Skip to main content

Advertisement

SpringerLink
Log in

Platelet–neutrophil interactions under thromboinflammatory conditions

  • Review
  • Published:
Cellular and Molecular Life Sciences Aims and scope Submit manuscript

Abstract

Platelets primarily mediate hemostasis and thrombosis, whereas leukocytes are responsible for immune responses. Since platelets interact with leukocytes at the site of vascular injury, thrombosis and vascular inflammation are closely intertwined and occur consecutively. Recent studies using real-time imaging technology demonstrated that platelet–neutrophil interactions on the activated endothelium are an important determinant of microvascular occlusion during thromboinflammatory disease in which inflammation is coupled to thrombosis. Although the major receptors and counter receptors have been identified, it remains poorly understood how heterotypic platelet–neutrophil interactions are regulated under disease conditions. This review discusses our current understanding of the regulatory mechanisms of platelet–neutrophil interactions in thromboinflammatory disease.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Zarbock A, Ley K (2009) Neutrophil adhesion and activation under flow. Microcirculation 16(1):31–42

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Henderson RB, Lim LH, Tessier PA, Gavins FN, Mathies M, Perretti M, Hogg N (2001) The use of lymphocyte function-associated antigen (LFA)-1-deficient mice to determine the role of LFA-1, Mac-1, and alpha4 integrin in the inflammatory response of neutrophils. J Exp Med 194(2):219–226

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Phillipson M, Kubes P (2011) The neutrophil in vascular inflammation. Nat Med 17(11):1381–1390

    CAS  PubMed  Google Scholar 

  4. Muller WA, Weigl SA, Deng X, Phillips DM (1993) PECAM-1 is required for transendothelial migration of leukocytes. J Exp Med 178(2):449–460

    CAS  PubMed  Google Scholar 

  5. Khandoga A, Huettinger S, Khandoga AG, Li H, Butz S, Jauch KW, Vestweber D, Krombach F (2009) Leukocyte transmigration in inflamed liver: a role for endothelial cell-selective adhesion molecule. J Hepatol 50(4):755–765

    CAS  PubMed  Google Scholar 

  6. Lou O, Alcaide P, Luscinskas FW, Muller WA (2007) CD99 is a key mediator of the transendothelial migration of neutrophils. J Immunol 178(2):1136–1143

    CAS  PubMed  Google Scholar 

  7. Bixel MG, Li H, Petri B, Khandoga AG, Khandoga A, Zarbock A, Wolburg-Buchholz K, Wolburg H, Sorokin L, Zeuschner D et al (2010) CD99 and CD99L2 act at the same site as, but independently of, PECAM-1 during leukocyte diapedesis. Blood 116(7):1172–1184

    CAS  PubMed  Google Scholar 

  8. Li J, Kim K, Hahm E, Molokie R, Hay N, Gordeuk VR, Du X, Cho J (2014) Neutrophil AKT2 regulates heterotypic cell–cell interactions during vascular inflammation. J Clin Invest 124(4):1483–1496

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Hidalgo A, Chang J, Jang JE, Peired AJ, Chiang EY, Frenette PS (2009) Heterotypic interactions enabled by polarized neutrophil microdomains mediate thromboinflammatory injury. Nat Med 15(4):384–391

    CAS  PubMed Central  PubMed  Google Scholar 

  10. Yang J, Hirata T, Croce K, Merrill-Skoloff G, Tchernychev B, Williams E, Flaumenhaft R, Furie BC, Furie B (1999) Targeted gene disruption demonstrates that P-selectin glycoprotein ligand 1 (PSGL-1) is required for P-selectin-mediated but not E-selectin-mediated neutrophil rolling and migration. J Exp Med 190(12):1769–1782

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Wang Y, Sakuma M, Chen Z, Ustinov V, Shi C, Croce K, Zago AC, Lopez J, Andre P, Plow E et al (2005) Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury. Circulation 112(19):2993–3000

    CAS  PubMed  Google Scholar 

  12. Simon DI, Chen Z, Xu H, Li CQ, Dong J, McIntire LV, Ballantyne CM, Zhang L, Furman MI, Berndt MC et al (2000) Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 192(2):193–204

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Wagner DD, Burger PC (2003) Platelets in inflammation and thrombosis. Arterioscler Thromb Vasc Biol 23(12):2131–2137

    CAS  PubMed  Google Scholar 

  14. Yang J, Furie BC, Furie B (1999) The biology of P-selectin glycoprotein ligand-1: its role as a selectin counterreceptor in leukocyte–endothelial and leukocyte–platelet interaction. Thromb Haemost 81(1):1–7

    CAS  PubMed  Google Scholar 

  15. Gross PL, Furie BC, Merrill-Skoloff G, Chou J, Furie B (2005) Leukocyte-versus microparticle-mediated tissue factor transfer during arteriolar thrombus development. J Leukoc Biol 78(6):1318–1326

    CAS  PubMed  Google Scholar 

  16. Zarbock A, Polanowska-Grabowska RK, Ley K (2007) Platelet–neutrophil–interactions: linking hemostasis and inflammation. Blood Rev 21(2):99–111

    CAS  PubMed  Google Scholar 

  17. Wagner DD, Frenette PS (2008) The vessel wall and its interactions. Blood 111(11):5271–5281

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Sprague AH, Khalil RA (2009) Inflammatory cytokines in vascular dysfunction and vascular disease. Biochem Pharmacol 78(6):539–552

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Cave AC, Brewer AC, Narayanapanicker A, Ray R, Grieve DJ, Walker S, Shah AM (2006) NADPH oxidases in cardiovascular health and disease. Antioxid Redox Signal 8(5–6):691–728

    CAS  PubMed  Google Scholar 

  20. Li P, Li M, Lindberg MR, Kennett MJ, Xiong N, Wang Y (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J Exp Med 207(9):1853–1862

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Massberg S, Grahl L, von Bruehl ML, Manukyan D, Pfeiler S, Goosmann C, Brinkmann V, Lorenz M, Bidzhekov K, Khandagale AB et al (2010) Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 16(8):887–896

    CAS  PubMed  Google Scholar 

  22. Thornton P, McColl BW, Greenhalgh A, Denes A, Allan SM, Rothwell NJ (2010) Platelet interleukin-1alpha drives cerebrovascular inflammation. Blood 115(17):3632–3639

    CAS  PubMed  Google Scholar 

  23. Gear AR, Camerini D (2003) Platelet chemokines and chemokine receptors: linking hemostasis, inflammation, and host defense. Microcirculation 10(3–4):335–350

    CAS  PubMed  Google Scholar 

  24. Steinhubl SR, Moliterno DJ (2005) The role of the platelet in the pathogenesis of atherothrombosis. Am J Cardiovasc Drugs 5(6):399–408

    CAS  PubMed  Google Scholar 

  25. Semple JW, Italiano JE Jr, Freedman J (2011) Platelets and the immune continuum. Nat Rev Immunol 11(4):264–274

    CAS  PubMed  Google Scholar 

  26. Gleissner CA, von Hundelshausen P, Ley K (2008) Platelet chemokines in vascular disease. Arterioscler Thromb Vasc Biol 28(11):1920–1927

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Bledzka K, Smyth SS, Plow EF (2013) Integrin alphaIIbbeta3: from discovery to efficacious therapeutic target. Circ Res 112(8):1189–1200

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Kenne E, Renne T (2014) Factor XII: a drug target for safe interference with thrombosis and inflammation. Drug Discovery Today 19(9):1459–1464

    CAS  PubMed  Google Scholar 

  29. Kleinschnitz C, Pozgajova M, Pham M, Bendszus M, Nieswandt B, Stoll G (2007) Targeting platelets in acute experimental stroke: impact of glycoprotein Ib, VI, and IIb/IIIa blockade on infarct size, functional outcome, and intracranial bleeding. Circulation 115(17):2323–2330

