The role of platelets in inflammation

Summary

There is growing recognition of the critical role of platelets in inflammation and immune responses. Recent studies have indicated that antiplatelet medications may reduce mortality from infections and sepsis, which suggests possible clinical relevance of modifying platelet responses to inflammation. Platelets release numerous inflammatory mediators that have no known role in haemostasis. Many of these mediators modify leukocyte and endothelial responses to a range of different inflammatory stimuli. Additionally, platelets form aggregates with leukocytes and form bridges between leukocytes and endothelium, largely mediated by platelet P-selectin. Through their interactions with monocytes, neutrophils, lymphocytes and the endothelium, platelets are therefore important coordinators of inflammation and both innate and adaptive immune responses.

Keywords

Platelets - inflammation - infection - immune response - thrombosis

• References

• 1 Semple JW. et al. Platelets and the immune continuum. Nat Rev Immunol 2011; 11: 264-274.
• 2 Varenhorst C. et al. Factors contributing to the lower mortality with ticagrelor compared with clopidogrel in patients undergoing coronary artery bypass surgery. J Am Coll Cardiol 2012; 60: 1623-1630.
• 3 Varenhorst C. et al. Causes of mortality with ticagrelor compared with clopidogrel in acute coronary syndromes. Heart 2014; 100: 1762-1769.
• 4 Storey RF. et al. Lower mortality following pulmonary adverse events and sepsis with ticagrelor compared to clopidogrel in the PLATO study. Platelets 2014; 25: 517-525.
• 5 Akinosoglou K. et al. Use of antiplatelet agents in sepsis: a glimpse into the future. Thromb Res 2014; 133: 131-138.
• 6 Kaushansky K. The molecular mechanisms that control thrombopoiesis. J Clin Invest 2005; 115: 3339-3347.
• 7 Harker LA, Finch CA. Thrombokinetics in man. J Clin Invest 1969; 48: 963-974.
• 8 Italiano JE, Shivdasani RA. Megakaryocytes and beyond: the birth of platelets. J Thromb Haemost 2003; 01: 1174-1182.
• 9 Kroll MH, Hellums JD, McIntire LV. et al. Platelets and shear stress. Blood 1996; 88: 1525-1541.
• 10 Furie B, Furie BC. Thrombus formation in vivo. J Clin Invest 2005; 115: 3355-3362.
• 11 Andrews RK, Berndt MC. Platelet physiology and thrombosis. Thromb Res 2004; 114: 447-453.
• 12 Storey RF. et al. The central role of the P(2T) receptor in amplification of human platelet activation, aggregation, secretion and procoagulant activity. Br J Haematol 2000; 110: 925-934.
• 13 Kulkarni S. et al. A revised model of platelet aggregation. J Clin Invest 2000; 105: 783-791.
• 14 Coppinger JA. et al. Moderation of the platelet releasate response by aspirin. Blood 2007; 109: 4786-4792.
• 15 Duerschmied D. et al. Platelet serotonin promotes the recruitment of neutrophils to sites of acute inflammation in mice. Blood 2013; 121: 1008-1015.
• 16 Rendu F, Brohard-Bohn B. The platelet release reaction: granules’ constituents, secretion and functions. Platelets 2001; 12: 261-273.
• 17 Blair P, Flaumenhaft R. Platelet alpha-granules: basic biology and clinical correlates. Blood Rev 2009; 23: 177-189.
• 18 Yeaman MR. et al. Platelet microbicidal proteins and neutrophil defensin disrupt the Staphylococcus aureus cytoplasmic membrane by distinct mechanisms of action. J Clin Invest 1998; 101: 178-187.
• 19 Nesmelova IV. et al. Platelet factor 4 and interleukin-8 CXC chemokine heterodimer formation modulates function at the quaternary structural level. J Biol Chem 2005; 280: 4948-4958.
• 20 Deuel TF. et al. Platelet Factor-4 Is Chemotactic for Neutrophils and Monocytes. Proc Natl Acad Sci USA 1981; 78: 4584-4587.
• 21 Petersen FF. et al. A chondroitin sulfate proteoglycan on human neutrophils specifically binds platelet factor 4 and is involved in cell activation. J Immunol 1998; 161: 4347-4355.
• 22 Scheuerer B. et al. The CXC-chemokine platelet factor 4 promotes monocyte survival and induces monocyte differentiation into macrophages. Blood 2000; 95: 1158-1166.
