Skip to main content
  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • ATVB Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Cover Art Award
    • ATVB Early Career Award
    • ATVB in Focus
    • Recent Brief Reviews of ATVB
    • Lecture Series
    • Collections
    • Recent Highlights of ATVB
    • Commentaries
    • Browse Abstracts
    • Insight into ATVB Authors
  • Resources
    • Instructions for Authors
    • Online Submission/Peer Review Site
    • Council on ATVB
    • Permissions and Rights Q&A
    • AHA Guidelines and Statements
    • Customer Service and Ordering Information
    • Author Reprints
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
  • Facebook
  • LinkedIn
  • Twitter

  • My alerts
  • Sign In
  • Join

  • Advanced search

Header Publisher Menu

  • American Heart Association
  • Science Volunteer
  • Warning Signs
  • Advanced Search
  • Donate

Arteriosclerosis, Thrombosis, and Vascular Biology

  • My alerts
  • Sign In
  • Join

  • Facebook
  • LinkedIn
  • Twitter
  • Home
  • About this Journal
    • Editorial Board
    • Meet the Editors
    • ATVB Journal History
    • General Statistics
  • All Issues
  • Subjects
    • All Subjects
    • Arrhythmia and Electrophysiology
    • Basic, Translational, and Clinical Research
    • Critical Care and Resuscitation
    • Epidemiology, Lifestyle, and Prevention
    • Genetics
    • Heart Failure and Cardiac Disease
    • Hypertension
    • Imaging and Diagnostic Testing
    • Intervention, Surgery, Transplantation
    • Quality and Outcomes
    • Stroke
    • Vascular Disease
  • Browse Features
    • Cover Art Award
    • ATVB Early Career Award
    • ATVB in Focus
    • Recent Brief Reviews of ATVB
    • Lecture Series
    • Collections
    • Recent Highlights of ATVB
    • Commentaries
    • Browse Abstracts
    • Insight into ATVB Authors
  • Resources
    • Instructions for Authors
    • Online Submission/Peer Review Site
    • Council on ATVB
    • Permissions and Rights Q&A
    • AHA Guidelines and Statements
    • Customer Service and Ordering Information
    • Author Reprints
    • International Users
    • AHA Newsroom
  • AHA Journals
    • AHA Journals Home
    • Arteriosclerosis, Thrombosis, and Vascular Biology (ATVB)
    • Circulation
    • → Circ: Arrhythmia and Electrophysiology
    • → Circ: Genomic and Precision Medicine
    • → Circ: Cardiovascular Imaging
    • → Circ: Cardiovascular Interventions
    • → Circ: Cardiovascular Quality & Outcomes
    • → Circ: Heart Failure
    • Circulation Research
    • Hypertension
    • Stroke
    • Journal of the American Heart Association
ATVB in Focus: Platelets Unplugged: Focus on Platelet Biology

Platelet–Leukocyte Interactions in Cardiovascular Disease and Beyond

Licia Totani, Virgilio Evangelista
Download PDF
https://doi.org/10.1161/ATVBAHA.110.207480
Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:2357-2361
Originally published November 17, 2010
Licia Totani
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Virgilio Evangelista
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Tables
  • Info & Metrics
  • eLetters

Jump to

  • Article
    • Abstract
    • Routes of Platelet–Leukocyte Communication
    • Platelet–Leukocyte Interactions in Atherothrombosis
    • Platelet–Leukocyte Interactions in Inflammatory Lung Disease
    • Platelet–Leukocyte Interactions in Inflammatory Bowel Disease
    • Platelet–Leukocyte Interactions in Inflammatory Skin Diseases
    • Platelet–Leukocyte Interactions in Glomerulonephritis
    • Concluding Remarks
    • New Pharmacological Avenues
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters
Loading

Abstract

Platelet–leukocyte interactions define a basic cell process that is characterized by the exchange of signals between platelets and different types of leukocytes and that bridges 2 fundamental pathophysiological events: atherothrombosis and inflammatory immune reactions. When this process takes place at the site of atherosclerotic plaque development or at the site of endothelial injury, platelet-dependent leukocyte recruitment and activation contributes to the inflammatory reaction of the vessel wall, which accounts for the exacerbation of atherosclerosis and for intimal hyperplasia and plaque instability. Moreover, platelet–leukocyte interactions may have a key role in modulating a wide array of responses of both the innate and adaptive immune systems, thus contributing to the pathogenesis of inflammatory diseases and tissue damage, as well as to host defense.

  • leukocytes
  • platelets
  • signal transduction
  • thrombosis
  • inflammation

Series Editor: Susan S. Smyth
ATVB in Focus Platelets Unplugged: Focus on Platelet Biology

Cross-talk between platelets and leukocytes is a common feature of atherothrombosis and inflammatory immune reactions. During the last 10 years, several authors have extensively reviewed the literature on platelet–leukocyte interactions, mainly focusing on their roles in cardiovascular disease.1,2 This present review initially briefly summarizes our recent advances in the understanding of the basic molecular mechanisms that underlie platelet–leukocyte communication. We then discuss selected studies that have defined the pathogenetic role of this process in animal models of vascular disease, inflammatory disorders of the respiratory tract, bowel and skin, glomerulonephritis, arthritis, and sepsis.