    CAS  PubMed  Google Scholar 

  30. Adams HP Jr, Effron MB, Torner J, Davalos A, Frayne J, Teal P, Leclerc J, Oemar B, Padgett L, Barnathan ES et al (2008) Emergency administration of abciximab for treatment of patients with acute ischemic stroke: results of an international phase III trial: Abciximab in Emergency Treatment of Stroke Trial (AbESTT-II). Stroke 39(1):87–99

    CAS  PubMed  Google Scholar 

  31. Li J, Kim K, Hahm E, Molokie R, Hay N, Gordeuk VR, Du X, Cho J (2014) Neutrophil Akt2 regulates heterotypic cell–cell interactions during vascular inflammation. J Clin Investig 124:1483–1496

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Thiagarajan RR, Winn RK, Harlan JM (1997) The role of leukocyte and endothelial adhesion molecules in ischemia-reperfusion injury. Thromb Haemost 78(1):310–314

    CAS  PubMed  Google Scholar 

  33. Coller BS (2005) Leukocytosis and ischemic vascular disease morbidity and mortality: is it time to intervene? Arterioscler Thromb Vasc Biol 25(4):658–670

    CAS  PubMed  Google Scholar 

  34. Yonekawa K, Harlan JM (2005) Targeting leukocyte integrins in human diseases. J Leukoc Biol 77(2):129–140

    CAS  PubMed  Google Scholar 

  35. Sreeramkumar V, Adrover JM, Ballesteros I, Cuartero MI, Rossaint J, Bilbao I, Nacher M, Pitaval C, Radovanovic I, Fukui Y et al (2014) Neutrophils scan for activated platelets to initiate inflammation. Science 346(6214):1234–1238

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Nieswandt B, Kleinschnitz C, Stoll G (2011) Ischaemic stroke: a thrombo-inflammatory disease? J Physiol 589(Pt 17):4115–4123

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Montalvo-Jave EE, Escalante-Tattersfield T, Ortega-Salgado JA, Pina E, Geller DA (2008) Factors in the pathophysiology of the liver ischemia-reperfusion injury. J Surg Res 147(1):153–159

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Looney MR, Gilliss BM, Matthay MA (2010) Pathophysiology of transfusion-related acute lung injury. Curr Opin Hematol 17(5):418–423

    PubMed  Google Scholar 

  39. Lievens D, von Hundelshausen P (2011) Platelets in atherosclerosis. Thromb Haemost 106(5):827–838

    CAS  PubMed  Google Scholar 

  40. Woollard KJ, Geissmann F (2010) Monocytes in atherosclerosis: subsets and functions. Nat Rev Cardiol 7(2):77–86

    PubMed Central  PubMed  Google Scholar 

  41. Nilsson B, Teramura Y, Ekdahl KN (2014) The role and regulation of complement activation as part of the thromboinflammation elicited in cell therapies. Mol Immunol 61(2):185–190

    CAS  PubMed  Google Scholar 

  42. Furie B, Furie BC, Flaumenhaft R (2001) A journey with platelet P-selectin: the molecular basis of granule secretion, signalling and cell adhesion. Thromb Haemost 86(1):214–221

    CAS  PubMed  Google Scholar 

  43. Carlow DA, Gossens K, Naus S, Veerman KM, Seo W, Ziltener HJ (2009) PSGL-1 function in immunity and steady state homeostasis. Immunol Rev 230(1):75–96

    CAS  PubMed  Google Scholar 

  44. Furie B, Furie BC (2004) Role of platelet P-selectin and microparticle PSGL-1 in thrombus formation. Trends Mol Med 10(4):171–178

    CAS  PubMed  Google Scholar 

  45. Andre P, Hartwell D, Hrachovinova I, Saffaripour S, Wagner DD (2000) Pro-coagulant state resulting from high levels of soluble P-selectin in blood. Proc Natl Acad Sci USA 97(25):13835–13840

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Liu W, Ramachandran V, Kang J, Kishimoto TK, Cummings RD, McEver RP (1998) Identification of N-terminal residues on P-selectin glycoprotein ligand-1 required for binding to P-selectin. J Biol Chem 273(12):7078–7087

    CAS  PubMed  Google Scholar 

  47. McEver RP, Cummings RD (1997) Perspectives series: cell adhesion in vascular biology. Role of PSGL-1 binding to selectins in leukocyte recruitment. J Clin Investig 100(3):485–491

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Martinez M, Joffraud M, Giraud S, Baisse B, Bernimoulin MP, Schapira M, Spertini O (2005) Regulation of PSGL-1 interactions with L-selectin, P-selectin, and E-selectin: role of human fucosyltransferase-IV and -VII. J Biol Chem 280(7):5378–5390

    CAS  PubMed  Google Scholar 

  49. Xiao B, Tong C, Jia X, Guo R, Lu S, Zhang Y, McEver RP, Zhu C, Long M (2012) Tyrosine replacement of PSGL-1 reduces association kinetics with P- and L-selectin on the cell membrane. Biophys J 103(4):777–785

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Jung U, Ley K (1999) Mice lacking two or all three selectins demonstrate overlapping and distinct functions for each selectin. J Immunol 162(11):6755–6762

    CAS  PubMed  Google Scholar 

  51. Evangelista V, Manarini S, Sideri R, Rotondo S, Martelli N, Piccoli A, Totani L, Piccardoni P, Vestweber D, de Gaetano G et al (1999) Platelet/polymorphonuclear leukocyte interaction: P-selectin triggers protein-tyrosine phosphorylation-dependent CD11b/CD18 adhesion: role of PSGL-1 as a signaling molecule. Blood 93(3):876–885

    CAS  PubMed  Google Scholar 

  52. Caron A, Theoret JF, Mousa SA, Merhi Y (2002) Anti-platelet effects of GPIIb/IIIa and P-selectin antagonism, platelet activation, and binding to neutrophils. J Cardiovasc Pharmacol 40(2):296–306

    CAS  PubMed  Google Scholar 

  53. Konstantopoulos K, Neelamegham S, Burns AR, Hentzen E, Kansas GS, Snapp KR, Berg EL, Hellums JD, Smith CW, McIntire LV et al (1998) Venous levels of shear support neutrophil-platelet adhesion and neutrophil aggregation in blood via P-selectin and beta2-integrin. Circulation 98(9):873–882

    CAS  PubMed  Google Scholar 

  54. Lam FW, Burns AR, Smith CW, Rumbaut RE (2011) Platelets enhance neutrophil transendothelial migration via P-selectin glycoprotein ligand-1. Am J Physiol Heart Circ Physiol 300(2):H468–H475

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Falati S, Liu Q, Gross P, Merrill-Skoloff G, Chou J, Vandendries E, Celi A, Croce K, Furie BC, Furie B (2003) Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 197(11):1585–1598

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Lopez JA, Dong JF (1997) Structure and function of the glycoprotein Ib–IX–V complex. Curr Opin Hematol 4(5):323–329

    CAS  PubMed  Google Scholar 

  57. Li R, Emsley J (2013) The organizing principle of the platelet glycoprotein Ib–IX–V complex. J Thromb Haemost 11(4):605–614

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Andrews RK, Berndt MC (2013) Bernard–Soulier syndrome: an update. Semin Thromb Hemost 39(6):656–662

    CAS  PubMed  Google Scholar 

  59. Huizinga EG, Tsuji S, Romijn RA, Schiphorst ME, de Groot PG, Sixma JJ, Gros P (2002) Structures of glycoprotein Ibalpha and its complex with von Willebrand factor A1 domain. Science 297(5584):1176–1179