• 23 Kasper BB. et al. Platelet factor 4 (CXC chemokine ligand 4) differentially regulates respiratory burst, survival, and cytokine expression of human monocytes by using distinct signalling pathways. J Immunol 2007; 179: 2584-2591.
• 24 Hundelshausen von P. et al. Heterophilic interactions of platelet factor 4 and RANTES promote monocyte arrest on endothelium. Blood 2005; 105: 924-930.
• 25 Yu G. et al. Endothelial expression of E-selectin is induced by the platelet-specific chemokine platelet factor 4 through LRP in an NF-kappaB-dependent manner. Blood 2005; 105: 3545-3551.
• 26 Mause SF. et al. Platelet microparticles: a transcellular delivery system for RANTES promoting monocyte recruitment on endothelium. Arterioscler Thromb Vasc Biol 2005; 25: 1512-1518.
• 27 la Motte de C. et al. Cutting edge: T cells trigger CD40-dependent platelet activation and granular RANTES release: a novel pathway for immune response amplification. J Immunol 2004; 172: 2011-2015.
• 28 Lindemann S. et al. Activated platelets mediate inflammatory signalling by regulated interleukin 1beta synthesis. J Cell Biol 2001; 154: 485-490.
• 29 Pillitteri D. et al. Thrombin-induced interleukin 1beta synthesis in platelet suspensions: impact of contaminating leukocytes. Platelets 2007; 18: 119-127.
• 30 Loppnow H, Libby P. Proliferating or interleukin 1-activated human vascular smooth muscle cells secrete copious interleukin 6. J Clin Invest 1990; 85: 731-738.
• 31 Loppnow H. et al. Platelet-derived interleukin-1 induces cytokine production, but not proliferation of human vascular smooth muscle cells. Blood 1998; 91: 134-141.
• 32 Ignarro LJ. et al. Role of the arginine-nitric oxide pathway in the regulation of vascular smooth muscle cell proliferation. Proc Natl Acad Sci USA 2001; 98: 4202-4208.
• 33 Bevilacqua MP. et al. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest 1985; 76: 2003-2011.
• 34 Gawaz M. et al. Platelets induce alterations of chemotactic and adhesive properties of endothelial cells mediated through an interleukin-1-dependent mechanism. Implications for atherogenesis. Atherosclerosis 2000; 148: 75-85.
• 35 Deshmane SL. et al. Monocyte chemoattractant protein-1 (MCP-1): an overview. J Interferon Cytokine Res 2009; 29: 313-326.
• 36 Blann A. The adhesion molecule P-selectin and cardiovascular disease. Eur Heart J 2003; 24: 2166-2179.
• 37 Stenberg PEP. et al. A platelet alpha-granule membrane protein (GMP-140) is expressed on the plasma membrane after activation. J Cell Biol 1985; 101: 880-886.
• 38 Spertini OO. et al. P-selectin glycoprotein ligand 1 is a ligand for L-selectin on neutrophils, monocytes, and CD34+ hematopoietic progenitor cells. J Cell Biol 1996; 135: 523-531.
• 39 Symon FA. et al. Functional and structural characterization of the eosinophil P-selectin ligand. J Immunol 1996; 157: 1711-1719.
• 40 Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Ann Rev Immunol 1998; 16: 111-135.
• 41 Anand SX. et al. Membrane-associated CD40L and sCD40L in atherothrombotic disease. Thromb Haemost 2003; 90: 377-384.
• 42 Lindmark E. et al. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol; 2000; 20: 2322-2328.
• 43 Elzey BD. et al. Platelet-derived CD154 enables T-cell priming and protection against Listeria monocytogenes challenge. Blood 2008; 111: 3684-3691.
• 44 Henn V. et al. CD40 ligand on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391: 591-594.
• 45 Déchanet J. et al. CD40 ligand stimulates proinflammatory cytokine production by human endothelial cells. J Immunol 1997; 159: 5640-5647.
• 46 Henn V. The inflammatory action of CD40 ligand (CD154) expressed on activated human platelets is temporally limited by coexpressed CD40. Blood 2001; 98: 1047-1054.
• 47 Lim HS. Soluble CD40 Ligand, Soluble P-Selectin, Interleukin-6, and Tissue Factor in Diabetes Mellitus: Relationships to Cardiovascular Disease and Risk Factor Intervention. Circulation 2004; 109: 2524-2528.