Routes of Platelet–Leukocyte Communication

Platelets communicate biochemical signals to neutrophils, monocytes, and subsets of lymphocytes through adhesive receptors and a multitude of secreted soluble mediators. Vice versa, leukocyte-released factors, including proteases and nitric oxide, can modulate platelet responses. On the one hand, platelet–leukocyte “transcellular metabolism” of arachidonic acid amplifies the synthesis of proinflammatory and vasoconstrictive compounds, such as the leukotrienes and thromboxane A2, and, on the other hand, it leads to the generation of lipoxins, which mediate the resolution of inflammation. Moreover, activated platelets may interact with vascular endothelium in several ways and induce expression of adhesive molecules and chemokines, which in turn mediate leukocyte recruitment.

The adhesive receptors that mediate the tight contacts between platelets and leukocytes have been characterized in detail. The initial contact is driven by the exposure of P-selectin on the activated platelets, which is recognized by P-selectin glycoprotein ligand (PSGL)-1 on the leukocyte surface. After ligation, PSGL-1 triggers activation-dependent conformational changes in the β2 integrins, which mainly involve Mac-1, and promote the firm adhesion of the neutrophils.3 In a similar way, platelet binding triggers the adhesiveness of β1 and β2 integrins in monocytes4 and promotes tethering of lymphocytes to peripheral lymph node addressin, thus facilitating lymphocyte delivery to high endothelial venules5 and lymphocyte homing during adaptive immune responses.6

The key molecular events that link PSGL-1 to β2-integrin activation were identified recently. The binding of P-selectin to PSGL-1 results in Src family kinase (SFK)-dependent phosphorylation of Naf-1 (Nef-associated factor 1), which is constitutively associated with the cytoplasmic domain of PSGL-1. The phosphorylated Naf-1 recruits phosphoinositide 3-OH kinase p85-p110δ, which then mediates Mac-1 activation.7 Moreover, a SFK-mediated, outside-in signal that is transduced by Mac-1 and that leads to phosphorylation of Pyk2 (proline-rich tyrosine kinase-2) is necessary to stabilize integrin adhesion.3,8

Leukocyte tethering by platelet P-selectin not only induces rapid β2 integrin activation but also triggers delayed responses, which include gene expression and protein synthesis; these are fundamental for leukocytes to acquire an inflammatory phenotype. Delayed responses require the concerted actions of outside-in signaling that is transmitted by adhesive receptors (mainly PSGL-1 and β2 integrins) and of signals transduced by chemokine or cytokine receptors. For example, P-selectin and RANTES act in concert to induce nuclear translocation of nuclear factor κB, gene expression, and synthesis of monocyte chemotactic protein (MCP)-1 and interleukin (IL)-8 in monocytes.9 More recently, Dixon et al demonstrated that prolonged interaction with activated platelets induces cyclooxygenase (COX)-2 expression in monocytes.10 In this model, binding of P-selectin to PSGL-1 triggers nuclear factor κB activation and transcription of COX-2 gene; a second signal elicited by IL-1β, which is also synthesized in the context of platelet-monocyte interaction, then mediates COX-2 mRNA stabilization and efficient COX-2 protein synthesis. Thus, platelet-induced signals finely regulate COX-2 expression in monocytes by acting at transcriptional and posttranscriptional checkpoints.10 Because COX-2–derived eicosanoids in monocytes may have deleterious effects in inflammation and atherothrombosis, this observation underscores a potential mechanism by which platelet–monocyte interaction may contribute to inflammatory syndromes and ischemic heart disease.

Platelets contain a multitude of chemokines that can be displayed on the cell surface or released as soluble molecules on activation, including the CC (RANTES, MCP-1, MIP-1α, TARC) and CXC (platelet factor-4, ENA-78, GROβ) chemokines, β-thromboglobulin (converted to the CXC chemokine NAP-2 by neutrophil cathepsin G), CD40L, and TREM-1 (triggering receptor expressed on myeloid cell-1) ligand (reviewed elsewhere2). Within the close microenvironment between leukocytes and adherent platelet membranes, these mediators can activate their cognate receptors and induce immediate and/or delayed responses in immune cells (Figure 1).

Figure1
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 1. Molecular pathways of platelet–leukocyte communication. Recognition is the first step of platelet–leukocyte adhesion, and it is mainly mediated through the binding of P-selectin to PSGL-1. The rapid response follows signals transduced by the adhesive receptors (initially by PSGL-1, and subsequently by the engaged β2 integrins) and by platelet-derived CC and CXC chemokine receptors. These are 7-transmembrane domain receptors that are coupled to G proteins and initiate signal transduction, to trigger a multitude of cellular responses. Together, these signals induce immediate responses in leukocytes in particular: full integrin activation and firm adhesion, chemotaxis, and transmigration, release of granule contents, and ROS production. The delayed response is regulated by the concerted action of outside-in signaling, which is transmitted by adhesive receptors (mainly PSGL-1 and β2 integrins) and signals transmitted by receptors for chemokines and cytokines that are presented on the platelet surface or that are released as soluble molecules by activated platelets. These signals induce the nuclear translocation of the transcription factor nuclear factor κB (NF-kB), which mediates expression of the inflammatory phenotype.