    CAS  PubMed  Google Scholar 

  60. Ruggeri ZM, Zarpellon A, Roberts JR, McClintock RA, Jing H, Mendolicchio GL (2010) Unravelling the mechanism and significance of thrombin binding to platelet glycoprotein Ib. Thromb Haemost 104(5):894–902

    CAS  PubMed  Google Scholar 

  61. Romo GM, Dong JF, Schade AJ, Gardiner EE, Kansas GS, Li CQ, McIntire LV, Berndt MC, Lopez JA (1999) The glycoprotein Ib–IX–V complex is a platelet counterreceptor for P-selectin. J Exp Med 190(6):803–814

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Mayadas TN, Cullere X (2005) Neutrophil beta2 integrins: moderators of life or death decisions. Trends Immunol 26(7):388–395

    CAS  PubMed  Google Scholar 

  63. Phillipson M, Heit B, Colarusso P, Liu L, Ballantyne CM, Kubes P (2006) Intraluminal crawling of neutrophils to emigration sites: a molecularly distinct process from adhesion in the recruitment cascade. J Exp Med 203(12):2569–2575

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Sumagin R, Prizant H, Lomakina E, Waugh RE, Sarelius IH (2010) LFA-1 and Mac-1 define characteristically different intralumenal crawling and emigration patterns for monocytes and neutrophils in situ. J Immunol 185(11):7057–7066

    CAS  PubMed Central  PubMed  Google Scholar 

  65. McDonald B, Pittman K, Menezes GB, Hirota SA, Slaba I, Waterhouse CC, Beck PL, Muruve DA, Kubes P (2010) Intravascular danger signals guide neutrophils to sites of sterile inflammation. Science 330(6002):362–366

    CAS  PubMed  Google Scholar 

  66. Whitlock BB, Gardai S, Fadok V, Bratton D, Henson PM (2000) Differential roles for alpha(M)beta(2) integrin clustering or activation in the control of apoptosis via regulation of akt and ERK survival mechanisms. J Cell Biol 151(6):1305–1320

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Coxon A, Rieu P, Barkalow FJ, Askari S, Sharpe AH, von Andrian UH, Arnaout MA, Mayadas TN (1996) A novel role for the beta 2 integrin CD11b/CD18 in neutrophil apoptosis: a homeostatic mechanism in inflammation. Immunity 5(6):653–666

    PubMed  Google Scholar 

  68. Behnen M, Leschczyk C, Moller S, Batel T, Klinger M, Solbach W, Laskay T (2014) Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcgammaRIIIB and Mac-1. J Immunol 193(4):1954–1965

    CAS  PubMed  Google Scholar 

  69. Corken A, Russell S, Dent J, Post SR, Ware J (2014) Platelet glycoprotein Ib-IX as a regulator of systemic inflammation. Arterioscler Thromb Vasc Biol 34(5):996–1001

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Du X (2007) Signaling and regulation of the platelet glycoprotein Ib–IX–V complex. Curr Opin Hematol 14(3):262–269

    CAS  PubMed  Google Scholar 

  71. Li Z (1999) The alphaMbeta2 integrin and its role in neutrophil function. Cell Res 9(3):171–178

    CAS  PubMed  Google Scholar 

  72. Weber C, Springer TA (1997) Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIbbeta3 and stimulated by platelet-activating factor. J Clin Investig 100(8):2085–2093

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Scholz T, Zhao L, Temmler U, Bath P, Heptinstall S, Losche W (2002) The GPIIb/IIIa antagonist eptifibatide markedly potentiates platelet–leukocyte interaction and tissue factor expression following platelet activation in whole blood in vitro. Platelets 13(7):401–406

    CAS  PubMed  Google Scholar 

  74. Bazzoni G (2003) The JAM family of junctional adhesion molecules. Curr Opin Cell Biol 15(5):525–530

    CAS  PubMed  Google Scholar 

  75. Chavakis T, Keiper T, Matz-Westphal R, Hersemeyer K, Sachs UJ, Nawroth PP, Preissner KT, Santoso S (2004) The junctional adhesion molecule-C promotes neutrophil transendothelial migration in vitro and in vivo. J Biol Chem 279(53):55602–55608

    CAS  PubMed  Google Scholar 

  76. 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

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Aurrand-Lions M, Lamagna C, Dangerfield JP, Wang S, Herrera P, Nourshargh S, Imhof BA (2005) Junctional adhesion molecule-C regulates the early influx of leukocytes into tissues during inflammation. J Immunol 174(10):6406–6415

    CAS  PubMed  Google Scholar 

  78. Weber C, Fraemohs L, Dejana E (2007) The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 7(6):467–477

    CAS  PubMed  Google Scholar 

  79. Palmer G, Busso N, Aurrand-Lions M, Talabot-Ayer D, Chobaz-Peclat V, Zimmerli C, Hammel P, Imhof BA, Gabay C (2007) Expression and function of junctional adhesion molecule-C in human and experimental arthritis. Arthritis Res Ther 9(4):R65

    PubMed Central  PubMed  Google Scholar 

  80. Shagdarsuren E, Djalali-Talab Y, Aurrand-Lions M, Bidzhekov K, Liehn EA, Imhof BA, Weber C, Zernecke A (2009) Importance of junctional adhesion molecule-C for neointimal hyperplasia and monocyte recruitment in atherosclerosis-prone mice-brief report. Arterioscler Thromb Vasc Biol 29(8):1161–1163

    CAS  PubMed  Google Scholar 

  81. 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

    CAS  PubMed  Google Scholar 

  82. Andre P, Prasad KS, Denis CV, He M, Papalia JM, Hynes RO, Phillips DR, Wagner DD (2002) CD40L stabilizes arterial thrombi by a beta3 integrin–dependent mechanism. Nat Med 8(3):247–252

    CAS  PubMed  Google Scholar 

  83. Schonbeck U, Libby P (2001) The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 58(1):4–43

    CAS  PubMed  Google Scholar 

  84. Lievens D, Eijgelaar WJ, Biessen EA, Daemen MJ, Lutgens E (2009) The multi-functionality of CD40L and its receptor CD40 in atherosclerosis. Thromb Haemost 102(2):206–214

    CAS  PubMed  Google Scholar 

  85. Rahman M, Zhang S, Chew M, Syk I, Jeppsson B, Thorlacius H (2013) Platelet shedding of CD40L is regulated by matrix metalloproteinase-9 in abdominal sepsis. J Thromb Haemost 11(7):1385–1398

    CAS  PubMed  Google Scholar 

  86. Pamukcu B, Lip GY, Snezhitskiy V, Shantsila E (2011) The CD40-CD40L system in cardiovascular disease. Ann Med 43(5):331–340

    CAS  PubMed  Google Scholar 

  87. Antoniades C, Bakogiannis C, Tousoulis D, Antonopoulos AS, Stefanadis C (2009) The CD40/CD40 ligand system: linking inflammation with atherothrombosis. J Am Coll Cardiol 54(8):669–677

    CAS  PubMed  Google Scholar 

  88. Setianto BY, Hartopo AB, Gharini PP, Anggrahini DW, Irawan B (2010) Circulating soluble CD40 ligand mediates the interaction between neutrophils and platelets in acute coronary syndrome. Heart Vessels 25(4):282–287

    PubMed  Google Scholar 

  89. Zhao Z, Robinson RG, Barnett SF, Defeo-Jones D, Jones RE, Hartman GD, Huber HE, Duggan ME, Lindsley CW (2008) Development of potent, allosteric dual Akt1 and Akt2 inhibitors with improved physical properties and cell activity. Bioorg Med Chem Lett 18(1):49–53

