierelli L, Lendaro E, Ragona G, Frati G, De Falco E (2016) GMP-grade platelet lysate enhances proliferation and migration of tenon fibroblasts. Front Biosci 8:84–99
Carr BI, Cavallini A, D’Alessandro R, Refolo MG, Lippolis C, Mazzocca A, Messa C (2014) Platelet extracts induce growth, migration and invasion in human hepatocellular carcinoma in vitro. BMC Cancer 14:43
Chamot EM, Mason C (1947) Handbook of chemical microscopy, vol 1. Brownian movement.
Charest PG, Firtel RA (2007) Big roles for small GTPases in the control of directed cell movement. Biochem J 401(2):377–390
Chatterjee M, Gawaz M (2013) Platelet-derived CXCL12 (SDF-1alpha): basic mechanisms and clinical implications. J Thromb Haemost 11(11):1954–1967
Chatterjee M, Seizer P, Borst O, Schonberger T, Mack A, Geisler T, Langer HF, May AE, Vogel S, Lang F, Gawaz M (2014) SDF-1alpha induces differential trafficking of CXCR4-CXCR7 involving cyclophilin A, CXCR7 ubiquitination and promotes platelet survival. FASEB J 28(7):2864–2878
Chatterjee M, von Ungern-Sternberg SN, Seizer P, Schlegel F, Buttcher M, Sindhu NA, Muller S, Mack A, Gawaz M (2015) Platelet-derived CXCL12 regulates monocyte function, survival, differentiation into macrophages and foam cells through differential involvement of CXCR4-CXCR7. Cell Death Dis 6:e1989
Ciferri S, Emiliani C, Guglielmini G, Orlacchio A, Nenci GG, Gresele P (2000) Platelets release their lysosomal content in vivo in humans upon activation. Thromb Haemost 83(1):157–164
Clemetson KJ, Clemetson JM, Proudfoot AE, Power CA, Baggiolini M, Wells TN (2000) Functional expression of CCR1, CCR3, CCR4, and CXCR4 chemokine receptors on human platelets. Blood 96(13):4046–4054
Cognasse F, Hamzeh H, Chavarin P, Acquart S, Genin C, Garraud O (2005) Evidence of Toll-like receptor molecules on human platelets. Immunol Cell Biol 83(2):196–198
Coyle AJ, Page CP, Atkinson L, Flanagan R, Metzger WJ (1990) The requirement for platelets in allergen-induced late asthmatic airway obstruction. Eosinophil infiltration and heightened airway responsiveness in allergic rabbits. Am Rev Respir Dis 142(3):587–593
Czapiga M, Kirk AD, Lekstrom-Himes J (2004) Platelets deliver costimulatory signals to antigen-presenting cells: a potential bridge between injury and immune activation. Exp Hematol 32(2):135–139
Czapiga M, Gao JL, Kirk A, Lekstrom-Himes J (2005) Human platelets exhibit chemotaxis using functional N-formyl peptide receptors. Exp Hematol 33(1):73–84
Danese S, de la Motte C, Reyes BM, Sans M, Levine AD, Fiocchi C (2004) Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol 172(4):2011–2015
Deuel TF, Keim PS, Farmer M, Heinrikson RL (1977) Amino acid sequence of human platelet factor 4. Proc Natl Acad Sci U S A 74(6):2256–2258
Diacovo TG, Roth SJ, Buccola JM, Bainton DF, Springer TA (1996) Neutrophil rolling, arrest, and transmigration across activated, surface-adherent platelets via sequential action of P-selectin and the beta 2-integrin CD11b/CD18. Blood 88(1):146–157
Duerschmied D, Suidan GL, Demers M, Herr N, Carbo C, Brill A, Cifuni SM, Mauler M, Cicko S, Bader M, Idzko M, Bode C, Wagner DD (2013) Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 121(6):1008–1015
Duquesnoy RJ, Lorentsen DF, Aster RH (1975) Platelet migration inhibition: a new method for detection of platelet antibodies. Blood 45(6):741–747
Endresen GK (1981) Investigation of blood platelets in synovial fluid from patients with rheumatoid arthritis. Scand J Rheumatol 10(3):204–208