• 48 Aukrust P. et al. Enhanced Levels of Soluble and Membrane-Bound CD40 Ligand in Patients With Unstable Angina : Possible Reflection of T Lymphocyte and Platelet Involvement in the Pathogenesis of Acute Coronary Syndromes. Circulation 1999; 100: 614-620.
• 49 Garlichs CD. et al. Patients with acute coronary syndromes express enhanced CD40 ligand/CD154 on platelets. Heart 2001; 86: 649-655.
• 50 Klesney-Tait J. et al. The TREM receptor family and signal integration. Nat Immunol 2006; 07: 1266-1273.
• 51 Haselmayer P. et al. TREM-1 ligand expression on platelets enhances neutrophil activation. Blood 2007; 110: 1029-1035.
• 52 Evangelista V. et al. Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: Role of PSGL-1 as a signalling molecule. Blood 1999; 93: 876-885.
• 53 Mine S. et al. Activated platelets and endothelial cell interaction with neutrophils under flow conditions. Intern Med 2001; 40: 1085-1092.
• 54 Doré MM. et al. P-selectin mediates spontaneous leukocyte rolling in vivo. Blood 1993; 82: 1308-1316.
• 55 Buttrum SM. et al. Selectin-mediated rolling of neutrophils on immobilized platelets. Blood 1993; 82: 1165-1174.
• 56 Yeo EL. et al. Role of P-selectin and leukocyte activation in polymorphonuclear cell adhesion to surface adherent activated platelets under physiologic shear conditions (an injury vessel wall model). Blood 1994; 83: 2498-2507.
• 57 Moore KL. et al. P-selectin glycoprotein ligand-1 mediates rolling of human neutrophils on P-selectin. J Cell Biol 1995; 128: 661-671.
• 58 da Costa Martins PA. et al. 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.
• 59 Ma Y-Q. et al. P-selectin binding to P-selectin glycoprotein ligand-1 induces an intermediate state of alphaMbeta2 activation and acts cooperatively with extra-cellular stimuli to support maximal adhesion of human neutrophils. Blood 2004; 104: 2549-2556.
• 60 Blanks JE. et al. Stimulation of P-selectin glycoprotein ligand-1 on mouse neutrophils activates beta(2)-integrin mediated cell attachment to ICAM-1. Eur J Immunol 1998; 28: 433-443.
• 61 Peters MJ. et al. Circulating platelet-neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing. Br J Haematol 1999; 106: 391-399.
• 62 Weyrich AS. et al. Monocyte tethering by P-selectin regulates monocyte chemotactic protein-1 and tumor necrosis factor-alpha secretion. Signal integration and NF-kappa B translocation. J Clin Invest 1995; 95: 2297-2303.
• 63 Tersteeg C. et al. FLow-induced PRotrusions (FLIPRs): a platelet-derived platform for the retrieval of microparticles by monocytes and neutrophils. Circ Res 2014; 114: 780-791.
• 64 Passacquale G. et al. Monocyte-platelet interaction induces a pro-inflammatory phenotype in circulating monocytes. PLoS One 2011; 06: e25595-5.
• 65 Brown KA. et al. Neutrophils in development of multiple organ failure in sepsis. Lancet 2006; 368: 157-169.
• 66 Salter JW. et al. Platelets modulate ischemia/reperfusion-induced leukocyte recruitment in the mesenteric circulation. Am J Physiol Gastrointest Liver Physiol 2001; 281: G1432-1439.
• 67 Singbartl K. et al. Platelet, but not endothelial, P-selectin is critical for neutro-phil-mediated acute postischemic renal failure. FASEB J 2001; 15: 2337-2344.
• 68 Asaduzzaman M. et al. Platelets support pulmonary recruitment of neutrophils in abdominal sepsis. Crit Care Med 2009; 37: 1389-1396.
• 69 Zarbock A. et al. Complete reversal of acid-induced acute lung injury by blocking of platelet-neutrophil aggregation. J Clin Invest 2006; 116: 3211-3219.
• 70 Sarma J. et al. Increased platelet binding to circulating monocytes in acute coronary syndromes. Circulation 2002; 105: 2166-2171.
• 71 Thomas MR, Storey RF. Effect of P2Y₁₂ inhibitors on inflammation and immunity. Thromb Haemost 2015; 114: 490-497.
• 72 Thomas MR. et al. A platelet P-selectin test predicts adverse cardiovascular events in patients with acute coronary syndromes treated with aspirin and clopidogrel. Platelets 2014; 25: 612-618.