    PubMed  Google Scholar 

  90. Jin R, Yu S, Song Z, Zhu X, Wang C, Yan J, Wu F, Nanda A, Granger DN, Li G (2013) Soluble CD40 ligand stimulates CD40-dependent activation of the beta2 integrin Mac-1 and protein kinase C zeda (PKCzeta) in neutrophils: implications for neutrophil–platelet interactions and neutrophil oxidative burst. PLoS ONE 8(6):e64631

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Rahman M, Zhang S, Chew M, Ersson A, Jeppsson B, Thorlacius H (2009) Platelet-derived CD40L (CD154) mediates neutrophil upregulation of Mac-1 and recruitment in septic lung injury. Ann Surg 250(5):783–790

    PubMed  Google Scholar 

  92. Vanichakarn P, Blair P, Wu C, Freedman JE, Chakrabarti S (2008) Neutrophil CD40 enhances platelet-mediated inflammation. Thromb Res 122(3):346–358

    CAS  PubMed  Google Scholar 

  93. Armant MA, Fenton MJ (2002) Toll-like receptors: a family of pattern-recognition receptors in mammals. Genome Biol. 3(8):REVIEWS:3011

    Google Scholar 

  94. Clark SR, Ma AC, Tavener SA, McDonald B, Goodarzi Z, Kelly MM, Patel KD, Chakrabarti S, McAvoy E, Sinclair GD et al (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 13(4):463–469

    CAS  PubMed  Google Scholar 

  95. Stahl AL, Sartz L, Nelsson A, Bekassy ZD, Karpman D (2009) Shiga toxin and lipopolysaccharide induce platelet–leukocyte aggregates and tissue factor release, a thrombotic mechanism in hemolytic uremic syndrome. PLoS ONE 4(9):e6990

    PubMed Central  PubMed  Google Scholar 

  96. Lievens D, Zernecke A, Seijkens T, Soehnlein O, Beckers L, Munnix IC, Wijnands E, Goossens P, van Kruchten R, Thevissen L et al (2010) Platelet CD40L mediates thrombotic and inflammatory processes in atherosclerosis. Blood 116(20):4317–4327

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Cognasse F, Lafarge S, Chavarin P, Acquart S, Garraud O (2007) Lipopolysaccharide induces sCD40L release through human platelets TLR4, but not TLR2 and TLR9. Intensive Care Med 33(2):382–384

    PubMed  Google Scholar 

  98. Montrucchio G, Bosco O, Del Sorbo L, Fascio Pecetto P, Lupia E, Goffi A, Omede P, Emanuelli G, Camussi G (2003) Mechanisms of the priming effect of low doses of lipopoly-saccharides on leukocyte-dependent platelet aggregation in whole blood. Thromb Haemost 90(5):872–881

    CAS  PubMed  Google Scholar 

  99. Blair P, Rex S, Vitseva O, Beaulieu L, Tanriverdi K, Chakrabarti S, Hayashi C, Genco CA, Iafrati M, Freedman JE (2009) Stimulation of Toll-like receptor 2 in human platelets induces a thromboinflammatory response through activation of phosphoinositide 3-kinase. Circ Res 104(3):346–354

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Assinger A, Laky M, Schabbauer G, Hirschl AM, Buchberger E, Binder BR, Volf I (2011) Efficient phagocytosis of periodontopathogens by neutrophils requires plasma factors, platelets and TLR2. J Thromb Haemost 9(4):799–809

    CAS  PubMed  Google Scholar 

  101. Koupenova M, Vitseva O, MacKay CR, Beaulieu LM, Benjamin EJ, Mick E, Kurt-Jones EA, Ravid K, Freedman JE (2014) Platelet-TLR7 mediates host survival and platelet count during viral infection in the absence of platelet-dependent thrombosis. Blood 124(5):791–802

    CAS  PubMed  Google Scholar 

  102. Futosi K, Fodor S, Mocsai A (2013) Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol 17(3):638–650

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Hayashi F, Means TK, Luster AD (2003) Toll-like receptors stimulate human neutrophil function. Blood 102(7):2660–2669

    CAS  PubMed  Google Scholar 

  104. Ding ZM, Babensee JE, Simon SI, Lu H, Perrard JL, Bullard DC, Dai XY, Bromley SK, Dustin ML, Entman ML et al (1999) Relative contribution of LFA-1 and Mac-1 to neutrophil adhesion and migration. J Immunol 163(9):5029–5038

    CAS  PubMed  Google Scholar 

  105. Kuijper PH, Gallardo Tores HI, Lammers JW, Sixma JJ, Koenderman L, Zwaginga JJ (1998) Platelet associated fibrinogen and ICAM-2 induce firm adhesion of neutrophils under flow conditions. Thromb Haemost 80(3):443–448

    CAS  PubMed  Google Scholar 

  106. Aigner S, Sthoeger ZM, Fogel M, Weber E, Zarn J, Ruppert M, Zeller Y, Vestweber D, Stahel R, Sammar M et al (1997) CD24, a mucin-type glycoprotein, is a ligand for P-selectin on human tumor cells. Blood 89(9):3385–3395

    CAS  PubMed  Google Scholar 

  107. Aigner S, Ramos CL, Hafezi-Moghadam A, Lawrence MB, Friederichs J, Altevogt P, Ley K (1998) CD24 mediates rolling of breast carcinoma cells on P-selectin. FASEB J 12(12):1241–1251

    CAS  PubMed  Google Scholar 

  108. de Bruijne-Admiraal LG, Modderman PW, Von dem Borne AE, Sonnenberg A (1992) P-selectin mediates Ca(2+)-dependent adhesion of activated platelets to many different types of leukocytes: detection by flow cytometry. Blood 80(1):134–142

    PubMed  Google Scholar 

  109. Li Z, Delaney MK, O’Brien KA, Du X (2010) Signaling during platelet adhesion and activation. Arterioscler Thromb Vasc Biol 30(12):2341–2349

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Senis YA, Mazharian A, Mori J (2014) Src family kinases: at the forefront of platelet activation. Blood 124(13):2013–2024

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Okutani D, Lodyga M, Han B, Liu M (2006) Src protein tyrosine kinase family and acute inflammatory responses. Am J Physiol Lung Cell Mol Physiol 291(2):L129–L141

    CAS  PubMed  Google Scholar 

  112. Xiang B, Zhang G, Stefanini L, Bergmeier W, Gartner TK, Whiteheart SW, Li Z (2012) The Src family kinases and protein kinase C synergize to mediate Gq-dependent platelet activation. J Biol Chem 287(49):41277–41287

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Falati S, Edmead CE, Poole AW (1999) Glycoprotein Ib-V-IX, a receptor for von Willebrand factor, couples physically and functionally to the Fc receptor gamma-chain, Fyn, and Lyn to activate human platelets. Blood 94(5):1648–1656

    CAS  PubMed  Google Scholar 

  114. Mangin P, Yuan Y, Goncalves I, Eckly A, Freund M, Cazenave JP, Gachet C, Jackson SP, Lanza F (2003) Signaling role for phospholipase C gamma 2 in platelet glycoprotein Ib alpha calcium flux and cytoskeletal reorganization. Involvement of a pathway distinct from FcR gamma chain and Fc gamma RIIA. J Biol Chem 278(35):32880–32891

    CAS  PubMed  Google Scholar 

  115. Yin H, Liu J, Li Z, Berndt MC, Lowell CA, Du X (2008) Src family tyrosine kinase Lyn mediates VWF/GPIb-IX-induced platelet activation via the cGMP signaling pathway. Blood 112(4):1139–1146

