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The roles of thrombin and protease-activated receptors in inflammation

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Abstract

Inflammation and coagulation constitute two host defence systems with complementary physiological roles in limiting tissue damage, restoring homeostasis and eliminating invading pathogens, functions reliant on effective regulation of both processes at a variety of levels. Dysfunctional activation or regulation of either pathway may lead to pathology and contribute to human diseases as diverse as myocardial infarction and septic shock. The serine protease thrombin, a key protein in the coagulation pathway, can activate cellular signalling directly via proteolytic cleavage of the N-terminal domain of a family of G protein-coupled receptors or indirectly through the generation of molecules such as activated protein C. These events transmit signals to many cell types and can elicit the production of various pro-inflammatory mediators such as cytokines, chemokines and growth factors, thereby influencing cell activation, differentiation, survival and migration. This review discusses recent progress in understanding how thrombin and protease-activated receptors influence biological processes, highlighting the detrimental and protective cellular effects of thrombin and its signalling pathways.

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References

  1. Cirino G, Napoli C, Bucci M, Cicala C (2000) Inflammation-coagulation network: are serine protease receptors the knot? Trends Pharmacol Sci 21:170–172

    Article  PubMed  CAS  Google Scholar 

  2. Coughlin SR (2000) Thrombin signalling and protease-activated receptors. Nature 407:258–264

    Article  PubMed  CAS  Google Scholar 

  3. Coughlin SR (2001) Protease-activated receptors in vascular biology. Thromb Haemost 86:298–307

    PubMed  CAS  Google Scholar 

  4. Macfarlane SR, Seatter MJ, Kanke T, Hunter GD, Plevin R (2001) Proteinase-activated receptors. Pharmacol Rev 53:245–282

    PubMed  CAS  Google Scholar 

  5. Martorell L, Martinez-Gonzalez J, Rodriguez C, Gentile M, Calvayrac O, Badimon L (2008) Thrombin and protease-activated receptors (PARS) in atherothrombosis. Thromb Haemost 99:305–315

    PubMed  CAS  Google Scholar 

  6. Santilli F, Davi G (2009) Thrombin as a common downstream target blocking both platelet and monocyte activation. Thromb Haemost 101:220–221

    PubMed  CAS  Google Scholar 

  7. Nierodzik ML, Kajumo F, Karpatkin S (1992) Effect of thrombin treatment of tumor cells on adhesion of tumor cells to platelets in vitro and tumor metastasis in vivo. Cancer Res 52:3267–3272

    PubMed  CAS  Google Scholar 

  8. Kaplanski G, Marin V, Fabrigoule M, Boulay V, Benoliel AM, Bongrand P et al (1998) Thrombin-activated human endothelial cells support monocyte adhesion in vitro following expression of intercellular adhesion molecule-1 (ICAM-1; CD54) and vascular cell adhesion molecule-1 (VCAM-1; CD106). Blood 92:1259–1267

    PubMed  CAS  Google Scholar 

  9. Ossovskaya VS, Bunnett NW (2004) Protease-activated receptors: contribution to physiology and disease. Physiol Rev 84:579–621

    Article  PubMed  CAS  Google Scholar 

  10. Coughlin SR (2005) Protease-activated receptors in hemostasis, thrombosis and vascular biology. J Thromb Haemost 3:1800–1814

    Article  PubMed  CAS  Google Scholar 

  11. Steinhoff M, Buddenkotte J, Shpacovitch V, Rattenholl A, Moormann C, Vergnolle N et al (2005) Proteinase-activated receptors: transducers of proteinase-mediated signalling in inflammation and immune response. Endocr Rev 26:1–43

    Article  PubMed  CAS  Google Scholar 

  12. Steinhoff M, Corvera CU, Thoma MS, Kong W, McAlpine BE, Caughey GH et al (1999) Proteinase-activated receptor-2 in human skin: tissue distribution and activation of keratinocytes by mast cell tryptase. Exp Dermatol 8:282–294

