Plasmin(ogen) at the Nexus of Fibrinolysis, Inflammation, and Complement

 

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Abstract

The diverse mechanisms by which the plasmin(ogen) system is involved in human physiology and pathology are constantly being delineated. For many years, the plasmin(ogen) system was chiefly known as the system responsible for vascular fibrinolysis. Although this is an important function of the plasmin(ogen) system, we now recognize that plasmin(ogen) is critically important as a mediator of inflammation and the innate immune system, which impacts upon a diverse set of mechanisms underlying the pathologies of many diseases. The current review focuses on recent developments in plasmin(ogen) system activation and regulation and how dysregulation of this finely tuned system may contribute to inflammatory disease (atherosclerosis), impaired wound healing, and infection.

• References

• 1 Levin EG, Marzec U, Anderson J, Harker LA. Thrombin stimulates tissue plasminogen activator release from cultured human endothelial cells. J Clin Invest 1984; 74 (6) 1988-1995
  CrossrefPubMedGoogle Scholar
• 2 Shatos MA, Orfeo T, Doherty JM, Penar PL, Collen D, Mann KG. Alpha-thrombin stimulates urokinase production and DNA synthesis in cultured human cerebral microvascular endothelial cells. Arterioscler Thromb Vasc Biol 1995; 15 (7) 903-911
  CrossrefPubMedGoogle Scholar
• 3 Kim PY, Tieu LD, Stafford AR, Fredenburgh JC, Weitz JI. A high affinity interaction of plasminogen with fibrin is not essential for efficient activation by tissue-type plasminogen activator. J Biol Chem 2012; 287 (7) 4652-4661
  CrossrefPubMedGoogle Scholar
• 4 Horrevoets AJ, Pannekoek H, Nesheim ME. A steady-state template model that describes the kinetics of fibrin-stimulated [Glu1]- and [Lys78]plasminogen activation by native tissue-type plasminogen activator and variants that lack either the finger or kringle-2 domain. J Biol Chem 1997; 272 (4) 2183-2191
  CrossrefPubMedGoogle Scholar
• 5 Walker JB, Nesheim ME. A kinetic analysis of the tissue plasminogen activator and DSPAalpha1 cofactor activities of untreated and TAFIa-treated soluble fibrin degradation products of varying size. J Biol Chem 2001; 276 (5) 3138-3148
  CrossrefPubMedGoogle Scholar
• 6 Lijnen HR, Zamarron C, Blaber M, Winkler ME, Collen D. Activation of plasminogen by pro-urokinase. I. Mechanism. J Biol Chem 1986; 261 (3) 1253-1258
  PubMedGoogle Scholar
• 7 Miles LA, Greengard JS, Griffin JH. A comparison of the abilities of plasma kallikrein, beta-Factor XIIa, Factor XIa and urokinase to activate plasminogen. Thromb Res 1983; 29 (4) 407-417
  CrossrefPubMedGoogle Scholar
• 8 de Maat S, Björkqvist J, Suffritti C , et al. Plasmin is a natural trigger for bradykinin production in patients with hereditary angioedema with factor XII mutations. J Allergy Clin Immunol 2016; 138 (5) 1414-1423.e9
  CrossrefPubMedGoogle Scholar
• 9 Foley JH, Cook PF, Nesheim ME. Kinetics of activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-catalyzed cleavage of C-terminal lysine residues of fibrin degradation products and removal of plasminogen-binding sites. J Biol Chem 2011; 286 (22) 19280-19286
  CrossrefPubMedGoogle Scholar
• 10 Godier A, Hunt BJ. Plasminogen receptors and their role in the pathogenesis of inflammatory, autoimmune and malignant disease. J Thromb Haemost 2013; 11 (1) 26-34