    CAS  PubMed Central  PubMed  Google Scholar 

  116. Piccardoni P, Sideri R, Manarini S, Piccoli A, Martelli N, de Gaetano G, Cerletti C, Evangelista V (2001) Platelet/polymorphonuclear leukocyte adhesion: a new role for SRC kinases in Mac-1 adhesive function triggered by P-selectin. Blood 98(1):108–116

    CAS  PubMed  Google Scholar 

  117. Xu T, Zhang L, Geng ZH, Wang HB, Wang JT, Chen M, Geng JG (2007) P-selectin cross-links PSGL-1 and enhances neutrophil adhesion to fibrinogen and ICAM-1 in a Src kinase-dependent, but GPCR-independent mechanism. Cell Adhes Migr 1(3):115–123

    Google Scholar 

  118. Evangelista V, Pamuklar Z, Piccoli A, Manarini S, Dell’elba G, Pecce R, Martelli N, Federico L, Rojas M, Berton G et al (2007) Src family kinases mediate neutrophil adhesion to adherent platelets. Blood 109(6):2461–2469

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Kovacs M, Nemeth T, Jakus Z, Sitaru C, Simon E, Futosi K, Botz B, Helyes Z, Lowell CA, Mocsai A (2014) The Src family kinases Hck, Fgr, and Lyn are critical for the generation of the in vivo inflammatory environment without a direct role in leukocyte recruitment. J Exp Med 211(10):1993–2011

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Woollard KJ, Kling D, Kulkarni S, Dart AM, Jackson S, Chin-Dusting J (2006) Raised plasma soluble P-selectin in peripheral arterial occlusive disease enhances leukocyte adhesion. Circ Res 98(1):149–156

    CAS  PubMed  Google Scholar 

  121. Cockcroft S (2006) The latest phospholipase C, PLCeta, is implicated in neuronal function. Trends Biochem Sci 31(1):4–7

    CAS  PubMed  Google Scholar 

  122. Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF (2012) Platelet signaling. Handb Exp Pharmacol 210:59–85

    CAS  PubMed  Google Scholar 

  123. Futosi K, Fodor S, Mocsai A (2013) Reprint of Neutrophil cell surface receptors and their intracellular signal transduction pathways. Int Immunopharmacol 17(4):1185–1197

    CAS  PubMed  Google Scholar 

  124. Resendiz JC, Kroll MH, Lassila R (2007) Protease-activated receptor-induced Akt activation–regulation and possible function. J Thromb Haemost 5(12):2484–2493

    CAS  PubMed  Google Scholar 

  125. Pasquet JM, Bobe R, Gross B, Gratacap MP, Tomlinson MG, Payrastre B, Watson SP (1999) A collagen-related peptide regulates phospholipase Cgamma2 via phosphatidylinositol 3-kinase in human platelets. Biochem J 342(Pt 1):171–177

    CAS  PubMed Central  PubMed  Google Scholar 

  126. Asselin J, Gibbins JM, Achison M, Lee YH, Morton LF, Farndale RW, Barnes MJ, Watson SP (1997) A collagen-like peptide stimulates tyrosine phosphorylation of syk and phospholipase C gamma2 in platelets independent of the integrin alpha2beta1. Blood 89(4):1235–1242

    CAS  PubMed  Google Scholar 

  127. Li Z, Jiang H, Xie W, Zhang Z, Smrcka AV, Wu D (2000) Roles of PLC-beta2 and -beta3 and PI3Kgamma in chemoattractant-mediated signal transduction. Science 287(5455):1046–1049

    CAS  PubMed  Google Scholar 

  128. Jiang H, Kuang Y, Wu Y, Xie W, Simon MI, Wu D (1997) Roles of phospholipase C beta2 in chemoattractant-elicited responses. Proc Natl Acad Sci USA 94(15):7971–7975

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Laurent PA, Severin S, Gratacap MP, Payrastre B (2014) Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1. Adv Biol Regul 54:162–174

    CAS  PubMed  Google Scholar 

  130. Hawkins PT, Stephens LR, Suire S, Wilson M (2010) PI3K signaling in neutrophils. Curr Topics Microbiol Immunol 346:183–202

    CAS  Google Scholar 

  131. Bhaskar PT, Hay N (2007) The two TORCs and Akt. Dev Cell 12(4):487–502

    CAS  PubMed  Google Scholar 

  132. Watson SP, Auger JM, McCarty OJ, Pearce AC (2005) GPVI and integrin alphaIIb beta3 signaling in platelets. J Thromb Haemost 3(8):1752–1762

    CAS  PubMed  Google Scholar 

  133. Weng Z, Li D, Zhang L, Chen J, Ruan C, Chen G, Gartner TK, Liu J (2010) PTEN regulates collagen-induced platelet activation. Blood 116(14):2579–2581

    CAS  PubMed  Google Scholar 

  134. Lioubin MN, Algate PA, Tsai S, Carlberg K, Aebersold A, Rohrschneider LR (1996) p150Ship, a signal transduction molecule with inositol polyphosphate-5-phosphatase activity. Genes Dev 10(9):1084–1095

    CAS  PubMed  Google Scholar 

  135. Mondal S, Subramanian KK, Sakai J, Bajrami B, Luo HR (2012) Phosphoinositide lipid phosphatase SHIP1 and PTEN coordinate to regulate cell migration and adhesion. Mol Biol Cell 23(7):1219–1230

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Chen M, Geng JG (2001) Inhibition of protein tyrosine phosphatases suppresses P-selectin exocytosis in activated human platelets. Biochem Biophys Res Commun 286(4):831–838

    CAS  PubMed  Google Scholar 

  137. Kovacsovics TJ, Bachelot C, Toker A, Vlahos CJ, Duckworth B, Cantley LC, Hartwig JH (1995) Phosphoinositide 3-kinase inhibition spares actin assembly in activating platelets but reverses platelet aggregation. J Biol Chem 270(19):11358–11366

    CAS  PubMed  Google Scholar 

  138. Libersan D, Merhi Y (2003) Platelet P-selectin expression: requirement for protein kinase C, but not protein tyrosine kinase or phosphoinositide 3-kinase. Thromb Haemost 89(6):1016–1023

    CAS  PubMed  Google Scholar 

  139. Watanabe N, Nakajima H, Suzuki H, Oda A, Matsubara Y, Moroi M, Terauchi Y, Kadowaki T, Suzuki H, Koyasu S et al (2003) Functional phenotype of phosphoinositide 3-kinase p85alpha-null platelets characterized by an impaired response to GP VI stimulation. Blood 102(2):541–548

    CAS  PubMed  Google Scholar 

  140. Yap CL, Anderson KE, Hughan SC, Dopheide SM, Salem HH, Jackson SP (2002) Essential role for phosphoinositide 3-kinase in shear-dependent signaling between platelet glycoprotein Ib/V/IX and integrin alpha(IIb)beta(3). Blood 99(1):151–158

    CAS  PubMed  Google Scholar 

  141. Gao XP, Zhu X, Fu J, Liu Q, Frey RS, Malik AB (2007) Blockade of class IA phosphoinositide 3-kinase in neutrophils prevents NADPH oxidase activation- and adhesion-dependent inflammation. J Biol Chem 282(9):6116–6125

    CAS  PubMed  Google Scholar 

  142. Mueller H, Stadtmann A, Van Aken H, Hirsch E, Wang D, Ley K, Zarbock A (2010) Tyrosine kinase Btk regulates E-selectin-mediated integrin activation and neutrophil recruitment by controlling phospholipase C (PLC) gamma2 and PI3Kgamma pathways. Blood 115(15):3118–3127