Endresen GK, Forre O (1992) Human platelets in synovial fluid. A focus on the effects of growth factors on the inflammatory responses in rheumatoid arthritis. Clin Exp Rheumatol 10(2):181–187
Farr M, Wainwright A, Salmon M, Hollywell CA, Bacon PA (1984) Platelets in the synovial fluid of patients with rheumatoid arthritis. Rheumatol Int 4(1):13–17
Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM (1998a) Neutrophils emigrate from venules by a transendothelial cell pathway in response to FMLP. J Exp Med 187(6):903–915
Feng D, Nagy JA, Pyne K, Dvorak HF, Dvorak AM (1998b) Platelets exit venules by a transcellular pathway at sites of F-met peptide-induced acute inflammation in guinea pigs. Int Arch Allergy Immunol 116(3):188–195
Forlow SB, McEver RP, Nollert MU (2000) Leukocyte-leukocyte interactions mediated by platelet microparticles under flow. Blood 95(4):1317–1323
Gawaz M, Brand K, Dickfeld T, Pogatsa-Murray G, Page S, Bogner C, Koch W, Schomig A, Neumann F (2000) Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 148(1):75–85
Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115(12):3378–3384
George M, Vaughan JH (1962) In vitro cell migration as a model for delayed hypersensitivity. Proc Soc Exp Biol Med 111:514–521
Germena G, Hirsch E (2013) PI3Ks and small GTPases in neutrophil migration: two sides of the same coin. Mol Immunol 55(1):83–86
Giannini S, Falcinelli E, Bury L, Guglielmini G, Rossi R, Momi S, Gresele P (2011) Interaction with damaged vessel wall in vivo in humans induces platelets to express CD40L resulting in endothelial activation with no effect of aspirin intake. Am J Physiol Heart Circ Physiol 300(6):H2072–2079
Gidlof O, van der Brug M, Ohman J, Gilje P, Olde B, Wahlestedt C, Erlinge D (2013) Platelets activated during myocardial infarction release functional miRNA, which can be taken up by endothelial cells and regulate ICAM1 expression. Blood 121(19):3908–3917, S3901–S3926
Ginsberg MH, Breth G, Skosey JL (1978) Platelets in the synovial space. Arthritis Rheum 21(8):994–995
Gleissner CA, von Hundelshausen P, Ley K (2008) Platelet chemokines in vascular disease. Arterioscler Thromb Vasc Biol 28(11):1920–1927
Goggs R, Williams CM, Mellor H, Poole AW (2015) Platelet Rho GTPases-a focus on novel players, roles and relationships. Biochem J 466(3):431–442
Hamburger SA, McEver RP (1990) GMP-140 mediates adhesion of stimulated platelets to neutrophils. Blood 75(3):550–554
Hartwig JH (2006) The platelet: form and function. Semin Hematol 43(1 Suppl 1):S94–100
Hasegawa S, Tashiro N, Matsubara T, Furukawa S, Ra C (2001) A comparison of FcepsilonRI-mediated RANTES release from human platelets between allergic patients and healthy individuals. Int Arch Allergy Immunol 125(Suppl 1):42–47
Heijnen HFG, Korporaal SJA (2017) Platelet morphology and ultrastructure. In: Gresele P et al (eds) Platelets in thrombotic and non-thrombotic disorders. Springer, Cham, pp 21–37
Henn V, Slupsky JR, Grafe M, Anagnostopoulos I, Forster R, Muller-Berghaus G, Kroczek RA (1998) CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 391(6667):591–594
Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K (2003) Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 9(1):61–67
Ishizuka T, Okajima F, Ishiwara M, Iizuka K, Ichimonji I, Kawata T, Tsukagoshi H, Dobashi K, Nakazawa T, Mori M (2001) Sensitized mast cells migrate toward the antigen: a response regulated by p38 mitogen-activated protein kinase and Rho-associated coiled-coil-forming protein kinase. J Immunol 167(4):2298–2304
Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ (2005) Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer. Int J Cancer 113(5):752–760
Janowska-Wieczorek A, Marquez-Curtis LA, Wysoczynski M, Ratajczak MZ (2006) Enhancing effect of platelet-derived microvesicles on the invasive potential of breast cancer cells. Transfusion 46(7):1199–1209
Jenne CN, Urrutia R, Kubes P (2013) Platelets: bridging hemostasis, inflammation, and immunity. Int J Lab Hematol 35(3):254–261
Jin T (2013) Gradient sensing during chemotaxis. Curr Opin Cell Biol 25(5):532–537
Kaplanski G, Porat R, Aiura K, Erban JK, Gelfand JA, Dinarello CA (1993) Activated platelets induce endothelial secretion of interleukin-8 in vitro via an interleukin-1-mediated event. Blood 81(10):2492–2495
Klouche M, Klinger MH, Kuhnel W, Wilhelm D (1997) Endocytosis, storage, and release of IgE by human platelets: differences in patients with type I allergy and nonatopic subjects. J Allergy Clin Immunol 100(2):235–241
Konttinen YT, Gronblad M, Bergroth V, Santavirta S, Antti-Poika I (1989) Presence of platelet glycoproteins Ib and IIb-IIIa in inflammatory and noninflammatory synovium. J Rheumatol 16(5):578–584
Kowalska MA, Ratajczak J, Hoxie J, Brass LF, Gewirtz A, Poncz M, Ratajczak MZ (1999) Megakaryocyte precursors, megakaryocytes and platelets express the HIV co-receptor CXCR4 on their surface: determination of response to stromal-derived factor-1 by megakaryocytes and platelets. Br J Haematol 104(2):220–229
Kowalska MA, Ratajczak MZ, Majka M, Jin J, Kunapuli S, Brass L, Poncz M (2000) Stromal cell-derived factor-1 and macrophage-derived chemokine: 2 chemokines that activate platelets. Blood 96(1):50–57
Kraemer BF, Borst O, Gehring EM, Schoenberger T, Urban B, Ninci E, Seizer P, Schmidt C, Bigalke B, Koch M, Martinovic I, Daub K, Merz T, Schwanitz L, Stellos K, Fiesel F, Schaller M, Lang F, Gawaz M, Lindemann S (2010) PI3 kinase-dependent stimulation of platelet migration by stromal cell-derived factor 1 (SDF-1). J Mol Med 88(12):1277–1288
Kraemer BF, Schmidt C, Urban B, Bigalke B, Schwanitz L, Koch M, Seizer P, Schaller M, Gawaz M, Lindemann S (2011) High shear flow induces migration of adherent human platelets. Platelets 22(6):415–421
Kuijper PH, Gallardo Torres HI, Houben LA, Lammers JW, Zwaginga JJ, Koenderman L (1998) P-selectin and MAC-1 mediate monocyte rolling and adhesion to ECM-bound platelets under flow conditions. J Leukoc Biol 64(4):467–473
Labelle M, Begum S, Hynes RO (2014) Platelets guide the formation of early metastatic niches. Proc Natl Acad Sci U S A 111(30):E3053–3061
Laffont B, Corduan A, Rousseau M, Duchez AC, Lee CH, Boilard E, Provost P (2016) Platelet microparticles reprogram macrophage gene expression and function. Thromb Haemost 115(2):311–323
Laidlaw TM, Boyce JA (2012) Cysteinyl leukotriene receptors, old and new; implications for asthma. Clin Exp Allergy 42(9):1313–1320
Laitinen LA (1993) Allergy. Platelets
Lang PA, Contaldo C, Georgiev P, El-Badry AM, Recher M, Kurrer M, Cervantes-Barragan L, Ludewig B, Calzascia T, Bolinger B, Merkler D, Odermatt B, Bader M, Graf R, Clavien PA, Hegazy AN, Lohning M, Harris NL, Ohashi PS, Hengartner H, Zinkernagel RM, Lang KS (2008) Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 14(7):756–761
Langer H, May AE, Daub K, Heinzmann U, Lang P, Schumm M, Vestweber D, Massberg S, Schonberger T, Pfisterer I, Hatzopoulos AK, Gawaz M (2006) Adherent platelets recruit and induce differentiation of murine embryonic endothelial progenitor cells to mature endothelial cells in vitro. Circ Res 98(2):e2–10