  CrossrefPubMedGoogle Scholar
• 11 Plow EF, Herren T, Redlitz A, Miles LA, Hoover-Plow JL. The cell biology of the plasminogen system. FASEB J 1995; 9 (10) 939-945
  CrossrefPubMedGoogle Scholar
• 12 Ditzel HJ, Strik MC, Larsen MK , et al. Cancer-associated cleavage of cytokeratin 8/18 heterotypic complexes exposes a neoepitope in human adenocarcinomas. J Biol Chem 2002; 277 (24) 21712-21722
  CrossrefPubMedGoogle Scholar
• 13 Seipelt J, Liebig HD, Sommergruber W, Gerner C, Kuechler E. 2A proteinase of human rhinovirus cleaves cytokeratin 8 in infected HeLa cells. J Biol Chem 2000; 275 (26) 20084-20089
  CrossrefPubMedGoogle Scholar
• 14 Vaisar T, Kassim SY, Gomez IG , et al. MMP-9 sheds the beta2 integrin subunit (CD18) from macrophages. Mol Cell Proteomics 2009; 8 (5) 1044-1060
  CrossrefPubMedGoogle Scholar
• 15 Jevnikar Z, Obermajer N, Doljak B , et al. Cathepsin X cleavage of the beta2 integrin regulates talin-binding and LFA-1 affinity in T cells. J Leukoc Biol 2011; 90 (1) 99-109
  CrossrefPubMedGoogle Scholar
• 16 Deora AB, Kreitzer G, Jacovina AT, Hajjar KA. An annexin 2 phosphorylation switch mediates p11-dependent translocation of annexin 2 to the cell surface. J Biol Chem 2004; 279 (42) 43411-43418
  CrossrefPubMedGoogle Scholar
• 17 MacLeod TJ, Kwon M, Filipenko NR, Waisman DM. Phospholipid-associated annexin A2-S100A10 heterotetramer and its subunits: characterization of the interaction with tissue plasminogen activator, plasminogen, and plasmin. J Biol Chem 2003; 278 (28) 25577-25584
  CrossrefPubMedGoogle Scholar
• 18 Kassam G, Le BH, Choi KS , et al. The p11 subunit of the annexin II tetramer plays a key role in the stimulation of t-PA-dependent plasminogen activation. Biochemistry 1998; 37 (48) 16958-16966
  CrossrefPubMedGoogle Scholar
• 19 Swisher JF, Khatri U, Feldman GM. Annexin A2 is a soluble mediator of macrophage activation. J Leukoc Biol 2007; 82 (5) 1174-1184
  CrossrefPubMedGoogle Scholar
• 20 Pancholi V. Multifunctional alpha-enolase: its role in diseases. Cell Mol Life Sci 2001; 58 (7) 902-920
  CrossrefPubMedGoogle Scholar
• 21 Das R, Burke T, Plow EF. Histone H2B as a functionally important plasminogen receptor on macrophages. Blood 2007; 110 (10) 3763-3772
  CrossrefPubMedGoogle Scholar
• 22 Das R, Burke T, Van Wagoner DR, Plow EF. L-type calcium channel blockers exert an antiinflammatory effect by suppressing expression of plasminogen receptors on macrophages. Circ Res 2009; 105 (2) 167-175
  CrossrefPubMedGoogle Scholar
• 23 Das R, Plow EF. Phosphatidylserine as an anchor for plasminogen and its plasminogen receptor, histone H2B, to the macrophage surface. J Thromb Haemost 2011; 9 (2) 339-349
  CrossrefPubMedGoogle Scholar
• 24 Andronicos NM, Chen EI, Baik N , et al. Proteomics-based discovery of a novel, structurally unique, and developmentally regulated plasminogen receptor, Plg-RKT, a major regulator of cell surface plasminogen activation. Blood 2010; 115 (7) 1319-1330
  CrossrefPubMedGoogle Scholar
• 25 Abdul S, Leebeek FW, Rijken DC, Uitte de Willige S. Natural heterogeneity of α2-antiplasmin: functional and clinical consequences. Blood 2016; 127 (5) 538-545
  CrossrefPubMedGoogle Scholar