In addition to direct cell–cell interactions, activated platelets can transfer released chemokines to the surface of inflamed or atherosclerotic endothelium. In this way, activated platelets leave a “message” on the vessel wall that can be “read” by circulating monocytes and can contribute to their recruitment and inflammatory activation at sites prone to atherosclerosis. Moreover, activated platelets disseminate microparticles, which are intact vesicles that form by budding from the membrane. As with whole platelets, these microparticles interact with leukocytes and other inflammatory cells and can amplify inflammation in human and experimental models of arthritis.11

Collectively, the data discussed above indicate that platelets contribute to inflammation through leukocyte recruitment and activation. This is achieved by induction of integrin adhesion and chemotaxis; by stimulation of rapid responses, such as release of reactive oxygen species, myeloperoxidase, and proteases in neutrophils; and by inducing intracellular signals, leading to inflammatory and prothrombotic gene expression in monocytes. Through these common mechanisms, platelet–leukocyte interactions exacerbate vascular injury in atherothrombosis and tissue damage in a variety of inflammatory diseases.

Platelet–Leukocyte Interactions in Atherothrombosis

Circulating platelet–leukocyte aggregates are increased in acute coronary syndromes,12 and they may contribute to cardiac dysfunction after ischemia and reperfusion. Additionally, neutrophil infiltration at the culprit lesions in patients who have died following acute myocardial infarction suggests that platelet–neutrophil interactions occur at the site of ruptured plaques.13

Recent studies in animal models have indicated a fundamental role for platelet–leukocyte interactions in the development and progression of atherosclerosis. In hypercholesterolemic animals, activated platelets and platelet–leukocyte aggregates adhere to the endothelium at sites that are prone to plaque formation and deliver RANTES and platelet factor-4; these in turn amplify the recruitment of monocytes and accelerate atherosclerosis.14 In vitro, activated platelets enhance the rate of cholesteryl ester accumulation by cultured monocyte-derived macrophages, and they induce CD34+ myeloid progenitor cells to differentiate into foam cells.15

Furthermore, platelet-mediated neutrophil recruitment promotes the development of intimal hyperplasia after experimental endovascular injury.16

Using a Dacron graft implanted within an arteriovenous shunt in baboons, Palabrica et al reported that P-selectin–mediated leukocyte accumulation in the developing thrombus promoted fibrin deposition.17 In vitro, platelet-derived CD40L and P-selectin provide signals that induce the expression of the procoagulant tissue factor in monocytes18 and granulocytes19 and stimulate procoagulant phosphatidylserine expression on the membrane of monocytes.20 In the mouse, high levels of soluble P-selectin stimulated the generation of leukocyte-derived procoagulant microparticles and induced a procoagulant state.21 Thus, platelet–leukocyte interaction may contribute to clot formation by mechanisms that are beyond the rapid formation of hemostatic plug.

Platelet–Leukocyte Interactions in Inflammatory Lung Disease

Platelet–leukocyte interactions occur in inflammatory lung disease. In a murine model of acute lung injury, platelet depletion or immunologic blockade of P-selectin reduced the histological changes and the protein leakage in the lung and reduced neutrophil accumulation in the intravascular, interstitial, and alveolar compartments, which indicated that platelet P-selectin mediates neutrophil recruitment.22 In vitro studies have suggested that thromboxane A2, which is released during platelet–neutrophil interactions, can stimulate intercellular adhesion molecule-1 expression by endothelial cells and the accumulation of neutrophils in the lungs.22 In a murine model of allergic inflammation, pharmacologically induced platelet depletion reduced eosinophil and lymphocyte accumulation in the lungs after exposure of animals to specific allergens. Here, leukocyte recruitment was completely or partially restored by injection of wild-type, and not P-selectin–deficient, platelets.23

Clinical and experimental observations have suggested a role for platelet–neutrophil interactions in cystic fibrosis (CF), a genetic disease in which mutations in the gene of the CF transmembrane conductance regulator (CFTR) result in reduced secretion of Cl− and HCO3− ions, thickened mucosal secretions, and chronic infections of the airways. An excessive and persistent accumulation of neutrophils and tissue damage characterize the airways of patients with CF. These patients show increased levels of neutrophil–platelet and monocyte–platelet aggregates in their circulating blood and increased Mac-1 expression on their neutrophils and monocytes.24,25 Interestingly, in vitro blockade of CFTR in platelets and neutrophils from healthy subjects results in reduced generation of lipoxin A4 by platelet–neutrophil coincubation and prolonged neutrophil survival,25 suggesting that dysfunctional platelet–neutrophil interaction may contribute to lung inflammation in CF.

