Лектиновый путь активации комплемента и его взаимодействия с системой свертывания крови и кининовой системой при церебральной ишемии

С. Фумагалли, М.-Г. ДеСимони

Department of Neuroscience, IRCCS – Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy.


  1. Kozarcanin H., Lood C., Munthe-Fog L., Sandholm K., Hamad O.A., Bengtsson A.A., et al. The lectin complement pathway serine proteases (MASPs) represent a possible crossroad between the coagulation and complement systems in thromboinflammation. J Thromb Haemost. 2016;14:531–545. doi: 10.1111/jth.13208.
  2. Kenawy H.I., Boral I., Bevington A. Complement-coagulation cross-talk: a potential mediator of the physiological activation ­of complement by low pH. Front Immunol. 2015;6:215. doi: 10.3389/fimmu.2015.00215.
  3. Conway E.M. Reincarnation of ancient links between coagulation and complement. J Thromb Haemost. 2015;13(suppl 1):S121–S132. doi:10.1111/jth.12950.
  4. Markiewski M.M., Nilsson B., Ekdahl K.N., Mollnes T.E., Lambris J.D. Complement and coagulation: strangers or partners ­in crime? Trends Immunol. 2007;28:184–192. doi: 10.1016/j.it.2007.02.006.
  5. Fumagalli S., Perego C., Pischiutta F., Zanier E.R., De Simoni M.G. ­The ischemic environment drives microglia and macrophage function. Front Neurol. 2015;6:81. doi: 10.3389/fneur.2015.00081.
  6. Orsini F., De Blasio D., Zangari R., Zanier E.R., De Simoni M.G. Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis. Front Cell Neurosci. 2014;8:380. ­doi: 10.3389/fncel.2014.00380.
  7. Ricklin D., Reis E.S., Lambris J.D. Complement in disease: a defence system turning offensive. Nat Rev Nephrol. 2016;12:383–401. ­doi: 10.1038/nrneph.2016.70.
  8. Alawieh A., Elvington A., Tomlinson S. Complement in the homeostatic and ischemic brain. Front Immunol. 2015;6:417. doi: 10.3389/fimmu.2015.00417.
  9. Endo Y., Matsushita M., Fujita T. New insights into the role of ficolins in the lectin pathway of innate immunity. Int Rev Cell Mol Biol. 2015;316:49–110. doi: 10.1016/bs.ircmb.2015.01.003.
  10. Esmon C. Do-all receptor takes on coagulation, inflammation. Nat Med. 2005;11:475–477. doi: 10.1038/nm0505-475.
  11. Matsushita M., Fujita T. Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease. J Exp Med. 1992;176:1497–1502.
  12. Pavlov V.I., Skjoedt M.O., Siow Tan Y., Rosbjerg A., Garred P., Stahl G.L. Endogenous and natural complement inhibitor attenuates myocardial injury and arterial thrombogenesis. Circulation. 2012;126:2227–2235. doi: 10.1161/CIRCULATIONAHA.112.123968.
  13. Castellano G., Melchiorre R., Loverre A., Ditonno P., Montinaro V., Rossini M., et al. Therapeutic targeting of classical and lectin pathways of complement protects from ischemia-reperfusion-induced renal damage. Am J Pathol. 2010;176:1648–1659. doi: 10.2353/ajpath.2010.090276.
  14. Møller-Kristensen M., Wang W., Ruseva M., Thiel S., Nielsen S., Takahashi K., et al. Mannan-binding lectin recognizes structures on ischaemic reperfused mouse kidneys and is implicated in tissue injury. Scand J Immunol. 2005;61:426–434. doi: 10.1111/j.1365-3083.2005.01591.x.
  15. McMullen M.E., Hart M.L., Walsh M.C., Buras J., Takahashi K., Stahl G.L. Mannose-binding lectin binds IgM to activate the lectin complement pathway in vitro and in vivo. Immunobiology. 2006;211:759–766. doi:10.1016/j.imbio.2006.06.011.
  16. Cervera A., Planas A.M., Justicia C., Urra X., Jensenius J.C., Torres F., et al. Genetically-defined deficiency of mannose-binding lectin is associated with protection after experimental stroke in mice and outcome in human stroke. PLoS One. 2010;5:e8433. doi: 10.1371/journal.pone.0008433.
  17. Füst G., Munthe-Fog L., Illes Z., Széplaki G., Molnar T., Pusch G., et al. Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. J Neuroinflammation. 2011;8:185. doi: 10.1186/1742-2094-8-185.
  18. Osthoff M., Katan M., Fluri F., Schuetz P., Bingisser R., Kappos L., et al. Mannose-binding lectin deficiency is associated with smaller infarction size and favorable outcome in ischemic stroke patients. PLoS One. 2011;6:e21338. doi: 10.1371/journal.pone.0021338.