• 26 Hall SW, Humphries JE, Gonias SL. Inhibition of cell surface receptor-bound plasmin by alpha 2-antiplasmin and alpha 2-macroglobulin. J Biol Chem 1991; 266 (19) 12329-12336
  PubMedGoogle Scholar
• 27 Schneider M, Nesheim M. A study of the protection of plasmin from antiplasmin inhibition within an intact fibrin clot during the course of clot lysis. J Biol Chem 2004; 279 (14) 13333-13339
  CrossrefPubMedGoogle Scholar
• 28 Wu C, Kim PY, Swystun LL, Liaw PC, Weitz JI. Activation of protein C and thrombin activable fibrinolysis inhibitor on cultured human endothelial cells. J Thromb Haemost 2016; 14 (2) 366-374
  CrossrefPubMedGoogle Scholar
• 29 Redlitz A, Tan AK, Eaton DL, Plow EF. Plasma carboxypeptidases as regulators of the plasminogen system. J Clin Invest 1995; 96 (5) 2534-2538
  CrossrefPubMedGoogle Scholar
• 30 Wygrecka M, Marsh LM, Morty RE , et al. Enolase-1 promotes plasminogen-mediated recruitment of monocytes to the acutely inflamed lung. Blood 2009; 113 (22) 5588-5598
  CrossrefPubMedGoogle Scholar
• 31 Schlechte W, Murano G, Boyd D. Examination of the role of the urokinase receptor in human colon cancer mediated laminin degradation. Cancer Res 1989; 49 (21) 6064-6069
  PubMedGoogle Scholar
• 32 Jimenez JJ, Iribarren JL, Lorente L , et al. Tranexamic acid attenuates inflammatory response in cardiopulmonary bypass surgery through blockade of fibrinolysis: a case control study followed by a randomized double-blind controlled trial. Crit Care 2007; 11 (6) R117
  CrossrefPubMedGoogle Scholar
• 33 Jiménez JJ, Iribarren JL, Brouard M , et al. Safety and effectiveness of two treatment regimes with tranexamic acid to minimize inflammatory response in elective cardiopulmonary bypass patients: a randomized double-blind, dose-dependent, phase IV clinical trial. J Cardiothorac Surg 2011; 6: 138
  CrossrefPubMedGoogle Scholar
• 34 Later AF, Sitniakowsky LS, van Hilten JA , et al. Antifibrinolytics attenuate inflammatory gene expression after cardiac surgery. J Thorac Cardiovasc Surg 2013; 145 (6) 1611-1616 , 1616.e1–1616.e4
  CrossrefPubMedGoogle Scholar
• 35 Greilich PE, Brouse CF, Whitten CW, Chi L, Dimaio JM, Jessen ME. Antifibrinolytic therapy during cardiopulmonary bypass reduces proinflammatory cytokine levels: a randomized, double-blind, placebo-controlled study of epsilon-aminocaproic acid and aprotinin. J Thorac Cardiovasc Surg 2003; 126 (5) 1498-1503
  CrossrefPubMedGoogle Scholar
• 36 Graham EM, Atz AM, Gillis J , et al. Differential effects of aprotinin and tranexamic acid on outcomes and cytokine profiles in neonates undergoing cardiac surgery. J Thorac Cardiovasc Surg 2012; 143 (5) 1069-1076
  CrossrefPubMedGoogle Scholar
• 37 Renckens R, Weijer S, de Vos AF , et al. Inhibition of plasmin activity by tranexamic acid does not influence inflammatory pathways during human endotoxemia. Arterioscler Thromb Vasc Biol 2004; 24 (3) 483-488
  CrossrefPubMedGoogle Scholar
• 38 Del Rosso M, Fibbi G, Pucci M, Margheri F, Serrati S. The plasminogen activation system in inflammation. Front Biosci 2008; 13: 4667-4686
  PubMedGoogle Scholar
• 39 Romer J, Bugge TH, Pyke C , et al. Impaired wound healing in mice with a disrupted plasminogen gene. Nat Med 1996; 2 (3) 287-292
  CrossrefPubMedGoogle Scholar
• 40 Yuasa M, Mignemi NA, Nyman JS , et al. Fibrinolysis is essential for fracture repair and prevention of heterotopic ossification. J Clin Invest 2015; 125 (8) 3117-3131
