Molecular circuits in thrombosis and inflammation

Charles T. Esmon

doi:10.1160/TH12-08-0634

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2013; 109(03): 416-420
DOI: 10.1160/TH12-08-0634

Theme Issue Article

Schattauer GmbH

Molecular circuits in thrombosis and inflammation

Charles T. Esmon

¹Coagulation Biology Laboratory, Oklahoma Medical Research Foundation, Howard Hughes Medical Institute, Oklahoma City, Oklahoma, USA

²Departments of Pathology and Biochemistry & Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA

› Institutsangaben

Abstract

Summary

Inflammatory cytokines promote the activation of coagulation through the induction of tissue factor, downregulation of thrombomodulin and upregulation of plasminogen activator inhibitor. In addition to these mechanisms, infections can trigger the release of extracellular traps from leukocytes consisting of DNA and histones. Tissue injury results in release of nucleosomes. Either of these histone containing structures activate platelets and form a potent procoagulant surface on polyphosphates secreted from the platelets, thereby augmenting thrombus formation. In addition, the histones can inhibit thrombomodulin function. The combination of augmenting the platelet procoagulant activity and impairing thrombomodulin activity probably explains the microvascular thrombotic problems observed when histones are infused into mice. Of the histones, H4 is the most potent in all of these activities. DNAase or blocking histone H4 can decrease the thrombotic response initiated by either the extracellular traps or nucleosomes. In addition to the direct prothrombotic activity of histone-DNA complexes, the complexes trigger activation of the toll-like receptors 2, 4 and 9 thereby increasing inflammatory cytokine formation and fostering thrombotic responses through the mechanisms mentioned previously. Furthermore, these cytokines are likely to increase cell necrosis and apoptosis releasing nucleosomes and further augmenting the activation of leukocytes with the subsequent release of extracellular traps. Blocking this histone-mediated cascade has the potential to impact a variety of clinical conditions including sepsis, trauma, chemical toxicity, transplant injury and reperfusion injury.