Platelet–Leukocyte Interactions in Inflammatory Bowel Disease

Recent advances in animal models have highlighted a key role for platelet–leukocyte–endothelial cell interactions in the pathogenesis of inflammatory bowel diseases.26 Intravital video microscopy of colonic venules in mice subjected to experimental colitis has demonstrated that leukocytes that adhere to the vessel walls recruit the circulating platelets. The use of neutralizing monoclonal antibodies or the induction of colitis in P-selectin−/− mice indicated that P-selectin and PSGL-1 mediate the accumulation of platelets and leukocytes, and the extent of their accumulation correlates with disease severity.27 In addition to P-selectin–PSGL-1 pair, CD40L appears to mediate platelet–leukocyte interaction in experimental colitis. Genetic deletion or pharmacological inhibition of CD40-CD40L pathway reduces platelet and leukocyte accumulation in the colonic microvasculature and attenuate the disease.28 Thus, platelet and leukocyte recruitment in the microvasculature of the colon mucosa are codependent and may be responsible for microthrombosis, fibrin deposition, focal arteritis, and microinfarctions that have been observed in biopsies of patients with inflammatory bowel diseases. Hypercoagulability and the prothrombotic state of the inflamed mucosal microvasculature are also sustained by increased expression of the procoagulant tissue factor. In a mouse model of colitis, a blockade of tissue factor using monoclonal antibodies prevented platelet and leukocyte recruitment and reduced tissue injury and microthrombosis.29

In patients with inflammatory bowel diseases, platelets circulate in an activated state, and they form heterotypic aggregates with circulating leukocytes and are an important source of inflammatory mediators.30 In addition to contributing to thrombotic and inflammatory reactions at the intravascular side of the intestinal microcirculation, platelets migrate across the mucosal epithelium together with neutrophils. Interestingly, transmigrated platelets release large amounts of ATP, which is metabolized to adenosine by ectonucleotidases expressed on the apical surface of intestinal epithelial cells. Adenosine, in turn, induces chloride secretion and concomitant water movement into the intestinal lumen. In this way, transmigrated platelets can affect important functions at the luminal surface of the epithelium.31

Platelet–Leukocyte Interactions in Inflammatory Skin Diseases

Recently, the role of platelet–leukocyte interactions was investigated in a mouse model of chronic contact hypersensitivity.32 Flow cytometric analysis of the blood of the elicited animals showed increased P-selectin expression in circulating platelets and the formation of mixed platelet–leukocyte conjugates. Leukocyte recruitment and inflammatory skin reactions were significantly decreased in mice that were made thrombocytopenic, and they were restored by injection of platelets from wild-type, and not P-selectin–deficient, mice.33 Platelet-derived chemokines, MIP-1α, RANTES, and TARC, were also involved in leukocyte recruitment at the sites of skin inflammation.33In a mouse model of cutaneous Arthus reaction, an inflammatory disease that is initiated by deposition of IgG-containing immune complexes, genetic deletion of P-selectin or PSGL-1 reduced leukocyte recruitment into the inflamed skin and reduced edema and hemorrhage in normal, but not in thrombocytopenic, mice,34 confirming that platelets cooperate in leukocyte recruitment into inflamed skin through the interaction of P-selectin with PSGL-1.

Platelet–Leukocyte Interactions in Glomerulonephritis

Detection of platelet-derived and neutrophil-derived cationic proteins in the glomeruli of patients with lupus nephritis and cryoglobulinemia-associated nephritis has suggested the involvement of both neutrophils and platelets in inflammatory glomerular diseases. In animal models of immune complex nephritis, which are characterized by diffuse proliferative nephritis and deposition of fibrin, neutrophils, and platelets colocalize into the glomerulus in a platelet P-selectin–dependent manner,35 and they cooperate in the development of renal injury.36

Concluding Remarks

This review supports the concept that platelet–leukocyte interactions have a pivotal role in promoting the inflammatory reactions of the vessel wall, which are fundamental for initiation and progression of atherothrombosis. Beyond atherosclerosis and acute thrombotic events, platelet–leukocyte interactions are involved in a range of inflammatory diseases, which supports the view that platelets are fundamental partners of the immune system. During these interactions, platelets trigger intracellular signaling in immune cells, and, in this way, they modulate inflammatory immune responses, most frequently by amplification. Moreover, platelet–neutrophil adhesion triggers the phagocytic clearance of activated platelets by neutrophils,37 a process that plausibly limits the proinflammatory and prothrombotic potential of activated platelets.

Finally, platelet–neutrophil interactions may contribute to host defense, through stimulating the formation of neutrophil extracellular traps to ensnare bacteria.38 (Figure 2).

Figure2
  • Download figure
  • Open in new tab
  • Download powerpoint

Figure 2. Contribution of platelet–leukocyte interactions to inflammatory immune responses. Platelets are activated at the site of endothelial damage or in the microcirculation of infected/inflamed tissue. Activated platelets bind leukocytes to form heterotypic complexes and communicate signals that result in a variety of specific responses. Platelets mediate the recruitment of leukocytes at the site of atherosclerosis or thrombus formation, as well as in inflamed tissue. In some cases, these interactions mediate platelet–leukocyte comigration across the mucosal epithelium. In this way, platelets contribute to the promotion of inflammatory reactions, which, when not controlled, can exacerbate tissue damage. Platelets may support lymphocyte homing in peripheral lymph nodes, stimulate isotype switching and production of IgG by B lymphocytes, and help lymphocyte responses to viruses and neutrophil response to bacteria. In this way, platelets contribute to host defense.