Langer HF, Choi EY, Zhou H, Schleicher R, Chung KJ, Tang Z, Gobel K, Bdeir K, Chatzigeorgiou A, Wong C, Bhatia S, Kruhlak MJ, Rose JW, Burns JB, Hill KE, Qu H, Zhang Y, Lehrmann E, Becker KG, Wang Y, Simon DI, Nieswandt B, Lambris JD, Li X, Meuth SG, Kubes P, Chavakis T (2012) Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 110(9):1202–1210
Lellouch-Tubiana A, Lefort J, Pirotzky E, Vargaftig BB, Pfister A (1985) Ultrastructural evidence for extravascular platelet recruitment in the lung upon intravenous injection of platelet-activating factor (PAF-acether) to guinea-pigs. Br J Exp Pathol 66(3):345–355
Levine SJ, Brubaker DB (1983) Detection of platelet antibodies using the platelet migration inhibition assay. Am J Clin Pathol 80(1):43–48
Li Z, Burns AR, Han L, Rumbaut RE, Smith CW (2011) IL-17 and VEGF are necessary for efficient corneal nerve regeneration. Am J Pathol 178(3):1106–1116
Lowenhaupt RW (1978) Human platelet chemotaxis: requirement for plasma factor(s) and the role of collagen. Am J Physiol 235(1):H23–28
Lowenhaupt RW (1982) Human platelet chemotaxis can be induced by low molecular substance(s) derived from the interaction of plasma and collagen. Prog Clin Biol Res 89:269–280
Lowenhaupt RW, Miller MA, Glueck HI (1973) Platelet migration and chemotaxis demonstrated in vitro. Thromb Res 3:477–486
Lowenhaupt RW, Glueck HI, Miller MA, Kline DL (1977) Factors which influence blood platelet migration. J Lab Clin Med 90(1):37–45
Lowenhaupt RW, Silberstein EB, Sperling MI, Mayfield G (1982) A quantitative method to measure human platelet chemotaxis using indium-111-oxine-labeled gel-filtered platelets. Blood 60(6):1345–1352
Marchesi VT (1966) Mechanisms of cell migration and macromolecule transport across the walls of blood vessels. Gastroenterology 51(5):875–892
Massberg S, Konrad I, Schurzinger K, Lorenz M, Schneider S, Zohlnhoefer D, Hoppe K, Schiemann M, Kennerknecht E, Sauer S, Schulz C, Kerstan S, Rudelius M, Seidl S, Sorge F, Langer H, Peluso M, Goyal P, Vestweber D, Emambokus NR, Busch DH, Frampton J, Gawaz M (2006) Platelets secrete stromal cell-derived factor 1alpha and recruit bone marrow-derived progenitor cells to arterial thrombi in vivo. J Exp Med 203(5):1221–1233
Mause SF, von Hundelshausen P, Zernecke A, Koenen RR, Weber C (2005) Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 25(7):1512–1518
Mayadas TN, Johnson RC, Rayburn H, Hynes RO, Wagner DD (1993) Leukocyte rolling and extravasation are severely compromised in P selectin-deficient mice. Cell 74(3):541–554
Merten M, Pakala R, Thiagarajan P, Benedict CR (1999) Platelet microparticles promote platelet interaction with subendothelial matrix in a glycoprotein IIb/IIIa-dependent mechanism. Circulation 99(19):2577–2582
Metzger WJ, Hunninghake GW, Richerson HB (1985) Late asthmatic responses: inquiry into mechanisms and significance. Clin Rev Allergy 3(2):145–165
Metzger WJ, Sjoerdsma K, Richerson HB, Moseley P, Zavala D, Monick M, Hunninghake GW (1987) Platelets in bronchoalveolar lavage from asthmatic patients and allergic rabbits with allergen-induced late phase responses. Agents Actions Suppl 21:151–159
Mohamed MM, Sloane BF (2006) Cysteine cathepsins: multifunctional enzymes in cancer. Nat Rev Cancer 6(10):764–775
Momi S, Wiwanitkit V (2017) Phylogeny of blood platelets. In: Gresele P et al (eds) Platelets in thrombotic and non-thrombotic disorders. Springer, Cham, pp 11–19
Moore KL, Patel KD, Bruehl RE, Li F, Johnson DA, Lichenstein HS, Cummings RD, Bainton DF, McEver RP (1995) P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 128(4):661–671