    Article  PubMed  CAS  Google Scholar 

  13. Molino M, Barnathan ES, Numerof R, Clark J, Dreyer M, Cumashi A et al (1997) Interactions of mast cell tryptase with thrombin receptors and PAR-2. J Biol Chem 272:4043–4049

    Article  PubMed  CAS  Google Scholar 

  14. Nystedt S, Emilsson K, Larsson AK, Strombeck B, Sundelin J (1995) Molecular cloning and functional expression of the gene encoding the human proteinase-activated receptor 2. Eur J Biochem 232:84–89

    Article  PubMed  CAS  Google Scholar 

  15. Camerer E, Huang W, Coughlin SR (2000) Tissue factor- and factor X-dependent activation of protease-activated receptor 2 by factor VIIa. Proc Natl Acad Sci U S A 97:5255–5260

    Article  PubMed  CAS  Google Scholar 

  16. Warr TA, Rao LV, Rapaport SI (1990) Disseminated intravascular coagulation in rabbits induced by administration of endotoxin or tissue factor: effect of anti-tissue factor antibodies and measurement of plasma extrinsic pathway inhibitor activity. Blood 75:1481–1489

    PubMed  CAS  Google Scholar 

  17. Akahane K, Okamoto K, Kikuchi M, Todoroki H, Higure A, Ohuchida T et al (2001) Inhibition of factor Xa suppresses the expression of tissue factor in human monocytes and lipopolysaccharide-induced endotoxemia in rats. Surgery 130:809–818

    Article  PubMed  CAS  Google Scholar 

  18. Creasey AA, Chang AC, Feigen L, Wun TC, Taylor FB Jr, Hinshaw LB (1993) Tissue factor pathway inhibitor reduces mortality from Escherichia coli septic shock. J Clin Invest 91:2850–2860

    Article  PubMed  CAS  Google Scholar 

  19. Levi M, ten Cate H, Bauer KA, van der Poll T, Edgington TS, Buller HR et al (1994) Inhibition of endotoxin-induced activation of coagulation and fibrinolysis by pentoxifylline or by a monoclonal anti-tissue factor antibody in chimpanzees. J Clin Invest 93:114–120

    Article  PubMed  CAS  Google Scholar 

  20. Dackiw AP, McGilvray ID, Woodside M, Nathens AB, Marshall JC, Rotstein OD (1996) Prevention of endotoxin-induced mortality by antitissue factor immunization. Arch Surg 131:1273–1278, discussion 1278–1279

    Article  PubMed  CAS  Google Scholar 

  21. Pawlinski R, Pedersen B, Schabbauer G, Tencati M, Holscher T, Boisvert W et al (2004) Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia. Blood 103:1342–1347

    Article  PubMed  CAS  Google Scholar 

  22. Cunningham MA, Rondeau E, Chen X, Coughlin SR, Holdsworth SR, Tipping PG (2000) Protease-activated receptor 1 mediates thrombin-dependent, cell-mediated renal inflammation in crescentic glomerulonephritis. J Exp Med 191:455–462

    Article  PubMed  CAS  Google Scholar 

  23. Howell DC, Johns RH, Lasky JA, Shan B, Scotton CJ, Laurent GJ et al (2005) Absence of proteinase-activated receptor-1 signalling affords protection from bleomycin-induced lung inflammation and fibrosis. Am J Pathol 166:1353–1365

    Article  PubMed  CAS  Google Scholar 

  24. Shimizu S, Shimizu T, Morser J, Kobayashi T, Yamaguchi A, Qin L et al (2008) Role of the coagulation system in allergic inflammation in the upper airways. Clin Immunol 129:365–371

    Article  PubMed  CAS  Google Scholar 

  25. Strande JL, Phillips SA (2009) Thrombin increases inflammatory cytokine and angiogenic growth factor secretion in human adipose cells in vitro. J Inflamm (Lond) 6:4