• 73 Hohlfeld T, Schrör K. Antiinflammatory effects of aspirin in ACS: relevant to its cardiocoronary actions?. Thromb Haemost 2015; 114: 469-477.
• 74 Capra V. et al. Impact of vascular thromboxane prostanoid receptor activation on hemostasis, thrombosis, oxidative stress, and inflammation. J Thromb Hae-most 2014; 12: 126-137.
• 75 Larsen SB. et al. The influence of low-grade inflammation on platelets in patients with stable coronary artery disease. Thromb Haemost 2015; 114: 519-529.
• 76 Schrottmaier WC. et al. Aspirin and P2Y₁₂ Inhibitors in platelet-mediated activation of neutrophils and monocytes. Thromb Haemost 2015; 114: 478-489.
• 77 Brühl von M-L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
• 78 Rock KL. et al. The Sterile Inflammatory Response. Ann Rev Immunol 2010; 28: 321-342.
• 79 Zheng Y. et al. Cell death, damage-associated molecular patterns, and sterile inflammation in cardiovascular disease. Arterioscler Thromb Vasc Biol 2011; 31: 2781-2786.
• 80 Cognasse F. et al. The inflammatory role of platelets via their TLRs and Siglec receptors. Front Immunol. 2015 Epub ahead of print.
• 81 Orlova VV. et al. A novel pathway of HMGB1-mediated inflammatory cell recruitment that requires Mac-1-integrin. EMBO J 2007; 26: 1129-1139.
• 82 Maugeri N. et al. Activated platelets present high mobility group box 1 to neutrophils, inducing autophagy and promoting the extrusion of neutrophil extra-cellular traps. J Thromb Haemost 2014; 12: 2074-2088.
• 83 Hilf N. et al. Human platelets express heat shock protein receptors and regulate dendritic cell maturation. Blood 2002; 99: 3676-3682.
• 84 Cox D. et al. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost 2011; 09: 1097-1107.
• 85 Shannon O. et al. Severe streptococcal infection is associated with M protein-induced platelet activation and thrombus formation. Mol Microbiol 2007; 65: 1147-1157.
• 86 Brennan MP. et al. Elucidating the role of Staphylococcus epidermidis serine-aspartate repeat protein G in platelet activation. J Thromb Haemost 2009; 07: 1364-1372.
• 87 O’Seaghdha M. et al. Staphylococcus aureus protein A binding to von Wille-brand factor A1 domain is mediated by conserved IgG binding regions. FEBS J 2006; 273: 4831-4841.
• 88 Plummer C. et al. A serine-rich glycoprotein of Streptococcus sanguis mediates adhesion to platelets via GPIb. Br J Haematol 2005; 129: 101-109.
• 89 McNicol A. et al. Streptococcus sanguinis-induced cytokine release from platelets. J Thromb Haemost 2011; 09: 2038-2049.
• 90 Herzberg MC, Krishnan LK. Involvement of 2-Adrenoreceptors and G Proteins in the Modulation of Platelet Secretion in Response to Streptococcus sanguis. Crit Rev Oral Biol Med 1993; 04: 435-442.
• 91 Baughman RP. Thrombocytopenia in the intensive care unit. Chest 1993; 104: 1243.
• 92 Russwurm S. et al. Platelet and leukocyte activation correlate with the severity of septic organ dysfunction. Shock 2002; 17: 263-268.
• 93 Aslam R. et al. Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-alpha production in vivo. Blood 2006; 107: 637-641.
• 94 Koupenova M. et al. Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 2014; 124: 791-802.
• 95 Lu Y-C. et al. LPS/TLR4 signal transduction pathway. Cytokine 2008; 42: 145-151.
• 96 Ward JR. et al. Agonists of toll-like receptor (TLR)2 and TLR4 are unable to modulate platelet activation by adenosine diphosphate and platelet activating factor. Thromb Haemost 2005; 94: 831-838.
• 97 Andonegui G. Platelets express functional Toll-like receptor-4. Blood 2005; 106: 2417-2423.
• 98 Clark SR. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
• 99 Brinkmann V, Zychlinsky A. Neutrophil extracellular traps: is immunity the second function of chromatin?. J Cell Biol 2012; 198: 773-783.
• 100 Kaplan MJ, Radic M. Neutrophil extracellular traps: double-edged swords of innate immunity. J Immunol 2012; 189: 2689-2695.