Keywords

Neutrophils - histones - infection - inflammation - sepsis

Volltext

Referenzen

References
1 Esmon CT, Xu J, Lupu F. Innate immunity and coagulation. J Thromb Haemost 2011; 9 (Suppl. 01) 182-188.
2 Degen JL, Bugge TH, Goguen JD. Fibrin and fibrinolysis in infection and host defense. J Thromb Haemost 2007; 5: 24-31.
3 Herwald H, Mörgelin M, Olsén A. et al. Activation of the contact-phase system on bacterial surfaces - a clue to serious complications in infectious diseases. Nature Med 1998; 4: 298-302.
4 Falati S, Liu Q, Gross P. et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein 1 and platelet P-selectin. J Exp Med 2003; 197: 1585-1598.
5 Myers DD, Hawley AE, Farris DM. et al. P-selectin and leukocyte microparticles are associated with venous thrombogenesis. J Vasc Surg 2003; 38: 1075-1089.
6 Lindmark E, Tenno T, Siegbahn A. Role of platelet P-selectin and CD40 ligand in the induction of monocytic tissue factor expression. Arterioscler Thromb Vasc Biol 2000; 20: 2322-2328.
7 André P, Srinivasa Prasad KS, Denis CV. et al. CD40L stabilizes arterial thrombi by a β 3 integrin-dependent mechanism. Nature Med 2002; 8: 247-252.
8 Silasi-Mansat R, Zhu H, Popescu NI. et al. Complement inhibition decreases the procoagulant response and confers organ protection in a baboon model of Escherichia coli sepsis. Blood 2010; 116: 1002-1010.
9 Fuchs TA, Bhandari AA, Wagner DD. Histones induce rapid and profound thrombocytopenia in mice. Blood 2011; 118: 3708-3714.
10 Ma AC, Kubes P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J Thromb Haemost 2008; 6: 415-420.
11 Sodeinde OA, Subrahmanyam YV, Stark K. et al. A surface protease and the invasive character of plague. Science 1992; 258: 1004-1007.
12 Wang SH, Degen JL, Ginsburg D. Reduced thrombin generation increases host susceptibility to group A streptococcal infection. Blood 2009; 113: 1358-1364.
13 Sun H, Ringdahl U, Homeister JW. et al. Plasminogen is a critical host pathogenicity factor for group A streptococcal infection. Science 2004; 305: 1283-1286.
14 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
15 Urban CF, Reichard U, Brinkmann V. et al. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell Microbiol 2006; 8: 668-676.
16 Holdenrieder S, Stieber P, Bodenmuller H. et al. Nucleosomes in serum as a marker for cell death. Clin Chem Lab Med 2001; 39: 596-605.
17 Clark SR, Ma AC, Tavener SA. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nature Med 2007; 13: 463-469.
18 Bianchi M, Hakkim A, Brinkmann V. et al. Restoration of NET formation by gene therapy in CGD controls aspergillosis. Blood 2009; 114: 2619-2622.
19 Xu J, Zhang X, Pelayo R, Monestier M. et al. Extracellular histones are major mediators of death in sepsis. Nature Med 2009; 15: 1318-1321.
20 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
21 Semeraro F, Ammollo CT, Morrissey JH. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 2011; 118: 1952-1961.
22 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
23 Choi SH, Smith SA, Morrissey JH. Polyphosphate is a cofactor for the activation of factor XI by thrombin. Blood 2011; 118: 6730-6731.
24 Smith SA, Mutch NJ, Baskar D. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908.
25 Ammollo CT, Semeraro F, Xu J. et al. Extracellular histones increase plasma thrombin generation by impairing thrombomodulin-dependent protein C activation. J Thromb Haemost 2011; 9: 1795-1803.
26 Sills RH, Marlar RA, Montgomery RR. et al. Severe homozygous protein C deficiency. J Pediatrics 1984; 105: 409-413.
27 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-4746.
28 Antohi S, Popescu A. Lethal effect of protamine and histone on competent Bacillus subtilis cells. Mol Gen Genet 1979; 170: 345-349.
29 Hirsch JG. Bactericidal action of histone. J Exp Med 1958; 108: 925-944.
30 Kawasaki H, Iwamuro S. Potential roles of histones in host defense as antimicrobial agents. Infect Dis Drug Targets 2008; 8: 195-105.
31 Saffarzadeh M, Juenemann C, Queisser MA. et al. Neutrophil extracellular traps directly induce epithelial and endothelial cell death: a predominant role of histones. PLoS One 2012; 7: e32366.
32 Zeerleder S, Zwart B, Wuillemin WA. et al. Elevated nucleosome levels in systemic inflammation and sepsis. Crit Care Med 2003; 31: 1947-1951.
33 Lo YMD, Rainer TH, Chang LYS. et al. Plasma DNA as a prognostic marker in trauma patients. Clin Chem 2000; 46: 319-323.
34 Xu J, Zhang X, Monestier M. et al. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J Immunol 2011; 187: 2626-2631.
35 Loubele STBG, Spek CA, Leenders P. et al. Activated protein C protects against myocardial ischemia/reperfusion injury via inhibition of apoptosis and inflammation. Arterioscler Thromb Vasc Biol 2009; 29: 1087-1092.
36 Mizutani A, Okajima K, Uchiba M. et al. Activated protein C reduces ischemia/reperfusion-induced renal injury in rats by inhibiting leukocyte activation. Blood 2000; 95: 3781-3787.
37 Huang H, Evankovich J, Yan W. et al. Endogenous histones function as alarmins in sterile inflammatory liver injury through toll-like receptor 9. Hepatology 2011; 54: 999-1008.
38 Creasey AA. New potential therapeutic modalities: tissue factor pathway inhibitor. Sepsis 1999; 3: 173-182.
39 Massberg S, Grahl L, von Bruehl M-L. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nature Med 2010; 16: 887-897.
40 Holdenrieder S, Stieber P. Clinical use of circulating nucleosomes. Crit Rev Clin Lab Sci 2009; 46: 1-24.
41 Amoura Z, Piette JC, Bach JF. et al. The key role of nucleosomes in lupus. Arthritis Rheum 1999; 42: 833-843.
42 Toh C-H, Baluwa F, Zhang N. et al. Reduction of circulating histone toxicity is a major function of C-reactive protein after extensive tissue damage. Nature Precedings 2011; Available at http://precedings.nature.com/documents/6264/version/1. Accessed August 22, 2012.
43 Delvaeye M, Noris M, De Vriese A. et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N Engl J Med 2009; 361: 345-357.
44 Porcelli S, Morita CT, Brenner MB. CD1b restricts the response of human CD4-8-T lymphocytes to a microbial antigen. Nature 1992; 360: 593-597.
45 Oganesyan V, Oganesyan N, Terzyan S. et al. The crystal structure of the endothelial protein C receptor and a bound phospholipid. J Biol Chem 2002; 277: 24851-24854.
46 Dahlbäck B, Stenflo J. High molecular weight complex in human plasma between vitamin K-dependent protein S and complement component C4b-binding protein. Proc Natl Acad Sci USA 1981; 78: 2512-2516.
47 Bajzar L, Morser J, Nesheim M. TAFL, or plasma procarboxypeptidase B, couples the coagulation and fibrinolytic cascades through the thrombin-thrombomodulin complex. J Biol Chem 1996; 271: 16603-16608.
48 Myles T, Nishimura T, Yun TH. et al. Thrombin activatable fibrinolysis inhibitor: a potential regulator of vascular inflammation. J Biol Chem 2003; 278: 51059-51067.
49 Van de Wouwer M, Plaisance S, De Vriese A. et al. The lectin-like domain of thrombomodulin interferes with complement activation and protects against arthritis. Thromb Haemost 2006; 8: 1813-1824.