Nakamura M, Shibazaki M, Nitta Y, Endo Y (1998) Translocation of platelets into Disse spaces and their entry into hepatocytes in response to lipopolysaccharides, interleukin-1 and tumour necrosis factor: the role of Kupffer cells. J Hepatol 28(6):991–999
Nathan P (1973) The migration of human platelets in vitro. Thromb Diath Haemorrh 30(1):173–177
Orida N, Feldman JD, Katz DH, Liu FT (1983) IgE-mediated chemotaxis of rat basophilic leukemia cells towards specific antigen. J Exp Med 157(6):2166–2171
Page C, Pitchford S (2013) Neutrophil and platelet complexes and their relevance to neutrophil recruitment and activation. Int Immunopharmacol 17(4):1176–1184
Page CP, Paul W, Morley J (1984) Platelets and bronchospasm. Int Arch Allergy Appl Immunol 74(4):347–350
Palka JA, Karna E, Miltyk W (1997) Fibroblast chemotaxis and prolidase activity modulation by insulin-like growth factor II and mannose 6-phosphate. Mol Cell Biochem 168(1–2):177–183
Palmer DG, Hogg N, Revell PA (1986) Lymphocytes, polymorphonuclear leukocytes, macrophages and platelets in synovium involved by rheumatoid arthritis. A study with monoclonal antibodies. Pathology 18(4):431–437
Petersen F, Bock L, Flad HD, Brandt E (1999) Platelet factor 4-induced neutrophil-endothelial cell interaction: involvement of mechanisms and functional consequences different from those elicited by interleukin-8. Blood 94(12):4020–4028
Pirotzky E, Page CP, Roubin R, Pfister A, Paul W, Bonnet J, Benveniste J (1984) PAF-acether-induced plasma exudation in rat skin is independent of platelets and neutrophils. Microcirc Endothelium Lymphatics 1(1):107–122
Pitchford SC, Yano H, Lever R, Riffo-Vasquez Y, Ciferri S, Rose MJ, Giannini S, Momi S, Spina D, O’Connor B, Gresele P, Page CP (2003) Platelets are essential for leukocyte recruitment in allergic inflammation. J Allergy Clin Immunol 112(1):109–118
Pitchford SC, Riffo-Vasquez Y, Sousa A, Momi S, Gresele P, Spina D, Page CP (2004) Platelets are necessary for airway wall remodeling in a murine model of chronic allergic inflammation. Blood 103(2):639–647
Pitchford SC, Momi S, Giannini S, Casali L, Spina D, Page CP, Gresele P (2005) Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood 105(5):2074–2081
Pitchford SC, Momi S, Baglioni S, Casali L, Giannini S, Rossi R, Page CP, Gresele P (2008) Allergen induces the migration of platelets to lung tissue in allergic asthma. Am J Respir Crit Care Med 177(6):604–612
Polack B, Peyron F, Auriault C (1991) Platelet cytotoxicity against parasites. Nouv Rev Fr Hematol 33(4):317–322
Postea O, Vasina EM, Cauwenberghs S, Projahn D, Liehn EA, Lievens D, Theelen W, Kramp BK, Butoi ED, Soehnlein O, Heemskerk JW, Ludwig A, Weber C, Koenen RR (2012) Contribution of platelet CX(3)CR1 to platelet-monocyte complex formation and vascular recruitment during hyperlipidemia. Arterioscler Thromb Vasc Biol 32(5):1186–1193
Raftopoulou M, Hall A (2004) Cell migration: Rho GTPases lead the way. Dev Biol 265(1):23–32
Rath D, Chatterjee M, Borst O, Muller K, Stellos K, Mack AF, Bongartz A, Bigalke B, Langer H, Schwab M, Gawaz M, Geisler T (2014) Expression of stromal cell-derived factor-1 receptors CXCR4 and CXCR7 on circulating platelets of patients with acute coronary syndrome and association with left ventricular functional recovery. Eur Heart J 35(6):386–394
Robertson DN, Page CP (1987) Effect of platelet agonists on airway reactivity and intrathoracic platelet accumulation. Br J Pharmacol 92(1):105–111
