Extracellular nucleic acids as novel alarm signals in the vascular system

Summary

Upon vascular injury or tissue damage, the exposed intracellular material such as nucleic acids, histones and other macromolecules may come into contact with vessel wall cells and circulating blood cells and may thus, have an enduring influence on wound healing and body defence processes. This short review summarizes recent work related to extracellular DNA and RNA and their role as prominent alarm signals and inducers of different defence reactions related to innate immunity and thrombus formation. Of particular importance are DNA-histone complexes (nucleosome material) that, having been expelled during stimulation of the neutro-phils, not only trap and eliminate bacteria but also promote thrombus formation in the arterial and venous system. Consequently therefore, the administration of DNase exhibits strong antithrombotic functions. Similarly, extracellular RNA provokes activation of the contact phase system of blood coagulation and, by interacting with specific proteins and cytokines, it promotes vascular permeability and oedema formation. The development of RNA-mediated thrombosis, vasogenic oedema or proinflammatory responses are counteracted by the administration of RNase1 in several pathogenetic animal models. Thus, extra cellular nucleic acids appear not only to function as host alarm signals that serve to amplify the defence response, but they also provide important links to thrombus formation as part of the innate immune system.

Zusammenfassung

Bei Gefäßverletzung oder Gewebeschaden kommt es zur Freisetzung von intrazellulärem Material wie Nukleinsäuren, Histonen und anderen Makromolekülen, die in Kontakt mit Zellen der Gefäßwand und zirkulierenden Blutzellen treten und dabei die Prozesse der Wundheilung nachhaltig beeinflussen kön-nen. In dieser Übersicht sollen die aktuellen Kenntnisse zur Rolle von extrazellulärer DNA und RNA in der Thrombusbildung und ihre Funktionen als neue Alarmsignale in der angeborenen Immunität, u. a. als Induktoren von Abwehrreaktionen, dargestellt werden. Hierbei ist das nach Stimulierung von Neutro-philen aus diesen Zellen katapultierte Nukleo somenmaterial (DNA-Histon-Komplexe) von Bedeutung, das nicht nur einen neuen Mechanismus der extrazellulären Ab tötung von Bakterien darstellt, sondern auch maß-geblich zur Thrombosebildung im arteriellen wie im venösen System beiträgt. Konsequenterweise hat die Gabe von DNase eine prominente antithrombotische Wirkung. In ähnlicher Weise bewirkt extrazelluläre RNA nicht nur eine signifikante Aktivierung der Kontakt-phase der Blutgerinnung, sondern führt auch zur Erhöhung der Gefäßpermeabilität und Ödembildung aufgrund spezifischer Wechselwirkungen mit Proteinen und Zyto kinen. So gelingt es, durch Verabreichung von RNase1 in verschiedenen Pathogenitäts modellen in der Maus und Ratte die Thrombus- und Ödembildung sowie Entzündungsprozesse einzudämmen bzw. zu verhindern. Die extra-zellulären Funktionen von Nukleinsäuren sind nicht nur für die molekulare Alarmgebung von Bedeutung und führen zur Verstärkung von Abwehrreaktionen, sondern stellen auch wichtige Verbindungen zur Thrombusbildung als Teil der angeborenen Immunität her.

Keywords

Innate immunity - ribonuclease - desoxyribo-nuclease - thrombosis - extracellular RNA - neutrophil-extracellular-traps

Schlüsselwörter

Angeborene Immunität - Ribonuklease - Desoxy ribonuklease - Thrombose - extrazelluläre RNA - Neutrophil-Extracellular-Traps