• 101 Caudrillier A. et al. Platelets induce neutrophil extracellular traps in trans-fusion-related acute lung injury. J Clin Invest 2012; 122: 2661-2671.
• 102 McDonald B. et al. Intravascular Neutrophil Extracellular Traps Capture Bacteria from the Bloodstream during Sepsis. Cell Host Microbe 2012; 12: 324-333.
• 103 Rossaint J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 2014; 123: 2573-2584.
• 104 Martinod K, Wagner DD. Thrombosis: tangled up in NETs. Blood 2014; 123: 2768-2776.
• 105 Mangold A. et al. Coronary Neutrophil Extracellular Trap Burden and Deoxyribonuclease Activity in ST-Elevation Acute Coronary Syndrome Are Predictors of ST-Segment Resolution and Infarct Size. Circ Res 2015; 116: 1182-1192.
• 106 Totani L. et al. Prasugrel inhibits platelet-leukocyte interaction and reduces inflammatory markers in a model of endotoxic shock in the mouse. Thromb Haemost 2012; 107: 1130-1140.
• 107 Hagiwara S. et al. Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model. Shock 2011; 35: 289-292.
• 108 Lipcsey M. et al. Early endotoxin-mediated haemostatic and inflammatory responses in the clopidogrel-treated pig. Platelets 2005; 16: 408-414.
• 109 Ricklin D. et al. Complement: a key system for immune surveillance and home-ostasis. Nat Immunol 2010; 11: 785-797.
• 110 Peerschke EI. et al. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol Immunol 2010; 47: 2170-2175.
• 111 Patzelt J. et al. Platelets and the complement cascade in atherosclerosis. Front Physiol 2015; 06: 49.
• 112 Del Conde I. et al. Platelet activation leads to activation and propagation of the complement system. J Exp Med; 2005; 201: 871-879.
• 113 Hamad OA. et al. Complement activation triggered by chondroitin sulfate released by thrombin receptor-activated platelets. J Thromb Haemost 2008; 06: 1413-1421.
• 114 Yin W. et al. Expression of complement components and inhibitors on platelet microparticles. Platelets 2008; 19: 225-233.
• 115 Morrell CN. et al. Emerging roles for platelets as immune and inflammatory cells. Blood 2014; 123: 2759-2767.
• 116 McMorran BJ. et al. Platelets Kill Intraerythrocytic Malarial Parasites and Mediate Survival to Infection. Science 2009; 323: 797-800.
• 117 McMorran BJ. et al. Platelet Factor 4 and Duffy Antigen Required for Platelet Killing of Plasmodium falciparum. Science 2012; 338: 1348-1351.
• 118 Bendas G, Borsig L. Cancer cell adhesion and metastasis: selectins, integrins, and the inhibitory potential of heparins. Int J Cell Biol 2012; 2012: 676731-676731.
• 119 Schlesinger M. et al. The role of VLA-4 binding for experimental melanoma metastasis and its inhibition by heparin. Thromb Res 2014; 133: 855-862.
• 120 Rothwell PM. et al. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet 2012; 379: 1591-1601.
• 121 Schrör K. Pharmacology and cellular/molecular mechanisms of action of aspirin and non-aspirin NSAIDs in colorectal cancer. Best Pract Res Clin Gastroenterol 2011; 25: 473-484.
• 122 Maurer MM, Stebut von EE.. Macrophage inflammatory protein-1. Int J Biochem Cell Biol 2004; 36: 5-5.
• 123 Lindmark E. et al. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 2000; 20: 2322-2328.
• 124 Cox D. et al. Platelets and the innate immune system: mechanisms of bacterial-induced platelet activation. J Thromb Haemost 2011; 09: 1097-1107.
• 125 Bouchon AA. et al. Cutting edge: inflammatory responses can be triggered by TREM-1, a novel receptor expressed on neutrophils and monocytes. J Immunol 2000; 164: 4991-4995.
• 126 Brown GT, McIntyre TM. Lipopolysaccharide signalling without a nucleus: kinase cascades stimulate platelet shedding of proinflammatory IL-1 -rich microparticles. J Immunol 2011; 186: 5489-5496.
• 127 Italiano JE. et al. Clinical relevance of microparticles from platelets and megakaryocytes. Curr Opin Hematol 2010; 17: 578-584.
• 128 Vajen T. et al. Microvesicles from platelets: novel drivers of vascular inflammation. Thromb Haemost 2015; 114: 228-236.