New Pharmacological Avenues

Each of the molecular determinants of platelet–leukocyte cross-talk are promising pharmacological targets. Research on effective strategies targeting platelet–leukocyte interaction has been mainly focused on inhibitors of P-selectin. P-selectin antagonism showed efficacy in several animal models of disease, particularly in ischemia/reperfusion injury and arterial and venous thrombosis. As an example, monoclonal antibodies against P-selectin or a soluble recombinant form of PSGL-1, successfully paralleled enoxaparin for the treatment of deep vein thrombosis in nonhuman primates.39

The importance of platelet-derived chemokines in mediating platelet–monocyte communication highlighted the role of these chemokines as pharmacological targets to inhibit atherosclerosis. Koenen et al showed that selective disruption of RANTES–platelet factor-4 heterodimers by peptide inhibitors attenuates monocyte recruitment and reduces atherosclerosis in hyperlipidemic mice.40

Genetic and pharmacological targeting of the intracellular pathways that mediate PSGL-1–β2-integrin cross-talk have supported their pathophysiological importance in platelet-dependent granulocyte recruitment at the site of arterial injury8 and inflammation.7 This has, thus, emphasized the role of these molecular mechanisms, namely SFK- and phosphoinositide 3-kinase–mediated pathways, as novel targets for pharmacological interventions that are aimed at inhibiting platelet–leukocyte interactions.

Acknowledgments

We thank Christopher P. Berrie for editorial assistance, Matt Hazzard (Teaching and Academic Support Center, University of Kentucky) for preparation of the figures, and Roberta Le Donne for secretarial assistance. We also thank members of our laboratory for fundamental contributions to the work cited in this article.

Sources of Funding

This work was supported by the Fondazione Carichieti-Fondazione Negri Sud Onlus (to V.E.), the Ministero dell'Istruzione, dell'Universita e della Ricerca, Decreto Ministeriale (MIUR D.M.) 44/08, Comitato Esperti Politiche della Ricerca, Decreto Direttoriale (CEPR D,D). 484/Ric 2008 (to V.E.), and National Institutes of Health grant HL080166 (to V.E.).

Disclosures

None.

Footnotes

  • Received on: September 8, 2010; final version accepted on: October 12, 2010.