• References

• 1 Mandel P, Metais P. Les acides nucleíques du plasma sangiun chez l’homme. C R Acad Sci 1947; 112: 16.
• 2 Tan EM, Schur PH, Carr RI. et al. Deoxyribonucleic (DNA) and antibodies to DNA in the serum of patients with systemic lupus erythematosus. J Clin Invest 1966; 45: 1732-1740.
• 3 Wieczorek AJ, Rhyner C, Block LH. Isolation and characterization of an RNA-proteolipid complex associated with the malignant state in humans. Proc Natl Acad Sci USA 1985; 82: 3455-3459.
• 4 Kopreski MS, Benko FA, Gocke CD. Circulating RNA as a tumor marker: detection of 5T4 mRNA in breast and lung cancer patient serum. Ann NY Acad Sci 2001; 945: 172-178.
• 5 Garcia-Olmo DC, Ruiz-Piqueras R, Garcia-Olmo D. Circulating nucleic acids in plasma and serum (CNAPS) and its relation to stem cells and cancer metastasis: state of the issue. Histol Histopathol 2004; 19: 575-583.
• 6 Reddi KK, Holland JF. Elevated serum ribonuclease in patients with pancreatic cancer. Proc Natl Acad Sci USA 1976; 73: 2308-2310.
• 7 Rosi A, Guidoni L, Luciani AM. et al. RNA-lipid complexes released from the plasma membrane of human colon carcinoma cells. Cancer Lett 1988; 39: 153-160.
• 8 Sisco KL. Is RNA in serum bound to nucleoprotein complexes?. Clin Chem 2000; 47: 1744-1745.
• 9 Stroun M, Anker P, Beljanski M. et al. Presence of RNA in the nucleoprotein complex spontaneously released by human lymphocytes and frog auricles in culture. Cancer Res 1978; 38: 3546-3554.
• 10 Ekström K, Valadi H, Sjöstrand M. et al. Characterization of mRNA and microRNA in human mast cell-derived exosomes and their transfer to other mast cells and blood CD34 progenitor cells. J Extracell Vesicles 2012; 01: 1-12.
• 11 Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to make NETs. Nat Rev Microbiol 2007; 05: 577-582.
• 12 Brinkmann V, Reichard U, Goosmann C. et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532-1535.
• 13 Urban CF, Ermert D, Schmid M. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLoS Pathog 2009; 05: e1000639.
• 14 Oehmcke S, Mörgelin M, Herwald H. Activation of the human contact system on neutrophil extracellular traps. J Innate Immun 2009; 01: 225-230.
• 15 Massberg S, Grahl L, von Brühl ML. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat Med 2010; 16: 887-896.
• 16 Demers M, Krause DS, Schatzberg D. et al. Cancers predispose neutrophils to release extracellular DNA traps that contribute to cancer-associated thrombosis. Proc Natl Acad Sci USA 2012; 109: 13076-13081.
• 17 Kannemeier C, Shibamiya A, Nakazawa F. et al. Extracellular RNA constitutes a natural procoagulant cofactor in blood coagulation. Proc Natl Acad Sci USA 2007; 104: 6388-6393.
• 18 Fischer S, Gerriets T, Wessels C. et al. Extracellular RNA mediates endothelial-cell permeability via vascular endothelial growth factor. Blood 2007; 110: 2457-2465.
• 19 Romisch J, Vermohlen S, Feussner A. et al. The FVII activating protease cleaves single-chain plasminogen activators. Haemostasis 1999; 29: 292-299.
• 20 Muhl L, Nykjaer A, Wygrecka M. et al. Inhibition of PDGF-BB by factor VII-activating protease (FSAP) is neutralized by protease nexin-1 and the FSAP-inhibitor complexes are internalized via LRP. Biochem J 2007; 404: 191-196.
• 21 Zeerleder S, Zwart B, te Velthuis H. et al. Nucleosome-releasing factor: a new role for factor VII-activating protease (FSAP). FASEB J 2008; 22: 4077-4084.
• 22 Nakazawa F, Kannemeier C, Shibamiya A. et al. Extracellular RNA is a natural cofactor for the (auto-)activation of Factor VII-activating protease (FSAP). Biochem J 2005; 385: 831-838.
• 23 Altincicek B, Shibamiya A, Trusheim H. et al. A positively charged cluster in the epidermal growth factor-like domain of factor VII-activating protease (FSAP) is essential for polyanion binding. Biochem J 2006; 394: 687-692.