  CrossrefPubMedGoogle Scholar
• 41 Li J, Ny A, Leonardsson G, Nandakumar KS, Holmdahl R, Ny T. The plasminogen activator/plasmin system is essential for development of the joint inflammatory phase of collagen type II-induced arthritis. Am J Pathol 2005; 166 (3) 783-792
  CrossrefPubMedGoogle Scholar
• 42 Kremen M, Krishnan R, Emery I , et al. Plasminogen mediates the atherogenic effects of macrophage-expressed urokinase and accelerates atherosclerosis in apoE-knockout mice. Proc Natl Acad Sci U S A 2008; 105 (44) 17109-17114
  CrossrefPubMedGoogle Scholar
• 43 Kwaan HC, McMahon B. The role of plasminogen-plasmin system in cancer. Cancer Treat Res 2009; 148: 43-66
  PubMedGoogle Scholar
• 44 Syrovets T, Jendrach M, Rohwedder A, Schüle A, Simmet T. Plasmin-induced expression of cytokines and tissue factor in human monocytes involves AP-1 and IKKbeta-mediated NF-kappaB activation. Blood 2001; 97 (12) 3941-3950
  CrossrefPubMedGoogle Scholar
• 45 Burysek L, Syrovets T, Simmet T. The serine protease plasmin triggers expression of MCP-1 and CD40 in human primary monocytes via activation of p38 MAPK and janus kinase (JAK)/STAT signaling pathways. J Biol Chem 2002; 277 (36) 33509-33517
  CrossrefPubMedGoogle Scholar
• 46 Weide I, Tippler B, Syrovets T, Simmet T. Plasmin is a specific stimulus of the 5-lipoxygenase pathway of human peripheral monocytes. Thromb Haemost 1996; 76 (4) 561-568
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 Syrovets T, Tippler B, Rieks M, Simmet T. Plasmin is a potent and specific chemoattractant for human peripheral monocytes acting via a cyclic guanosine monophosphate-dependent pathway. Blood 1997; 89 (12) 4574-4583
  CrossrefPubMedGoogle Scholar
• 48 Tarui T, Majumdar M, Miles LA, Ruf W, Takada Y. Plasmin-induced migration of endothelial cells. A potential target for the anti-angiogenic action of angiostatin. J Biol Chem 2002; 277 (37) 33564-33570
  CrossrefPubMedGoogle Scholar
• 49 Laumonnier Y, Syrovets T, Burysek L, Simmet T. Identification of the annexin A2 heterotetramer as a receptor for the plasmin-induced signaling in human peripheral monocytes. Blood 2006; 107 (8) 3342-3349
  CrossrefPubMedGoogle Scholar
• 50 Li X, Syrovets T, Genze F , et al. Plasmin triggers chemotaxis of monocyte-derived dendritic cells through an Akt2-dependent pathway and promotes a T-helper type-1 response. Arterioscler Thromb Vasc Biol 2010; 30 (3) 582-590
  CrossrefPubMedGoogle Scholar
• 51 Borg RJ, Samson AL, Au AE , et al. Dendritic cell-mediated phagocytosis but not immune activation is enhanced by plasmin. PLoS ONE 2015; 10 (7) e0131216
  CrossrefPubMedGoogle Scholar
• 52 Shen Y, Guo Y, Du C, Wilczynska M, Hellström S, Ny T. Mice deficient in urokinase-type plasminogen activator have delayed healing of tympanic membrane perforations. PLoS ONE 2012; 7 (12) e51303
  CrossrefPubMedGoogle Scholar
• 53 Lund LR, Green KA, Stoop AA , et al. Plasminogen activation independent of uPA and tPA maintains wound healing in gene-deficient mice. EMBO J 2006; 25 (12) 2686-2697
  CrossrefPubMedGoogle Scholar
• 54 Shen Y, Guo Y, Mikus P , et al. Plasminogen is a key proinflammatory regulator that accelerates the healing of acute and diabetic wounds. Blood 2012; 119 (24) 5879-5887
  CrossrefPubMedGoogle Scholar