References

  1. ↵
    Cerletti C, Evangelista V, de Gaetano G. P-selectin-beta 2-integrin cross-talk: a molecular mechanism for polymorphonuclear leukocyte recruitment at the site of vascular damage. Thromb Haemost. 1999; 82: 787–793.
    OpenUrlPubMed
  2. ↵
    von Hundelshausen P, Weber C. Platelets as immune cells: bridging inflammation and cardiovascular disease. Circ Res. 2007; 100: 27–40.
    OpenUrlAbstract/FREE Full Text
  3. ↵
    Piccardoni P, Sideri R, Manarini S, Piccoli A, Martelli N, de Gaetano G, Cerletti C, Evangelista V. Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin. Blood. 2001; 98: 108–116.
    OpenUrlAbstract/FREE Full Text
  4. ↵
    da Costa Martins PA, van Gils JM, Mol A, Hordijk PL, Zwaginga JJ. Platelet binding to monocytes increases the adhesive properties of monocytes by up-regulating the expression and functionality of beta1 and beta2 integrins. J Leukoc Biol. 2006; 79: 499–507.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    Diacovo TG, Puri KD, Warnock RA, Springer TA, von Andrian UH. Platelet-mediated lymphocyte delivery to high endothelial venules. Science. 1996; 273: 252–255.
    OpenUrlAbstract
  6. ↵
    Elzey BD, Tian J, Jensen RJ, Swanson AK, Lees JR, Lentz SR, Stein CS, Nieswandt B, Wang Y, Davidson BL, Ratliff TL. Platelet-mediated modulation of adaptive immunity. A communication link between innate and adaptive immune compartments. Immunity. 2003; 19: 9–19.
    OpenUrlCrossRefPubMed
  7. ↵
    Wang HB, Wang JT, Zhang L, Geng ZH, Xu WL, Xu T, Huo Y, Zhu X, Plow EF, Chen M, Geng JG. P-selectin primes leukocyte integrin activation during inflammation. Nat Immunol. 2007; 8: 882–892.
    OpenUrlCrossRefPubMed
  8. ↵
    Evangelista V, Pamuklar Z, Piccoli A, Manarini S, Dell'elba G, Pecce R, Martelli N, Federico L, Rojas M, Berton G, Lowell CA, Totani L, Smyth SS. Src family kinases mediate neutrophil adhesion to adherent platelets. Blood. 2007; 109: 2461–2469.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    Weyrich AS, Elstad MR, McEver RP, McIntyre TM, Moore KL, Morrissey JH, Prescott SM, Zimmerman GA. Activated platelets signal chemokine synthesis by human monocytes. J Clin Invest. 1996; 97: 1525–1534.
    OpenUrlCrossRefPubMed
  10. ↵
    Dixon DA, Tolley ND, Bemis-Standoli K, Martinez ML, Weyrich AS, Morrow JD, Prescott SM, Zimmerman GA. Expression of COX-2 in platelet-monocyte interactions occurs via combinatorial regulation involving adhesion and cytokine signaling. J Clin Invest. 2006; 116: 2727–2738.
    OpenUrlCrossRefPubMed
  11. ↵
    Boilard E, Nigrovic PA, Larabee K, Watts GFM, Coblyn JS, Weinblat ME, Massarotti EM, Remold-O'Donnell E, Farndale RW, Ware J, Lee DM. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science. 2010; 327: 580–583.
    OpenUrlAbstract/FREE Full Text
  12. ↵
    Sarma J, Laan CA, Alam S, Jha A, Fox KA, Dransfield I. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation. 2002; 105: 2166–2171.
    OpenUrlAbstract/FREE Full Text
  13. ↵
    Naruko T, Ueda M, Haze K, van der Wal AC, van der Loos CM, Itoh A, Komatsu R, Ikura Y, Ogami M, Shimada Y, Ehara S, Yoshiyama M, Takeuchi K, Yoshikawa J, Becker AE. Neutrophil infiltration of culprit lesions in acute coronary syndromes. Circulation. 2002; 106: 2894–2900.
    OpenUrlAbstract/FREE Full Text
  14. ↵
    Huo Y, Schober A, Forlow SB, Smith DF, Hyman MC, Jung S, Littman DR, Weber C, Ley K. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med. 2003; 9: 61–67.
    OpenUrlCrossRefPubMed
  15. ↵
    Daub K, Langer H, Seizer P, Stellos K, May AE, Goyal P, Bigalke B, Schönberger T, Geisler T, Siegel-Axel D, Oostendorp RA, Lindemann S, Gawaz M. Platelets induce differentiation of human CD34+ progenitor cells into foam cells and endothelial cells. FASEB J. 2006; 20: 2559–2561.
    OpenUrlAbstract/FREE Full Text
  16. ↵
    Smyth SS, Reis ED, Zhang W, Fallon JT, Gordon RE, Coller BS. β3-Integrin-deficient mice but not P-selectin-deficient mice develop intimal hyperplasia after vascular injury. Circulation. 2001; 103: 2501–2507.
    OpenUrlAbstract/FREE Full Text
  17. ↵
    Palabrica T, Lobb R, Furie BC, Aronovitz M, Benjamin C, Hsu YM, Sajer SA, Furie B. Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets. Nature. 1992; 359: 848–851.
    OpenUrlCrossRefPubMed
  18. ↵
    Celi A, Pellegrini G, Lorenzet R, De Blasi A, Ready N, Furie BC, Furie B. P-selectin induces the expression of tissue factor on monocytes. Proc Natl Acad Sci U S A. 1994; 91: 8767–8771.
    OpenUrlAbstract/FREE Full Text
  19. ↵
    Maugeri N, Brambilla M, Camera M, Carbone A, Tremoli E, Donati MB, de Gaetano G, Cerletti C. Human polymorphonuclear leukocytes produce and express tissue factor upon stimulation. J Thromb Haemost. 2006; 4: 1323–1330.
    OpenUrlCrossRefPubMed
  20. ↵
    del Conde I, Nabi F, Tonda R, Thiagarajan P, Lopez JA, Kleiman NS. Effect of P-selectin on phosphatidylserine exposure and surface-dependent thrombin generation on monocytes. Arterioscler Throm Vasc Biol. 2005; 25: 1065–1070.
    OpenUrlAbstract/FREE Full Text
  21. ↵
    Hrachovinová I, Cambien B, Hafezi-Moghadam A, Kappelmayer J, Camphausen RT, Widom A, Xia L, Kazazian HH Jr, Schaub RG, McEver RP, Wagner DD. Interaction of P-selectin and PSGL-1 generates microparticles that correct hemostasis in a mouse model of hemophilia A. Nat Med. 2003; 9: 1020–1025.
    OpenUrlCrossRefPubMed
  22. ↵