• 24 Deindl E, Fischer S, Preissner KT. New directions in inflammation and immunity: the multi-functional role of the extracellular RNA/RNase system. Indian J Biochem Biophys 2009; 46: 461-466.
• 25 Maas C, Govers-Riemslag JW, Bouma B. et al. Misfolded proteins activate factor XII in humans, leading to kallikrein formation without initiating coagulation. J Clin Invest 2008; 118: 3208-3218.
• 26 Smith SA, Mutch NJ, Baskar D. et al. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci USA 2006; 103: 903-908.
• 27 Cochrane CG, Griffin JH. The biochemistry and pathophysiology of the contact system of plasma. Adv Immunol 1982; 33: 241-306.
• 28 Hojima Y, Cochrane CG, Wiggins RC. et al. In vitro activation of the contact (Hageman factor) system of plasma by heparin and chondroitin sulfate. Blood 1984; 63: 1453-1459.
• 29 Ratnoff OD, Saito H. Surface-mediated reactions. Curr Top Hematol 1979; 02: 1-57.
• 30 Colman RW, Schmaier AH. Contact system: a vascular biology modulator with anticoagulant, profibrinolytic, antiadhesive, and proinflammatory attributes. Blood 1997; 90: 3819-3843.
• 31 Müller F, Mutch NJ, Schenk WA. et al. Platelet polyphosphates are proinflammatory and procoagulant mediators in vivo. Cell 2009; 139: 1143-1156.
• 32 Clark SR, Ma AC, Tavener SA. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat Med 2007; 13: 463-469.
• 33 McDonald B, Urrutia R, Yipp BG. et al. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 2012; 12: 324-333.
• 34 Zeerleder S, Stephan F, Emonts M. et al. Circulating nucleosomes and severity of illness in children suffering from meningococcal sepsis treated with protein C. Crit Care Med 2012; 40: 3224-3229.
• 35 Xu J, Zhang X, Pelayo R. et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009; 15: 1318-1321.
• 36 Saffarzadeh M, Juenemann C, Queisser MA. et al. Neutrophil extracellular traps directly induce epithelial and endothelial death: a predominant role of histones. Plos ONE 2012; 07: e32366.
• 37 Von Brühl ML, Stark K, Steinhart A. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J Exp Med 2012; 209: 819-835.
• 38 Brill A, Fuchs TA, Savchenko AS. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J Thromb Haemost 2012; 10: 1777-1783.
• 39 Fuchs TA, Brill A, Duerschmied D. et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010; 107: 15880-15885.
• 40 De Meyer SF, Suidan GL, Fuchs TA. et al. Extracellular chromatin is an important mediator of ischemic stroke in mice. Arterioscler Thromb Vasc Biol 2012; 32: 1884-1891.
• 41 Gansler J, Jaax M, Leiting S. et al. Structural requirements for the procoagulant activity of nucleic acids. Plos ONE 2012; 07: e50399.
• 42 Paul A, Avci-Adali M, Neumann B. et al. Aptamers influence the hemostatic system by activating the intrinsic coagulation pathway in an in vitro Chandler-Loop model. Clin Appl Thromb Hemost 2010; 16: 161-169.
• 43 Fischer S, Nishio M, Peters SC. et al. Signaling mechanism of extracellular RNA in endothelial cells. FASEB J 2009; 23: 2100-2109.
• 44 Hashimoto C, Hudson KL, Anderson KV. The Toll gene of Drosophila, required for dorsal-ventral embryonic polarity, appears to encode a transmembrane protein. Cell 1988; 52: 269-279.
• 45 Medzhitov R, Preston-Hurburt P, Janeway CAJA. A human homologue of the Drophila Toll protein signals activation of adaptive immunity. Nature 1997; 368: 394-397.
• 46 Rock RL, Hardman G, Timans JC. et al. A family of human receptors structurally related to Drosophila Toll. Proc Natl Acad Sci USA 1998; 95: 588-593.
• 47 Palaniyar N, Nadesalingam J, Clark H. et al. Nucleid acid is a novel ligand for innate, immune pattern recognition collectins surfactant proteins A and D and mannose-binding lectin. J Biol Chem 2004; 279: 32728-32736.
• 48 Medzhitov R. Toll like receptors and innate immunity. Nat Rev Immunol 2001; 01: 135-145.
• 49 Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006; 124: 783-801.