• 55 Carmeliet P, Moons L, Lijnen R , et al. Urokinase-generated plasmin activates matrix metalloproteinases during aneurysm formation. Nat Genet 1997; 17 (4) 439-444
  CrossrefPubMedGoogle Scholar
• 56 Ajjan RA, Gamlen T, Standeven KF , et al. Diabetes is associated with posttranslational modifications in plasminogen resulting in reduced plasmin generation and enzyme-specific activity. Blood 2013; 122 (1) 134-142
  CrossrefPubMedGoogle Scholar
• 57 Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999; 340 (2) 115-126
  CrossrefPubMedGoogle Scholar
• 58 Viola J, Soehnlein O. Atherosclerosis – a matter of unresolved inflammation. Semin Immunol 2015; 27 (3) 184-193
  CrossrefPubMedGoogle Scholar
• 59 Tkachuk V, Stepanova V, Little PJ, Bobik A. Regulation and role of urokinase plasminogen activator in vascular remodelling. Clin Exp Pharmacol Physiol 1996; 23 (9) 759-765
  CrossrefPubMedGoogle Scholar
• 60 Hu JH, Du L, Chu T , et al. Overexpression of urokinase by plaque macrophages causes histological features of plaque rupture and increases vascular matrix metalloproteinase activity in aged apolipoprotein e-null mice. Circulation 2010; 121 (14) 1637-1644
  CrossrefPubMedGoogle Scholar
• 61 Hu JH, Touch P, Zhang J , et al. Reduction of mouse atherosclerosis by urokinase inhibition or with a limited-spectrum matrix metalloproteinase inhibitor. Cardiovasc Res 2015; 105 (3) 372-382
  CrossrefPubMedGoogle Scholar
• 62 Foley JH, Walton BL, Aleman MM , et al. Complement activation in arterial and venous thrombosis is mediated by plasmin. EBioMedicine 2016; 5: 175-182
  CrossrefPubMedGoogle Scholar
• 63 Amara U, Flierl MA, Rittirsch D , et al. Molecular intercommunication between the complement and coagulation systems. J Immunol 2010; 185 (9) 5628-5636
  CrossrefPubMedGoogle Scholar
• 64 Barthel D, Schindler S, Zipfel PF. Plasminogen is a complement inhibitor. J Biol Chem 2012; 287 (22) 18831-18842
  CrossrefPubMedGoogle Scholar
• 65 Bajic G, Degn SE, Thiel S, Andersen GR. Complement activation, regulation, and molecular basis for complement-related diseases. EMBO J 2015; 34 (22) 2735-2757
  CrossrefPubMedGoogle Scholar
• 66 Huber-Lang M, Sarma JV, Zetoune FS , et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat Med 2006; 12 (6) 682-687
  CrossrefPubMedGoogle Scholar
• 67 Castiblanco-Valencia MM, Fraga TR, Pagotto AH , et al. Plasmin cleaves fibrinogen and the human complement proteins C3b and C5 in the presence of Leptospira interrogans proteins: A new role of LigA and LigB in invasion and complement immune evasion. Immunobiology 2016; 221 (5) 679-689
  CrossrefPubMedGoogle Scholar
• 68 Agrahari G, Liang Z, Glinton K, Lee SW, Ploplis VA, Castellino FJ. Streptococcus pyogenes Employs Strain-dependent Mechanisms of C3b Inactivation to Inhibit Phagocytosis and Killing of Bacteria. J Biol Chem 2016; 291 (17) 9181-9189
  CrossrefPubMedGoogle Scholar
• 69 Sodeinde OA, Subrahmanyam YV, Stark K, Quan T, Bao Y, Goguen JD. A surface protease and the invasive character of plague. Science 1992; 258 (5084): 1004-1007
  CrossrefPubMedGoogle Scholar
• 70 Koch TK, Reuter M, Barthel D , et al. Staphylococcus aureus proteins Sbi and Efb recruit human plasmin to degrade complement C3 and C3b. PLoS ONE 2012; 7 (10) e47638
  CrossrefPubMedGoogle Scholar