    Zarbock A, Singbartl K, Ley K. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest. 2006; 116: 3211–3219.
    OpenUrlCrossRefPubMed
  23. ↵
    Pitchford SC, Momi S, Giannini S, Casali L, Spina D, Page CP, Gresele P. Platelet P-selectin is required for pulmonary eosinophil and lymphocyte recruitment in a murine model of allergic inflammation. Blood. 2005; 105: 2074–2081.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    O'Sullivan BP, Linden MD, Frelinger AL III, Barnard MR, Spencer-Manzon M, Morris JE, Salem RO, Laposata M, Michelson AD. Platelet activation in cystic fibrosis. Blood. 2005; 105: 4635–4641.
    OpenUrlAbstract/FREE Full Text
  25. ↵
    Mattoscio D, Evangelista V, De Cristofaro R, Recchiuti A, Pandolfi A, Di Silvestre S, Manarini S, Martelli N, Rocca B, Petrucci G, Angelini DF, Battistini L, Robuffo I, Pensabene T, Pieroni L, Furnari ML, Pardo F, Quattrucci S, Lancellotti S, Davì G, Romano M. Cystic fibrosis transmembrane conductance regulator (CFTR) expression in human platelets: impact on mediators and mechanisms of the inflammatory response. FASEB J. 2010; 24: 3970–3980.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    Deban L, Correale C, Vetrano S, Malesci A, Danese S. Multiple pathogenic roles of microvasculature in inflammatory bowel disease: a Jack of all trades. Am J Pathol. 2008; 172: 1457–1466.
    OpenUrlCrossRefPubMed
  27. ↵
    Gironella M, Mollà M, Salas A, Soriano A, Sans M, Closa D, Engel P, Salas A, Piqué JM, Panés J. The role of P-selectin in experimental colitis as determined by antibody immunoblockade and genetically deficient mice. J Leukoc Biol. 2002; 72: 56–64.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    Vowinkel T, Anthoni C, Wood KC, Stokes KY, Russell J, Gray L, Bharwani S, Senninger N, Alexander JS, Krieglstein CF, Grisham MB, Granger DN. CD40-CD40 ligand mediates the recruitment of leukocytes and platelets in the inflamed murine colon. Gastroenterology. 2007; 132: 955–965.
    OpenUrlCrossRefPubMed
  29. ↵
    Anthoni C, Russell J, Wood KC, Stokes KY, Vowinkel T, Kirchhofer D, Granger DN. Tissue factor: a mediator of inflammatory cell recruitment, tissue injury, and thrombus formation in experimental colitis. J Exp Med. 2007; 204: 1595–1601.
    OpenUrlAbstract/FREE Full Text
  30. ↵
    Pamuk GE, Vural O, Turgut B, Demir M, Umit H, Tezel A. Increased circulating platelet-neutrophil, platelet-monocyte complexes, and platelet activation in patients with ulcerative colitis: a comparative study. Am J Hematol. 2006; 81: 753–759.
    OpenUrlCrossRefPubMed
  31. ↵
    Weissmüller T, Campbell EL, Rosenberger P, Scully M, Beck PL, Furuta GT, Colgan SP. PMNs facilitate translocation of platelets across human and mouse epithelium and together alter fluid homeostasis via epithelial cell-expressed ecto-NTPDases. J Clin Invest. 2008; 118: 3682–3692.
    OpenUrlCrossRefPubMed
  32. ↵
    Tamagawa-Mineoka R, Katoh N, Ueda E, Takenaka H, Kita M, Kishimoto S. The role of platelets in leukocyte recruitment in chronic contact hypersensitivity induced by repeated elicitation. Am J Pathol. 2007; 170: 2019–2029.
    OpenUrlCrossRefPubMed
  33. ↵
    Ludwig RJ, Schultz JE, Boehncke WH, Podda M, Tandi C, Krombach F, Baatz H, Kaufmann R, von Andrian UH, Zollner TM. Activated, not resting, platelets increase leukocyte rolling in murine skin utilizing a distinct set of adhesion molecules. J Invest Dermatol. 2004; 122: 830–836.
    OpenUrlCrossRefPubMed
  34. ↵
    Hara T, Shimizu K, Ogawa F, Yanaba K, Iwata Y, Muroi E, Takenaka M, Komura K, Hasegawa M, Fujimoto M, Sato S. Platelets control leukocyte recruitment in a murine model of cutaneous arthus reaction. Am J Pathol. 2010; 176: 259–269.
    OpenUrlCrossRefPubMed
  35. ↵
    Zachem CR, Alpers CE, Way W, Shankland SJ, Couser WG, Johnson RJ. A role for P-selectin in neutrophil and platelet infiltration in immune complex glomerulonephritis. J Am Soc Nephrol. 1997; 8: 1838–1844.
    OpenUrlAbstract
  36. ↵
    Kuligowski MP, Kitching AR, Hickey MJ. Leukocyte recruitment to the inflamed glomerulus: a critical role for platelet-derived P-selectin in the absence of rolling. J Immunol. 2006; 176: 6991–6999.
    OpenUrlAbstract/FREE Full Text
  37. ↵
    Maugeri N, Rovere-Querini P, Evangelista V, Covino C, Capobianco A, Bertilaccio MT, Piccoli A, Totani L, Cianflone D, Maseri A, Manfredi AA. Neutrophils phagocytose activated platelets in vivo: a phosphatidylserine, P-selectin, and {beta}2 integrin-dependent cell clearance program. Blood. 2009; 113: 5254–5265.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chrakbarti S, McAvoy E, Sinclair GD, Keys EM, Allen-Vercoe E, DeVinney R, Doig CJ, Green FHY, Kubes P. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med. 2007; 13: 463–469.
    OpenUrlCrossRefPubMed
  39. ↵
    Ramaccioni E, Myers DD Jr, Wrobleski SK, Deatrick KB, Londy FJ, Rectenwald JE, Henke PK, Schaub RG, Wakefield TW. P-selectin/PSGL-1 inhibitors versus enoxaparin in the resolution of venous thrombosis: a meta-analysis. Thromb Res. 2010; 125: e138–e142.
    OpenUrlCrossRefPubMed
  40. ↵
    Koenen RR, von Hundelshausen P, Nesmelova IV, Zernecke A, Liehn EA, Sarabi A, Kramp BK, Piccinini AM, Paludan SR, Kowalska MA, Kungl AJ, Hackeng TM, Mayo KH, Weber C. Disrupting functional interactions between platelet chemokines inhibits atherosclerosis in hyperlipidemic mice. Nat Med. 2009; 15: 97–103.
    OpenUrlCrossRefPubMed
View Abstract
Back to top
Previous ArticleNext Article