    CAS  PubMed Central  PubMed  Google Scholar 

  143. Chen J, De S, Damron DS, Chen WS, Hay N, Byzova TV (2004) Impaired platelet responses to thrombin and collagen in AKT-1-deficient mice. Blood 104(6):1703–1710

    CAS  PubMed Central  PubMed  Google Scholar 

  144. Woulfe D, Jiang H, Morgans A, Monks R, Birnbaum M, Brass LF (2004) Defects in secretion, aggregation, and thrombus formation in platelets from mice lacking Akt2. J Clin Investig 113(3):441–450

    CAS  PubMed Central  PubMed  Google Scholar 

  145. O’Brien KA, Stojanovic-Terpo A, Hay N, Du X (2011) An important role for Akt3 in platelet activation and thrombosis. Blood 118(15):4215–4223

    PubMed Central  PubMed  Google Scholar 

  146. Chen J, Tang H, Hay N, Xu J, Ye RD (2010) Akt isoforms differentially regulate neutrophil functions. Blood 115(21):4237–4246

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9(7):484–496

    CAS  PubMed  Google Scholar 

  148. Chari R, Getz T, Nagy B Jr, Bhavaraju K, Mao Y, Bynagari YS, Murugappan S, Nakayama K, Kunapuli SP (2009) Protein kinase C[delta] differentially regulates platelet functional responses. Arterioscler Thromb Vasc Biol 29(5):699–705

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Kilpatrick LE, Sun S, Li H, Vary TC, Korchak HM (2010) Regulation of TNF-induced oxygen radical production in human neutrophils: role of delta-PKC. J Leukoc Biol 87(1):153–164

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Begonja AJ, Geiger J, Rukoyatkina N, Rauchfuss S, Gambaryan S, Walter U (2007) Thrombin stimulation of p38 MAP kinase in human platelets is mediated by ADP and thromboxane A2 and inhibited by cGMP/cGMP-dependent protein kinase. Blood 109(2):616–618

    CAS  PubMed  Google Scholar 

  151. Carestia A, Rivadeneyra L, Romaniuk MA, Fondevila C, Negrotto S, Schattner M (2013) Functional responses and molecular mechanisms involved in histone-mediated platelet activation. Thromb Haemost 110(5):1035–1045

    CAS  PubMed  Google Scholar 

  152. Khreiss T, Jozsef L, Chan JS, Filep JG (2004) Activation of extracellular signal-regulated kinase couples platelet-activating factor-induced adhesion and delayed apoptosis of human neutrophils. Cell Signal 16(7):801–810

    CAS  PubMed  Google Scholar 

  153. Totani L, Piccoli A, Dell’Elba G, Concetta A, Di Santo A, Martelli N, Federico L, Pamuklar Z, Smyth SS, Evangelista V (2014) Phosphodiesterase type 4 blockade prevents platelet-mediated neutrophil recruitment at the site of vascular injury. Arterioscler Thromb Vasc Biol 34(8):1689–1696

    CAS  PubMed  Google Scholar 

  154. Oeckinghaus A, Ghosh S (2009) The NF-kappaB family of transcription factors and its regulation. Cold Spring Harb Perspect Biol 1(4):a000034

    PubMed Central  PubMed  Google Scholar 

  155. Malaver E, Romaniuk MA, D’Atri LP, Pozner RG, Negrotto S, Benzadon R, Schattner M (2009) NF-kappaB inhibitors impair platelet activation responses. J Thromb Haemost 7(8):1333–1343

    CAS  PubMed  Google Scholar 

  156. Lee HS, Kim SD, Lee WM, Endale M, Kamruzzaman SM, Oh WJ, Cho JY, Kim SK, Cho HJ, Park HJ et al (2010) A noble function of BAY 11-7082: inhibition of platelet aggregation mediated by an elevated cAMP-induced VASP, and decreased ERK2/JNK1 phosphorylations. Eur J Pharmacol 627(1–3):85–91

    CAS  PubMed  Google Scholar 

  157. Rivadeneyra L, Carestia A, Etulain J, Pozner RG, Fondevila C, Negrotto S, Schattner M (2014) Regulation of platelet responses triggered by Toll-like receptor 2 and 4 ligands is another non-genomic role of nuclear factor-kappaB. Thromb Res 133(2):235–243

    CAS  PubMed  Google Scholar 

  158. Lalor PF, Herbert J, Bicknell R, Adams DH (2013) Hepatic sinusoidal endothelium avidly binds platelets in an integrin-dependent manner, leading to platelet and endothelial activation and leukocyte recruitment. Am J Physiol Gastrointest Liver Physiol 304(5):G469–G478

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Lee DH, Tam SS, Wang E, Taylor GR, Plante RK, Lau CY (1996) The NF-kappa B inhibitor, tepoxalin, suppresses surface expression of the cell adhesion molecules CD62E, CD11b/CD18 and CD106. Immunol Lett 53(2–3):109–113

    CAS  PubMed  Google Scholar 

  160. Takai Y, Sasaki T, Matozaki T (2001) Small GTP-binding proteins. Physiol Rev 81(1):153–208

    CAS  PubMed  Google Scholar 

  161. Aslan JE, McCarty OJ (2013) Rho GTPases in platelet function. J Thromb Haemost 11(1):35–46

    CAS  PubMed Central  PubMed  Google Scholar 

  162. Cherfils J, Zeghouf M (2013) Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev 93(1):269–309

    CAS  PubMed  Google Scholar 

  163. Akbar H, Kim J, Funk K, Cancelas JA, Shang X, Chen L, Johnson JF, Williams DA, Zheng Y (2007) Genetic and pharmacologic evidence that Rac1 GTPase is involved in regulation of platelet secretion and aggregation. J Thromb Haemost 5(8):1747–1755

    CAS  PubMed  Google Scholar 

  164. Akbar H, Shang X, Perveen R, Berryman M, Funk K, Johnson JF, Tandon NN, Zheng Y (2011) Gene targeting implicates Cdc42 GTPase in GPVI and non-GPVI mediated platelet filopodia formation, secretion and aggregation. PLoS ONE 6(7):e22117

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Pleines I, Dutting S, Cherpokova D, Eckly A, Meyer I, Morowski M, Krohne G, Schulze H, Gachet C, Debili N et al (2013) Defective tubulin organization and proplatelet formation in murine megakaryocytes lacking Rac1 and Cdc42. Blood 122(18):3178–3187

    CAS  PubMed  Google Scholar 

  166. Pleines I, Eckly A, Elvers M, Hagedorn I, Eliautou S, Bender M, Wu X, Lanza F, Gachet C, Brakebusch C et al (2010) Multiple alterations of platelet functions dominated by increased secretion in mice lacking Cdc42 in platelets. Blood 115(16):3364–3373

    CAS  PubMed  Google Scholar 

  167. Bialkowska K, Zaffran Y, Meyer SC, Fox JE (2003) 14-3-3 zeta mediates integrin-induced activation of Cdc42 and Rac. Platelet glycoprotein Ib-IX regulates integrin-induced signaling by sequestering 14-3-3 zeta. J Biol Chem 278(35):33342–33350

    CAS  PubMed  Google Scholar 

  168. Zhang G, Xiang B, Ye S, Chrzanowska-Wodnicka M, Morris AJ, Gartner TK, Whiteheart SW, White GC 2nd, Smyth SS, Li Z (2011) Distinct roles for Rap1b protein in platelet secretion and integrin alphaIIbbeta3 outside-in signaling. J Biol Chem 286(45):39466–39477

    CAS  PubMed Central  PubMed  Google Scholar 

  169. Hidari KI, Weyrich AS, Zimmerman GA, McEver RP (1997) Engagement of P-selectin glycoprotein ligand-1 enhances tyrosine phosphorylation and activates mitogen-activated protein kinases in human neutrophils. J Biol Chem 272(45):28750–28756