• 71 Barthel D, Singh B, Riesbeck K, Zipfel PF. Haemophilus influenzae uses the surface protein E to acquire human plasminogen and to evade innate immunity. J Immunol 2012; 188 (1) 379-385
  CrossrefPubMedGoogle Scholar
• 72 Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 2007; 5 (Suppl. 01) 24-31
  CrossrefPubMedGoogle Scholar
• 73 Lambris JD, Ricklin D, Geisbrecht BV. Complement evasion by human pathogens. Nat Rev Microbiol 2008; 6 (2) 132-142
  CrossrefPubMedGoogle Scholar
• 74 Shao Z, Nishimura T, Leung LL, Morser J. Carboxypeptidase B2 deficiency reveals opposite effects of complement C3a and C5a in a murine polymicrobial sepsis model. J Thromb Haemost 2015; 13 (6) 1090-1102
  CrossrefPubMedGoogle Scholar
• 75 Song JJ, Hwang I, Cho KH , et al; Consortium for the Longitudinal Evaluation of African Americans with Early Rheumatoid Arthritis (CLEAR) Registry. Plasma carboxypeptidase B downregulates inflammatory responses in autoimmune arthritis. J Clin Invest 2011; 121 (9) 3517-3527
  PubMedGoogle Scholar
• 76 Myles T, Nishimura T, Yun TH , et al. Thrombin activatable fibrinolysis inhibitor, a potential regulator of vascular inflammation. J Biol Chem 2003; 278 (51) 51059-51067
  CrossrefPubMedGoogle Scholar
• 77 Nishimura T, Myles T, Piliponsky AM, Kao PN, Berry GJ, Leung LL. Thrombin-activatable procarboxypeptidase B regulates activated complement C5a in vivo. Blood 2007; 109 (5) 1992-1997
  CrossrefPubMedGoogle Scholar
• 78 Ward PA. A plasmin-split fragment of C'3 as a new chemotactic factor. J Exp Med 1967; 126 (2) 189-206
  CrossrefPubMedGoogle Scholar
• 79 Foley JH, Peterson EA, Lei V, Wan LW, Krisinger MJ, Conway EM. Interplay between fibrinolysis and complement: plasmin cleavage of iC3b modulates immune responses. J Thromb Haemost 2015; 13 (4) 610-618
  CrossrefPubMedGoogle Scholar
• 80 Wojta J, Kaun C, Zorn G , et al. C5a stimulates production of plasminogen activator inhibitor-1 in human mast cells and basophils. Blood 2002; 100 (2) 517-523
  CrossrefPubMedGoogle Scholar
• 81 Kastl SP, Speidl WS, Kaun C , et al. The complement component C5a induces the expression of plasminogen activator inhibitor-1 in human macrophages via NF-kappaB activation. J Thromb Haemost 2006; 4 (8) 1790-1797
  CrossrefPubMedGoogle Scholar
• 82 Howes JM, Richardson VR, Smith KA , et al. Complement C3 is a novel plasma clot component with anti-fibrinolytic properties. Diab Vasc Dis Res 2012; 9 (3) 216-225
  CrossrefPubMedGoogle Scholar
• 83 Hess K, Alzahrani SH, Mathai M , et al. A novel mechanism for hypofibrinolysis in diabetes: the role of complement C3. Diabetologia 2012; 55 (4) 1103-1113
  CrossrefPubMedGoogle Scholar
• 84 Hess K, Alzahrani SH, Price JF , et al. Hypofibrinolysis in type 2 diabetes: the role of the inflammatory pathway and complement C3. Diabetologia 2014; 57 (8) 1737-1741
  CrossrefPubMedGoogle Scholar
• 85 Nikolajsen CL, Scavenius C, Enghild JJ. Human complement C3 is a substrate for transglutaminases. A functional link between non-protease-based members of the coagulation and complement cascades. Biochemistry 2012; 51 (23) 4735-4742
  CrossrefPubMedGoogle Scholar
• 86 Richardson VR, Schroeder V, Grant PJ, Standeven KF, Carter AM. Complement C3 is a substrate for activated factor XIII that is cross-linked to fibrin during clot formation. Br J Haematol 2013; 160 (1) 116-119
  CrossrefPubMedGoogle Scholar