    Article  Google Scholar 

  26. Vera PL, Wolfe TE, Braley AE, Meyer-Siegler KL (2010) Thrombin induces macrophage migration inhibitory factor release and upregulation in urothelium: a possible contribution to bladder inflammation. PLoS One 5:e15904

    Article  PubMed  CAS  Google Scholar 

  27. Minami T, Sugiyama A, Wu SQ, Abid R, Kodama T, Aird WC (2004) Thrombin and phenotypic modulation of the endothelium. Arterioscler Thromb Vasc Biol 24:41–53

    Article  PubMed  CAS  Google Scholar 

  28. Rahman A, Fazal F (2009) Hug tightly and say goodbye: role of endothelial ICAM-1 in leukocyte transmigration. Antioxid Redox Signal 11:823–839

    Article  PubMed  CAS  Google Scholar 

  29. Delekta PC, Apel IJ, Gu S, Siu K, Hattori Y, McAllister-Lucas LM et al (2010) Thrombin-dependent NF-{kappa}B activation and monocyte/endothelial adhesion are mediated by the CARMA3.Bcl10.MALT1 signalosome. J Biol Chem 285:41432–41442

    Article  PubMed  CAS  Google Scholar 

  30. Popovic M, Paskas S, Zivkovic M, Burysek L, Laumonnier Y (2010) Human cytomegalovirus increases HUVEC sensitivity to thrombin and modulates expression of thrombin receptors. J Thromb Thrombolysis 30:164–171

    Article  PubMed  CAS  Google Scholar 

  31. Chung SW, Park JW, Lee SA, Eo SK, Kim K (2010) Thrombin promotes proinflammatory phenotype in human vascular smooth muscle cell. Biochem Biophys Res Commun 396:748–754

    Article  PubMed  CAS  Google Scholar 

  32. Kastl SP, Speidl WS, Katsaros KM, Kaun C, Rega G, Assadian A et al (2009) Thrombin induces the expression of oncostatin M via AP-1 activation in human macrophages: a link between coagulation and inflammation. Blood 114:2812–2818

    Article  PubMed  CAS  Google Scholar 

  33. Bae JS, Kim YU, Park MK, Rezaie AR (2009) Concentration dependent dual effect of thrombin in endothelial cells via PAR-1 and PI3 kinase. J Cell Physiol 219:744–751

    Article  PubMed  CAS  Google Scholar 

  34. Bae JS, Yang L, Manithody C, Rezaie AR (2007) The ligand occupancy of endothelial protein c receptor switches the protease-activated receptor 1-dependent signalling specificity of thrombin from a permeability-enhancing to a barrier-protective response in endothelial cells. Blood 110:3909–3916

    Article  PubMed  CAS  Google Scholar 

  35. Bae JS, Rezaie AR (2008) Protease activated receptor 1 (PAR-1) activation by thrombin is protective in human pulmonary artery endothelial cells if endothelial protein c receptor is occupied by its natural ligand. Thromb Haemost 100:101–109

    PubMed  CAS  Google Scholar 

  36. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A et al (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709

    Article  PubMed  CAS  Google Scholar 

  37. Abraham E, Reinhart K, Opal S, Demeyer I, Doig C, Rodriguez AL et al (2003) Efficacy and safety of tifacogin (recombinant tissue factor pathway inhibitor) in severe sepsis: a randomized controlled trial. JAMA 290:238–247

    Article  PubMed  CAS  Google Scholar 

  38. Warren BL, Eid A, Singer P, Pillay SS, Carl P, Novak I et al (2001) Caring for the critically ill patient. High-dose antithrombin III in severe sepsis: a randomized controlled trial. JAMA 286:1869–1878

    Article  PubMed  CAS  Google Scholar 

  39. Ahamed J, Belting M, Ruf W (2005) Regulation of tissue factor-induced signalling by endogenous and recombinant tissue factor pathway inhibitor 1. Blood 105:2384–2391