Santoso S, Sachs UJ, Kroll H, Linder M, Ruf A, Preissner KT, Chavakis T (2002) The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 196(5):679–691
Schafer A, Schulz C, Eigenthaler M, Fraccarollo D, Kobsar A, Gawaz M, Ertl G, Walter U, Bauersachs J (2004) Novel role of the membrane-bound chemokine fractalkine in platelet activation and adhesion. Blood 103(2):407–412
Schenk BI, Petersen F, Flad HD, Brandt E (2002) Platelet-derived chemokines CXC chemokine ligand (CXCL)7, connective tissue-activating peptide III, and CXCL4 differentially affect and cross-regulate neutrophil adhesion and transendothelial migration. J Immunol 169(5):2602–2610
Schmidt EM, Munzer P, Borst O, Kraemer BF, Schmid E, Urban B, Lindemann S, Ruth P, Gawaz M, Lang F (2011) Ion channels in the regulation of platelet migration. Biochem Biophys Res Commun 415(1):54–60
Schmidt EM, Kraemer BF, Borst O, Munzer P, Schonberger T, Schmidt C, Leibrock C, Towhid ST, Seizer P, Kuhl D, Stournaras C, Lindemann S, Gawaz M, Lang F (2012) SGK1 sensitivity of platelet migration. Cell Physiol Biochem 30(1):259–268
Schmidtke DW, Diamond SL (2000) Direct observation of membrane tethers formed during neutrophil attachment to platelets or P-selectin under physiological flow. J Cell Biol 149(3):719–730
Schober A, Manka D, von Hundelshausen P, Huo Y, Hanrath P, Sarembock IJ, Ley K, Weber C (2002) Deposition of platelet RANTES triggering monocyte recruitment requires P-selectin and is involved in neointima formation after arterial injury. Circulation 106(12):1523–1529
Schraufstatter IU, Trieu K, Zhao M, Rose DM, Terkeltaub RA, Burger M (2003) IL-8-mediated cell migration in endothelial cells depends on cathepsin B activity and transactivation of the epidermal growth factor receptor. J Immunol 171(12):6714–6722
Schumacher HR Jr (1975) Synovial membrane and fluid morphologic alterations in early rheumatoid arthritis: microvascular injury and virus-like particles. Ann N Y Acad Sci 256:39–64
Schumacher D, Strilic B, Sivaraj KK, Wettschureck N, Offermanns S (2013) Platelet-derived nucleotides promote tumor-cell transendothelial migration and metastasis via P2Y2 receptor. Cancer Cell 24(1):130–137
Seizer P, May AE (2013) Platelets and matrix metalloproteinases. Thromb Haemost 110(5):903–909
Semple JW, Italiano JE Jr, Freedman J (2011) Platelets and the immune continuum. Nat Rev Immunol 11(4):264–274
Senior RM, Griffin GL, Huang JS, Walz DA, Deuel TF (1983) Chemotactic activity of platelet alpha granule proteins for fibroblasts. J Cell Biol 96(2):382–385
Slaba I, Kubes P (2017) Platelets and immunity. In: Gresele P et al (eds) Platelets in thrombotic and non-thrombotic disorders. Springer, Cham, pp 489–512
Stellos K, Langer H, Daub K, Schoenberger T, Gauss A, Geisler T, Bigalke B, Mueller I, Schumm M, Schaefer I, Seizer P, Kraemer BF, Siegel-Axel D, May AE, Lindemann S, Gawaz M (2008) Platelet-derived stromal cell-derived factor-1 regulates adhesion and promotes differentiation of human CD34+ cells to endothelial progenitor cells. Circulation 117(2):206–215
Suttitanamongkol S, Gear AR (2001) ADP receptor antagonists inhibit platelet aggregation induced by the chemokines SDF-1, MDC and TARC. FEBS Lett 490(1–2):84–87
Svensson L, Rudin A, Wenneras C (2004) Allergen extracts directly mobilize and activate human eosinophils. Eur J Immunol 34(6):1744–1751
Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ (2010) Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 115(17):3632–3639
Valone FH, Austen KF, Goetzl EJ (1974) Modulation of the random migration of human platelets. J Clin Invest 54(5):1100–1106