This Issue

Arteriosclerosis, Thrombosis, and Vascular Biology
December 2010, Volume 30, Issue 12
  • Table of Contents
Previous ArticleNext Article

Jump to

  • Article
    • Abstract
    • Routes of Platelet–Leukocyte Communication
    • Platelet–Leukocyte Interactions in Atherothrombosis
    • Platelet–Leukocyte Interactions in Inflammatory Lung Disease
    • Platelet–Leukocyte Interactions in Inflammatory Bowel Disease
    • Platelet–Leukocyte Interactions in Inflammatory Skin Diseases
    • Platelet–Leukocyte Interactions in Glomerulonephritis
    • Concluding Remarks
    • New Pharmacological Avenues
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Tables
  • Info & Metrics
  • eLetters

Article Tools

  • Print
  • Citation Tools
    Platelet–Leukocyte Interactions in Cardiovascular Disease and Beyond
    Licia Totani and Virgilio Evangelista
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:2357-2361, originally published November 17, 2010
    https://doi.org/10.1161/ATVBAHA.110.207480

    Citation Manager Formats

    • BibTeX
    • Bookends
    • EasyBib
    • EndNote (tagged)
    • EndNote 8 (xml)
    • Medlars
    • Mendeley
    • Papers
    • RefWorks Tagged
    • Ref Manager
    • RIS
    • Zotero
  •  Download Powerpoint
  • Article Alerts
    Log in to Email Alerts with your email address.
  • Save to my folders

Share this Article

  • Email

    Thank you for your interest in spreading the word on Arteriosclerosis, Thrombosis, and Vascular Biology.

    NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

    Enter multiple addresses on separate lines or separate them with commas.
    Platelet–Leukocyte Interactions in Cardiovascular Disease and Beyond
    (Your Name) has sent you a message from Arteriosclerosis, Thrombosis, and Vascular Biology
    (Your Name) thought you would like to see the Arteriosclerosis, Thrombosis, and Vascular Biology web site.
  • Share on Social Media
    Platelet–Leukocyte Interactions in Cardiovascular Disease and Beyond
    Licia Totani and Virgilio Evangelista
    Arteriosclerosis, Thrombosis, and Vascular Biology. 2010;30:2357-2361, originally published November 17, 2010
    https://doi.org/10.1161/ATVBAHA.110.207480
    del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Related Articles

Cited By...

Subjects

  • Vascular Disease
    • Thrombosis
  • Basic, Translational, and Clinical Research
    • Vascular Biology
    • Platelets

Arteriosclerosis, Thrombosis, and Vascular Biology

  • About ATVB
  • Instructions for Authors
  • AHA CME
  • Meeting Abstracts
  • Permissions
  • Email Alerts
  • Open Access Information
  • AHA Journals RSS
  • AHA Newsroom

Contact the Editorial Office:
email: atvb@atvb.org

Information for:
  • Advertisers
  • Subscribers
  • Subscriber Help
  • Institutions / Librarians
  • Institutional Subscriptions FAQ
  • International Users
American Heart Association Learn and Live
National Center
7272 Greenville Ave.
Dallas, TX 75231

Customer Service

  • 1-800-AHA-USA-1
  • 1-800-242-8721
  • Local Info
  • Contact Us

About Us

Our mission is to build healthier lives, free of cardiovascular diseases and stroke. That single purpose drives all we do. The need for our work is beyond question. Find Out More about the American Heart Association

  • Careers
  • SHOP
  • Latest Heart and Stroke News
  • AHA/ASA Media Newsroom

Our Sites

  • American Heart Association
  • American Stroke Association
  • For Professionals
  • More Sites

Take Action

  • Advocate
  • Donate
  • Planned Giving
  • Volunteer

Online Communities

  • AFib Support
  • Garden Community
  • Patient Support Network
  • Professional Online Network

Follow Us:

  • Follow Circulation on Twitter
  • Visit Circulation on Facebook
  • Follow Circulation on Google Plus
  • Follow Circulation on Instagram
  • Follow Circulation on Pinterest
  • Follow Circulation on YouTube
  • Rss Feeds
  • Privacy Policy
  • Copyright
  • Ethics Policy
  • Conflict of Interest Policy
  • Linking Policy
  • Diversity
  • Careers

©2018 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. The American Heart Association is a qualified 501(c)(3) tax-exempt organization.
*Red Dress™ DHHS, Go Red™ AHA; National Wear Red Day ® is a registered trademark.

  • PUTTING PATIENTS FIRST National Health Council Standards of Excellence Certification Program
  • BBB Accredited Charity
  • Comodo Secured