    Article  PubMed  CAS  Google Scholar 

  40. Rosen H, Goetzl EJ (2005) Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol 5:560–570

    Article  PubMed  CAS  Google Scholar 

  41. Singleton PA, Moreno-Vinasco L, Sammani S, Wanderling SL, Moss J, Garcia JG (2007) Attenuation of vascular permeability by methylnaltrexone: role of mOP-R and S1P3 transactivation. Am J Respir Cell Mol Biol 37:222–231

    Article  PubMed  CAS  Google Scholar 

  42. Feistritzer C, Riewald M (2005) Endothelial barrier protection by activated protein c through PAR1-dependent sphingosine 1-phosphate receptor-1 crossactivation. Blood 105:3178–3184

    Article  PubMed  CAS  Google Scholar 

  43. Singleton PA, Dudek SM, Ma SF, Garcia JG (2006) Transactivation of sphingosine 1-phosphate receptors is essential for vascular barrier regulation. Novel role for hyaluronan and CD44 receptor family. J Biol Chem 281:34381–34393

    Article  PubMed  CAS  Google Scholar 

  44. Niessen F, Schaffner F, Furlan-Freguia C, Pawlinski R, Bhattacharjee G, Chun J et al (2008) Dendritic cell PAR1-S1P3 signalling couples coagulation and inflammation. Nature 452:654–658

    Article  PubMed  CAS  Google Scholar 

  45. Esmon CT (2006) Inflammation and the activated protein C anticoagulant pathway. Semin Thromb Hemost 32(Suppl 1):49–60

    Article  PubMed  CAS  Google Scholar 

  46. Dahlback B, Villoutreix BO (2005) Regulation of blood coagulation by the protein C anticoagulant pathway: novel insights into structure-function relationships and molecular recognition. Arterioscler Thromb Vasc Biol 25:1311–1320

    Article  PubMed  Google Scholar 

  47. Mosnier LO, Zlokovic BV, Griffin JH (2007) The cytoprotective protein C pathway. Blood 109:3161–3172

    Article  PubMed  CAS  Google Scholar 

  48. Kerschen EJ, Fernandez JA, Cooley BC, Yang XV, Sood R, Mosnier LO et al (2007) Endotoxemia and sepsis mortality reduction by non-anticoagulant activated protein C. J Exp Med 204:2439–2448

    Article  PubMed  CAS  Google Scholar 

  49. Niessen F, Furlan-Freguia C, Fernandez JA, Mosnier LO, Castellino FJ, Weiler H et al (2009) Endogenous EPCR/APC-PAR1 signalling prevents inflammation-induced vascular leakage and lethality. Blood 113:2859–2866

    Article  PubMed  CAS  Google Scholar 

  50. Schuepbach RA, Feistritzer C, Fernandez JA, Griffin JH, Riewald M (2009) Protection of vascular barrier integrity by activated protein C in murine models depends on protease-activated receptor-1. Thromb Haemost 101:724–733

    PubMed  CAS  Google Scholar 

  51. Chen D, Carpenter A, Abrahams J, Chambers RC, Lechler RI, McVey JH et al (2008) Protease-activated receptor 1 activation is necessary for monocyte chemoattractant protein 1-dependent leukocyte recruitment in vivo. J Exp Med 205:1739–1746

    Article  PubMed  CAS  Google Scholar 

  52. Hamill CE, Goldshmidt A, Nicole O, McKeon RJ, Brat DJ, Traynelis SF (2005) Special lecture: glial reactivity after damage: implications for scar formation and neuronal recovery. Clin Neurosurg 52:29–44

    PubMed  Google Scholar 

  53. Henrich-Noack P, Riek-Burchardt M, Baldauf K, Reiser G, Reymann KG (2006) Focal ischemia induces expression of protease-activated receptor1 (PAR1) and PAR3 on microglia and enhances PAR4 labeling in the penumbra. Brain Res 1070:232–241