    CAS  PubMed  Google Scholar 

  170. M’Rabet L, Coffer P, Zwartkruis F, Franke B, Segal AW, Koenderman L, Bos JL (1998) Activation of the small GTPase rap1 in human neutrophils. Blood 92(6):2133–2140

    PubMed  Google Scholar 

  171. Caron E, Self AJ, Hall A (2000) The GTPase Rap1 controls functional activation of macrophage integrin alphaMbeta2 by LPS and other inflammatory mediators. Curr Biol 10(16):974–978

    CAS  PubMed  Google Scholar 

  172. Kumar S, Xu J, Perkins C, Guo F, Snapper S, Finkelman FD, Zheng Y, Filippi MD (2012) Cdc42 regulates neutrophil migration via crosstalk between WASp, CD11b, and microtubules. Blood 120(17):3563–3574

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Anderson KE, Chessa TA, Davidson K, Henderson RB, Walker S, Tolmachova T, Grys K, Rausch O, Seabra MC, Tybulewicz VL et al (2010) PtdIns3P and Rac direct the assembly of the NADPH oxidase on a novel, pre-phagosomal compartment during FcR-mediated phagocytosis in primary mouse neutrophils. Blood 116(23):4978–4989

    CAS  PubMed Central  PubMed  Google Scholar 

  174. Lassegue B, Griendling KK (2010) NADPH oxidases: functions and pathologies in the vasculature. Arterioscler Thromb Vasc Biol 30(4):653–661

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Peyssonaux C, Johnson RS (2004) An unexpected role for hypoxic response: oxygenation and inflammation. Cell Cycle 3(2):168–171

    PubMed  Google Scholar 

  176. Dewhirst MW, Cao Y, Moeller B (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev Cancer 8(6):425–437

    CAS  PubMed Central  PubMed  Google Scholar 

  177. Thompson AA, Elks PM, Marriott HM, Eamsamarng S, Higgins KR, Lewis A, Williams L, Parmar S, Shaw G, McGrath EE et al (2014) Hypoxia-inducible factor 2alpha regulates key neutrophil functions in humans, mice, and zebrafish. Blood 123(3):366–376

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Haddad JJ (2002) Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors. Cell Signal 14(11):879–897

    CAS  PubMed  Google Scholar 

  179. Kong T, Eltzschig HK, Karhausen J, Colgan SP, Shelley CS (2004) Leukocyte adhesion during hypoxia is mediated by HIF-1-dependent induction of beta2 integrin gene expression. Proc Natl Acad Sci USA 101(28):10440–10445

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Walmsley SR, Print C, Farahi N, Peyssonnaux C, Johnson RS, Cramer T, Sobolewski A, Condliffe AM, Cowburn AS, Johnson N et al (2005) Hypoxia-induced neutrophil survival is mediated by HIF-1alpha-dependent NF-kappaB activity. J Exp Med 201(1):105–115

    CAS  PubMed Central  PubMed  Google Scholar 

  181. van Uden P, Kenneth NS, Rocha S (2008) Regulation of hypoxia-inducible factor-1alpha by NF-kappaB. Biochem J 412(3):477–484

    PubMed Central  PubMed  Google Scholar 

  182. Walsh TG, Berndt MC, Carrim N, Cowman J, Kenny D, Metharom P (2014) The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation. Redox Biol 2:178–186

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Brill A, Chauhan AK, Canault M, Walsh MT, Bergmeier W, Wagner DD (2009) Oxidative stress activates ADAM17/TACE and induces its target receptor shedding in platelets in a p38-dependent fashion. Cardiovasc Res 84(1):137–144

    CAS  PubMed Central  PubMed  Google Scholar 

  184. Pignatelli P, Sanguigni V, Lenti L, Ferro D, Finocchi A, Rossi P, Violi F (2004) gp91phox-dependent expression of platelet CD40 ligand. Circulation 110(10):1326–1329

    CAS  PubMed  Google Scholar 

  185. Begonja AJ, Gambaryan S, Geiger J, Aktas B, Pozgajova M, Nieswandt B, Walter U (2005) Platelet NAD(P)H-oxidase-generated ROS production regulates alphaIIbbeta3-integrin activation independent of the NO/cGMP pathway. Blood 106(8):2757–2760

    CAS  PubMed  Google Scholar 

  186. Dinauer MC, Orkin SH, Brown R, Jesaitis AJ, Parkos CA (1987) The glycoprotein encoded by the X-linked chronic granulomatous disease locus is a component of the neutrophil cytochrome b complex. Nature 327(6124):717–720

    CAS  PubMed  Google Scholar 

  187. Quie PG, White JG, Holmes B, Good RA (1967) In vitro bactericidal capacity of human polymorphonuclear leukocytes: diminished activity in chronic granulomatous disease of childhood. J Clin Investig 46(4):668–679

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Pollock JD, Williams DA, Gifford MA, Li LL, Du X, Fisherman J, Orkin SH, Doerschuk CM, Dinauer MC (1995) Mouse model of X-linked chronic granulomatous disease, an inherited defect in phagocyte superoxide production. Nat Genet 9(2):202–209

    CAS  PubMed  Google Scholar 

  189. Fialkow L, Wang Y, Downey GP (2007) Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic Biol Med 42(2):153–164

    CAS  PubMed  Google Scholar 

  190. Carbone F, Camillo Teixeira P, Braunersreuther V, Mach F, Vuilleumier N, Montecucco F (2014) Pathophysiology and treatments of oxidative injury in ischemic stroke: focus on the phagocytic NADPH oxidase 2. Antioxid Redox Signal

  191. Radermacher KA, Wingler K, Langhauser F, Altenhofer S, Kleikers P, Hermans JJ, Hrabe de Angelis M, Kleinschnitz C, Schmidt HH (2013) Neuroprotection after stroke by targeting NOX4 as a source of oxidative stress. Antioxid Redox Signal 18(12):1418–1427

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Hagedorn I, Schmidbauer S, Pleines I, Kleinschnitz C, Kronthaler U, Stoll G, Dickneite G, Nieswandt B (2010) Factor XIIa inhibitor recombinant human albumin Infestin-4 abolishes occlusive arterial thrombus formation without affecting bleeding. Circulation 121(13):1510–1517

    CAS  PubMed  Google Scholar 

  193. Amantea D, Nappi G, Bernardi G, Bagetta G, Corasaniti MT (2009) Post-ischemic brain damage: pathophysiology and role of inflammatory mediators. FEBS J 276(1):13–26

    CAS  PubMed  Google Scholar 

  194. Yilmaz G, Granger DN (2008) Cell adhesion molecules and ischemic stroke. Neurol Res 30(8):783–793

    PubMed Central  PubMed  Google Scholar 

  195. Jin R, Yang G, Li G (2010) Inflammatory mechanisms in ischemic stroke: role of inflammatory cells. J Leukoc Biol 87(5):779–789

    CAS  PubMed Central  PubMed  Google Scholar 

  196. Jickling GC, Ander BP, Zhan X, Noblett D, Stamova B, Liu D (2014) microRNA expression in peripheral blood cells following acute ischemic stroke and their predicted gene targets. PLoS ONE 9(6):e99283

    PubMed Central  PubMed  Google Scholar 

  197. Kellert L, Hametner C, Rohde S, Bendszus M, Hacke W, Ringleb P, Stampfl S (2013) Endovascular stroke therapy: tirofiban is associated with risk of fatal intracerebral hemorrhage and poor outcome. Stroke 44(5):1453–1455