• 50 Barrat FJ, Meeker T, Gregorio J. et al. Nucleic acids of mammalian origin can act as endogenous ligands for Toll-like receptors and may promote systemic lupus erythematosus. J Exp Med 2005; 202: 1131-1139.
• 51 Bradly JR. TNF-mediated inflammatory disease. J Pathol 2008; 214: 149-160.
• 52 Moncellin S, Nitti D. TNF and cancer: the two sides of the coin. Front Biosci 2008; 13: 2774-2783.
• 53 Black RA, Rauch CT, Kozlosky CJ. et al. A metalloproteinase disintegrin that releases tumor-necrosis factor-alpha from cells. Nature 1997; 385: 729-733.
• 54 Peschon JJ, Slack JL, Reddy P. et al. An essential role for ectodomain shedding in mammalian development. Science 1998; 282: 1281-1284.
• 55 Göoz M, Göoz P, Luttrell LM. et al. 5-HT2A receptor induces ERK phosphorylation and proliferation through ADAM-17 tumor necrosis factoralpha-converting enzyme (TACE) activation and heparin-bound epidermal growth factor-like growth factor (HB-EGF) shedding in mesangial cells. J Biol Chem 2006; 281: 21004-21012.
• 56 Blobel CP. ADAMS: key components in EGFR signaling and development. Nat Rev Mol Cell Biol 2005; 06: 32-43.
• 57 Fischer S, Grantzow T, Pagel J-I. et al. Extracellular RNA promotes leukocyte recruitment in the vascular system by mobilizing proinflammatory cytokines. Thromb Haemost 2012; 108: 730-741.
• 58 Landre JBP, Hewett PW, Olivot J-M. et al. Human endothelial cells selectively express large amounts of pancreatic-type ribonuclease (RNase 1). J Cell Biochem 2002; 86: 540-552.
• 59 Moenner M, Hatzi E, Bader J. Secretion of ribonucleases by normal and immortalized cells grown in serum-free culture conditions. In Vitro Cell Dev Biol Anim 1997; 33: 553-61.
• 60 Weickmann JL, Olson EM, Glitz DG. Immunological assay of pancreatic ribonuclease in serum as an indicator of pancreatic cancer. Cancer Res 1984; 44: 1682-1687.
• 61 Beintema JJ, Wietzes P, Weickmann JL. et al. The amino acid sequence of human pancreatic ribonuclease. Anal Biochem 1984; 136: 48-64.
• 62 Weickmann JL, Elson M, Glitz DG. Purification and characterization of human pancreatic ribonuclease. Biochemistry 1981; 20: 1272-1278.
• 63 Ribo M, Benito A, Canals A. et al. Purification of engineered human pancreatic ribonuclease. Methods Enzymol 2001; 341: 221-234.
• 64 Beintema JJ, Hofsteenge J, Iwana M. et al. Amino acid sequence of the nonsecretory ribonuclease of human urine. Biochemistry 1988; 27: 4530-4538.
• 65 Bläser J, Triebel S, Kopp C. et al. A highly sensitive immunoenzymometric assay for the determination of angiogenin. Eur J Clin Chem Clin Biochem 1993; 31: 513-516.
• 66 Leland PA, Staniszewski KE, Park C. et al. The ribonucleolytic activity of angiogenin. Biochemistry 2002; 41: 1343-1350.
• 67 Fett JW, Strydom DJ, Lobb RR. et al. Isolation and characterization of angiogenin, an angiogenic protein from human carcinoma cells. Biochemistry 1985; 24: 5480-5486.
• 68 Fett JW, Bethune JL, Vallee BL. Induction of angiogenesis by mixtures of two angiogenic proteins, angiogenin and acidic fibroblast growth factor, in the chicken chorioallantoic membrane. Biochem Biophys Res Commun 1987; 146: 1122-1131.
• 69 Gaur D, Swaminathan S, Batra JK. Interaction of human pancreatic ribonuclease with human ribonuclease inhibitor: generation of inhibitor-resistant cytotoxic variants. J Biol Chem 2001; 276: 24978-24984.
• 70 Fischer S, Nishio M, Dadkhahi S. et al. Expression and localisation of vascular ribonucleases in endothelial cells. Thromb Haemost 2011; 105: 345-355.
• 71 Walberer M, Tschernatsch M, Fischer S. et al. RNase therapy assessed by magnetic resonance imaging reduces cerebral edema and infarction size in acute stroke. Curr Neurovasc Res 2009; 06: 12-19.
• 72 Engelmann B, Massberg S. Thrombosis as an intravascular effector of innate immunity. Nat Rev Immunol 2013; 13: 34-45.