    Article  PubMed  CAS  Google Scholar 

  54. Ishida Y, Nagai A, Kobayashi S, Kim SU (2006) Upregulation of protease-activated receptor-1 in astrocytes in Parkinson disease: astrocyte-mediated neuroprotection through increased levels of glutathione peroxidase. J Neuropathol Exp Neurol 65:66–77

    Article  PubMed  CAS  Google Scholar 

  55. Fabrizi C, Pompili E, Panetta B, Nori SL, Fumagalli L (2009) Protease-activated receptor-1 regulates cytokine production and induces the suppressor of cytokine signalling-3 in microglia. Int J Mol Med 24:367–371

    Article  PubMed  CAS  Google Scholar 

  56. Hamill CE, Mannaioni G, Lyuboslavsky P, Sastre AA, Traynelis SF (2009) Protease-activated receptor 1-dependent neuronal damage involves NMDA receptor function. Exp Neurol 217:136–146

    Article  PubMed  CAS  Google Scholar 

  57. Ikehara O, Hayashi H, Watanabe Y, Yamamoto H, Mochizuki T, Hoshino M et al (2010) Proteinase-activated receptors-1 and 2 induce electrogenic Cl− secretion in the mouse cecum by distinct mechanisms. Am J Physiol Gastrointest Liver Physiol 299:G115–G125

    Article  PubMed  CAS  Google Scholar 

  58. Wang H, Moreau F, Hirota CL, MacNaughton WK (2010) Proteinase-activated receptors induce interleukin-8 expression by intestinal epithelial cells through ERK/RSK90 activation and histone acetylation. FASEB J 24:1971–1980

    Article  PubMed  CAS  Google Scholar 

  59. Luyendyk JP, Sullivan BP, Guo GL, Wang R (2010) Tissue factor-deficiency and protease activated receptor-1-deficiency reduce inflammation elicited by diet-induced steatohepatitis in mice. Am J Pathol 176:177–186

    Article  PubMed  CAS  Google Scholar 

  60. Wee JL, Chionh YT, Ng GZ, Harbour SN, Allison C, Pagel CN et al (2010) Protease-activated receptor-1 down-regulates the murine inflammatory and humoral response to Helicobacter pylori. Gastroenterology 138:573–582

    Article  PubMed  CAS  Google Scholar 

  61. Sawicki G, Salas E, Murat J, Miszta-Lane H, Radomski MW (1997) Release of gelatinase A during platelet activation mediates aggregation. Nature 386:616–619

    Article  PubMed  CAS  Google Scholar 

  62. Kazes I, Elalamy I, Sraer JD, Hatmi M, Nguyen G (2000) Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: Involvement in MMP2 activation and platelet aggregation. Blood 96:3064–3069

    PubMed  CAS  Google Scholar 

  63. Galt SW, Lindemann S, Allen L, Medd DJ, Falk JM, McIntyre TM et al (2002) Outside-in signals delivered by matrix metalloproteinase-1 regulate platelet function. Circ Res 90:1093–1099

    Article  PubMed  CAS  Google Scholar 

  64. Trivedi V, Boire A, Tchernychev B, Kaneider NC, Leger AJ, O'Callaghan K et al (2009) Platelet matrix metalloprotease-1 mediates thrombogenesis by activating PAR1 at a cryptic ligand site. Cell 137:332–343

    Article  PubMed  CAS  Google Scholar 

  65. Lee EJ, Woo MS, Moon PG, Baek MC, Choi IY, Kim WK et al (2010) Alpha-synuclein activates microglia by inducing the expressions of matrix metalloproteinases and the subsequent activation of protease-activated receptor-1. J Immunol 185:615–623

    Article  PubMed  CAS  Google Scholar 

  66. Mao Y, Zhang M, Tuma RF, Kunapuli SP (2010) Deficiency of PAR4 attenuates cerebral ischemia/reperfusion injury in mice. J Cereb Blood Flow Metab 30:1044–1052