Van Keymeulen A, Wong K, Knight ZA, Govaerts C, Hahn KM, Shokat KM, Bourne HR (2006) To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front. J Cell Biol 174(3):437–445
Vargas L, Patino PJ, Rodriguez MF, Forero C, Montoya F, Montoya CJ, Sorensen RU, de Olarte DG (1999) Increase in granulocyte-macrophage-colony-stimulating factor secretion and the respiratory burst with decreased L-selectin expression in hyper-IgE syndrome patients. Ann Allergy Asthma Immunol 83(3):245–251
Vieira-de-Abreu A, Campbell RA, Weyrich AS, Zimmerman GA (2012) Platelets: versatile effector cells in hemostasis, inflammation, and the immune continuum. Semin Immunopathol 34(1):5–30
Vlodavsky I, Eldor A, Haimovitz-Friedman A, Matzner Y, Ishai-Michaeli R, Lider O, Naparstek Y, Cohen IR, Fuks Z (1992) Expression of heparanase by platelets and circulating cells of the immune system: possible involvement in diapedesis and extravasation. Invasion Metastasis 12(2):112–127
von Hundelshausen P, Weber KS, Huo Y, Proudfoot AE, Nelson PJ, Ley K, Weber C (2001) RANTES deposition by platelets triggers monocyte arrest on inflamed and atherosclerotic endothelium. Circulation 103(13):1772–1777
Wang JF, Liu ZY, Groopman JE (1998) The alpha-chemokine receptor CXCR4 is expressed on the megakaryocytic lineage from progenitor to platelets and modulates migration and adhesion. Blood 92(3):756–764
Weyrich AS, Zimmerman GA (2004) Platelets: signaling cells in the immune continuum. Trends Immunol 25(9):489–495
Wirtz TH, Tillmann S, Strussmann T, Kraemer S, Heemskerk JW, Grottke O, Gawaz M, von Hundelshausen P, Bernhagen J (2015) Platelet-derived MIF: a novel platelet chemokine with distinct recruitment properties. Atherosclerosis 239(1):1–10
Worthylake RA, Burridge K (2001) Leukocyte transendothelial migration: orchestrating the underlying molecular machinery. Curr Opin Cell Biol 13(5):569–577
Yamaguchi K, Yu Z, Kumamoto H, Sugawara Y, Kawamura H, Takada H, Yokochi T, Sugawara S, Endo Y (2006) Involvement of Kupffer cells in lipopolysaccharide-induced rapid accumulation of platelets in the liver and the ensuing anaphylaxis-like shock in mice. Biochim Biophys Acta 1762(3):269–275
Yan J, Jin T (2012) Signaling network from GPCR to the actin cytoskeleton during chemotaxis. Bioarchitecture 2(1):15–18
Yaron M, Djaldetti M (1978) Platelets in synovial fluid. Arthritis Rheum 21(5):607–608
Zachem CR, Alpers CE, Way W, Shankland SJ, Couser WG, Johnson RJ (1997) A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis. J Am Soc Nephrol 8(12):1838–1844
Zarrinpashneh E, Poggioli T, Sarathchandra P, Lexow J, Monassier L, Terracciano C, Lang F, Damilano F, Zhou JQ, Rosenzweig A, Rosenthal N, Santini MP (2013) Ablation of SGK1 impairs endothelial cell migration and tube formation leading to decreased neo-angiogenesis following myocardial infarction. PLoS One 8(11):e80268
Zernecke A, Liehn EA, Fraemohs L, von Hundelshausen P, Koenen RR, Corada M, Dejana E, Weber C (2006) Importance of junctional adhesion molecule-A for neointimal lesion formation and infiltration in atherosclerosis-prone mice. Arterioscler Thromb Vasc Biol 26(2):e10–13
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Petito, E., Momi, S., Gresele, P. (2017). The Migration of Platelets and their Interaction with Other Migrating Cells. In: Gresele, P., Kleiman, N., Lopez, J., Page, C. (eds) Platelets in Thrombotic and Non-Thrombotic Disorders. Springer, Cham. https://doi.org/10.1007/978-3-319-47462-5_25
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