    CAS  PubMed  Google Scholar 

  198. Stoll G, Kleinschnitz C, Nieswandt B (2008) Molecular mechanisms of thrombus formation in ischemic stroke: novel insights and targets for treatment. Blood 112(9):3555–3562

    CAS  PubMed  Google Scholar 

  199. Carvalho-Tavares J, Hickey MJ, Hutchison J, Michaud J, Sutcliffe IT, Kubes P (2000) A role for platelets and endothelial selectins in tumor necrosis factor-alpha-induced leukocyte recruitment in the brain microvasculature. Circ Res 87(12):1141–1148

    CAS  PubMed  Google Scholar 

  200. Soriano SG, Coxon A, Wang YF, Frosch MP, Lipton SA, Hickey PR, Mayadas TN (1999) Mice deficient in Mac-1 (CD11b/CD18) are less susceptible to cerebral ischemia/reperfusion injury. Stroke 30(1):134–139

    CAS  PubMed  Google Scholar 

  201. Walder CE, Green SP, Darbonne WC, Mathias J, Rae J, Dinauer MC, Curnutte JT, Thomas GR (1997) Ischemic stroke injury is reduced in mice lacking a functional NADPH oxidase. Stroke 28(11):2252–2258

    CAS  PubMed  Google Scholar 

  202. De Silva TM, Brait VH, Drummond GR, Sobey CG, Miller AA (2011) Nox2 oxidase activity accounts for the oxidative stress and vasomotor dysfunction in mouse cerebral arteries following ischemic stroke. PLoS ONE 6(12):e28393

    PubMed Central  PubMed  Google Scholar 

  203. Tang XN, Zheng Z, Giffard RG, Yenari MA (2011) Significance of marrow-derived nicotinamide adenine dinucleotide phosphate oxidase in experimental ischemic stroke. Ann Neurol 70(4):606–615

    CAS  PubMed Central  PubMed  Google Scholar 

  204. Kleinschnitz C, Grund H, Wingler K, Armitage ME, Jones E, Mittal M, Barit D, Schwarz T, Geis C, Kraft P et al (2010) Post-stroke inhibition of induced NADPH oxidase type 4 prevents oxidative stress and neurodegeneration. PLoS Biol 8(9)

  205. Bunn HF (1997) Pathogenesis and treatment of sickle cell disease. N Engl J Med 337(11):762–769

    CAS  PubMed  Google Scholar 

  206. Frenette PS, Atweh GF (2007) Sickle cell disease: old discoveries, new concepts, and future promise. J Clin Investig 117(4):850–858

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Ballas SK, Gupta K, Adams-Graves P (2012) Sickle cell pain: a critical reappraisal. Blood 120(18):3647–3656

    CAS  PubMed  Google Scholar 

  208. Polanowska-Grabowska R, Wallace K, Field JJ, Chen L, Marshall MA, Figler R, Gear AR, Linden J (2010) P-selectin-mediated platelet–neutrophil aggregate formation activates neutrophils in mouse and human sickle cell disease. Arterioscler Thromb Vasc Biol 30(12):2392–2399

    CAS  PubMed Central  PubMed  Google Scholar 

  209. Chang J, Patton JT, Sarkar A, Ernst B, Magnani JL, Frenette PS (2010) GMI-1070, a novel pan-selectin antagonist, reverses acute vascular occlusions in sickle cell mice. Blood 116(10):1779–1786

    PubMed Central  PubMed  Google Scholar 

  210. Almeida CB, Scheiermann C, Jang JE, Prophete C, Costa FF, Conran N, Frenette PS (2012) Hydroxyurea and a cGMP-amplifying agent have immediate benefits on acute vaso-occlusive events in sickle cell disease mice. Blood 120(14):2879–2888

    CAS  PubMed Central  PubMed  Google Scholar 

  211. Chen G, Zhang D, Fuchs TA, Manwani D, Wagner DD, Frenette PS (2014) Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123(24):3818–3827

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Wun T, Styles L, DeCastro L, Telen MJ, Kuypers F, Cheung A, Kramer W, Flanner H, Rhee S, Magnani JL et al (2014) Phase 1 study of the E-selectin inhibitor GMI 1070 in patients with sickle cell anemia. PLoS ONE 9(7):e101301

    PubMed Central  PubMed  Google Scholar 

  213. Okpala I. Investigational selectin-targeted therapy of sickle cell disease. Expert Opin Investig Drugs. 2014:1–10

  214. Martinod K, Demers M, Fuchs TA, Wong SL, Brill A, Gallant M, Hu J, Wang Y, Wagner DD (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc Natl Acad Sci USA 110(21):8674–8679

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Savchenko AS, Martinod K, Seidman MA, Wong SL, Borissoff JI, Piazza G, Libby P, Goldhaber SZ, Mitchell RN, Wagner DD (2014) Neutrophil extracellular traps form predominantly during the organizing stage of human venous thromboembolism development. J Thromb Haemost 12(6):860–870

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Knight JS, Luo W, O’Dell AA, Yalavarthi S, Zhao W, Subramanian V, Guo C, Grenn RC, Thompson PR, Eitzman DT et al (2014) Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ Res 114(6):947–956

    CAS  PubMed Central  PubMed  Google Scholar 

  217. Hebbel RP, Vercellotti GM, Pace BS, Solovey AN, Kollander R, Abanonu CF, Nguyen J, Vineyard JV, Belcher JD, Abdulla F et al (2010) The HDAC inhibitors trichostatin A and suberoylanilide hydroxamic acid exhibit multiple modalities of benefit for the vascular pathobiology of sickle transgenic mice. Blood 115(12):2483–2490

    CAS  PubMed Central  PubMed  Google Scholar 

  218. Belcher JD, Young M, Chen C, Nguyen J, Burhop K, Tran P, Vercellotti GM (2013) MP4CO, a pegylated hemoglobin saturated with carbon monoxide, is a modulator of HO-1, inflammation, and vaso-occlusion in transgenic sickle mice. Blood 122(15):2757–2764

    CAS  PubMed Central  PubMed  Google Scholar 

  219. Vercellotti GM, Khan FB, Nguyen J, Chen C, Bruzzone CM, Bechtel H, Brown G, Nath KA, Steer CJ, Hebbel RP et al (2014) H-ferritin ferroxidase induces cytoprotective pathways and inhibits microvascular stasis in transgenic sickle mice. Front Pharmacol. 5:79

    PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

We apologize to our colleagues whose works are not cited in this review due to space restrictions. We thank Soochong Kim for his helpful comments on the manuscript. This work was supported by grants from National Institutes of Health. J.L. and K.K. are recipients of the American Heart Association postdoctoral fellowship award.

Conflict of interest

All authors declare no competing financial interests.

Author information

Author notes

    Authors and Affiliations

    1. Department of Pharmacology, University of Illinois College of Medicine, 835 S. Wolcott Ave, E403, Chicago, IL, 60612, USA

      Jing Li, Kyungho Kim, Andrew Barazia, Alan Tseng & Jaehyung Cho

    2. Department of Anesthesiology, University of Illinois College of Medicine, 835 S. Wolcott Ave, E403, Chicago, IL, 60612, USA

      Alan Tseng & Jaehyung Cho

    Authors
    1. Jing Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Kyungho Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Andrew Barazia
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Alan Tseng
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Jaehyung Cho
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Jaehyung Cho.

    Additional information

    J. Li, K. Kim, and A. Barazia contributed equally to this review.

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Li, J., Kim, K., Barazia, A. et al. Platelet–neutrophil interactions under thromboinflammatory conditions. Cell. Mol. Life Sci. 72, 2627–2643 (2015). https://doi.org/10.1007/s00018-015-1845-y

    Download citation

    • Received:

    • Revised:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00018-015-1845-y

    Keywords

    Search

    Navigation