    Article  PubMed  CAS  Google Scholar 

  67. Russell FA, Veldhoen VE, Tchitchkan D, McDougall JJ (2010) Proteinase-activated receptor-4 (PAR4) activation leads to sensitization of rat joint primary afferents via a bradykinin B2 receptor-dependent mechanism. J Neurophysiol 103:155–163

    Article  PubMed  CAS  Google Scholar 

  68. Dabek M, Ferrier L, Roka R, Gecse K, Annahazi A, Moreau J et al (2009) Luminal cathepsin g and protease-activated receptor 4: a duet involved in alterations of the colonic epithelial barrier in ulcerative colitis. Am J Pathol 175:207–214

    Article  PubMed  CAS  Google Scholar 

  69. Megyeri M, Mako V, Beinrohr L, Doleschall Z, Prohaszka Z, Cervenak L et al (2009) Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function. J Immunol 183:3409–3416

    Article  PubMed  CAS  Google Scholar 

  70. Wilson BJ, Harada R, LeDuy L, Hollenberg MD, Nepveu A (2009) CUX1 transcription factor is a downstream effector of the proteinase-activated receptor 2 (PAR2). J Biol Chem 284:36–45

    Article  PubMed  CAS  Google Scholar 

  71. Jesmin S, Gando S, Zaedi S, Prodhan SH, Sawamura A, Miyauchi T et al (2009) Protease-activated receptor 2 blocking peptide counteracts endotoxin-induced inflammation and coagulation and ameliorates renal fibrin deposition in a rat model of acute renal failure. Shock 32:626–632

    Article  PubMed  CAS  Google Scholar 

  72. Rallabhandi P, Nhu QM, Toshchakov VY, Piao W, Medvedev AE, Hollenberg MD et al (2008) Analysis of proteinase-activated receptor 2 and TLR4 signal transduction: a novel paradigm for receptor cooperativity. J Biol Chem 283:24314–24325

    Article  PubMed  CAS  Google Scholar 

  73. Nhu QM, Shirey K, Teijaro JR, Farber DL, Netzel-Arnett S, Antalis TM et al (2010) Novel signalling interactions between proteinase-activated receptor 2 and toll-like receptors in vitro and in vivo. Mucosal Immunol 3:29–39

    Article  PubMed  CAS  Google Scholar 

  74. McIntosh K, Cunningham MR, Cadalbert L, Lockhart J, Boyd G, Ferrell WR et al (2010) Proteinase-activated receptor-2 mediated inhibition of TNFalpha-stimulated JNK activation—a novel paradigm for G(q/11) linked GPCRS. Cell Signal 22:265–273

    Article  PubMed  CAS  Google Scholar 

  75. Li R, Rohatgi T, Hanck T, Reiser G (2009) Alpha A-crystallin and alpha B-crystallin, newly identified interaction proteins of protease-activated receptor-2, rescue astrocytes from C2-ceramide- and staurosporine-induced cell death. J Neurochem 110:1433–1444

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Research in A. Dorling's laboratory is funded by the Medical Research Council (award G0801965), Guy's and St Thomas' Charity (R090741) and Novartis, via an unrestricted educational grant. The authors acknowledge the support of the MRC Centre for Transplantation and the additional financial support from the Department of Health via the National Institute for Health Research comprehensive Biomedical Research Centre award to Guy's and St Thomas' NHS Foundation Trust in partnership with the King's College London and King's College Hospital NHS Foundation Trust.

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  1. Medical Research Council (MRC) Centre for Transplantation, King’s College London, King’s Health Partners, Guy’s Hospital, Great Maze Pond, London, SE1 9RT, UK

    Liang Ma & Anthony Dorling

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  1. Liang Ma
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  2. Anthony Dorling
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Correspondence to Anthony Dorling.

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This article is published as part of the Special Issue on Coagulation & Inflammation [34:1].

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Ma, L., Dorling, A. The roles of thrombin and protease-activated receptors in inflammation. Semin Immunopathol 34, 63–72 (2012). https://doi.org/10.1007/s00281-011-0281-9

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