  19. Zangari R., Zanier E.R., Torgano G., Bersano A., Beretta S., Beghi E., et al. Early ficolin-1 is a sensitive prognostic marker for functional outcome in ischemic stroke. J Neuroinflammation. 2016;13:16. ­doi: 10.1186/s12974-016-0481-2.
  20. Gesuete R., Storini C., Fantin A., Stravalaci M., Zanier E.R., Orsini F., et al. Recombinant C1 inhibitor in brain ischemic injury. Ann Neurol. 2009;66:332–342. doi: 10.1002/ana.21740.
  21. Orsini F., Villa P., Parrella S., Zangari R., Zanier E.R., Gesuete R., et al. Targeting mannose-binding lectin confers long-lasting protection with ­a surprisingly wide therapeutic window in cerebral ischemia. Circulation. 2012;126:1484–1494. doi: 10.1161/CIRCULATIONAHA.112.103051.
  22. Garred P., Larsen F., Seyfarth J., Fujita R., Madsen H.O. Mannose-binding lectin and its genetic variants. Genes Immun. 2006;7:85–94. doi:10.1038/sj.gene.6364283.
  23. Zanier E.R., Zangari R., Munthe-Fog L., Hein E., Zoerle T., Conte V., et al. Ficolin-3-mediated lectin complement pathway activation ­in patients with subarachnoid hemorrhage. Neurology. 2014;82:126–134. doi:10.1212/WNL.0000000000000020.
  24. Eisen D.P., Dean M.M., Boermeester M.A., Fidler K.J., Gordon A.C., Kronborg G., et al. Low serum mannose-binding lectin level increases the risk of death due to pneumococcal infection. Clin Infect Dis. 2008;47:510–516. doi: 10.1086/590006.
  25. Széplaki G., Szegedi R., Hirschberg K., Gombos T., Varga L., Karádi I., et al. Strong complement activation after acute ischemic stroke is associated with unfavorable outcomes. Atherosclerosis. 2009;204:315–320. doi:10.1016/j.atherosclerosis.2008.07.044.
  26. Song F.Y., Wu M.H., Zhu L.H., Zhang Z.Q., Qi Q.D., Lou C.L. Elevated serum mannose-binding lectin levels are associated with poor outcome after acute ischemic stroke in patients with type 2 diabetes. Mol Neurobiol. 2015;52:1330–1340. doi: 10.1007/s12035-014-8941-0.
  27. Zhang Z.G., Wang C., Wang J., Zhang Z., Yang Y.L., Gao L., ­et al. Prognostic value of mannose-binding lectin: 90-day outcome ­in patients with acute ischemic stroke. Mol Neurobiol. 2015;51:230–239. doi: 10.1007/s12035-014-8682-0.
  28. Frauenknecht V., Thiel S., Storm L., Meier N., Arnold M., Schmid J.P., et al. Plasma levels of mannan-binding lectin (MBL)-associated serine proteases (MASPs) and MBL-associated protein in cardio- and cerebrovascular diseases. Clin Exp Immunol. 2013;173:112–120. ­doi: 10.1111/cei.12093.
  29. Petitbarat M., Durigutto P., Macor P., Bulla R., Palmioli A., Bernardi A., et al. Critical role and therapeutic control of the lectin pathway ­of complement activation in an abortion-prone mouse mating. ­J Immunol. 2015;195:5602–5607. doi: 10.4049/jimmunol.1501361.
  30. Bossi F., Peerschke E.I., Ghebrehiwet B., Tedesco F. Cross-talk between the complement and the kinin system in vascular permeability. Immunol Lett. 2011;140:7–13. doi: 10.1016/j.imlet.2011.06.006.
  31. Honoré C., Rørvig S., Munthe-Fog L., Hummelshøj T., Madsen H.O., Borregaard N., et al. The innate pattern recognition molecule ficolin-1 is secreted by monocytes/macrophages and is circulating in human plasma. Mol Immunol. 2008;45:2782–2789. doi: 10.1016/j.molimm.2008.02.005.
  32. Liu Y., Endo Y., Iwaki D., Nakata M., Matsushita M., Wada I., et al. Human M-ficolin is a secretory protein that activates the lectin complement pathway. J Immunol. 2005;175:3150–3156.
  33. Rørvig S., Honore C., Larsson L.I., Ohlsson S., Pedersen C.C., Jacobsen L.C., et al. Ficolin-1 is present in a highly mobilizable subset of human neutrophil granules and associates with the cell surface after stimulation with fMLP. J Leukoc Biol. 2009;86:1439–1449. ­doi: 10.1189/jlb.1008606.
  34. Zhang J., Yang L., Ang Z., Yoong S.L., Tran T.T., Anand G.S., et al. Secreted M-ficolin anchors onto monocyte transmembrane G protein-coupled receptor 43 and cross talks with plasma C-reactive protein to mediate immune signaling and regulate host defense. J Immunol. 2010;185:6899–6910. doi: 10.4049/jimmunol.1001225.
  35. Fumagalli S., Ortolano F., De Simoni M.G. A close look at brain dynamics: cells and vessels seen by in vivo two-photon microscopy. Prog Neurobiol. 2014;121:36–54. doi: 10.1016/j.pneurobio.2014.06.005.
  36. del Zoppo G.J., Mabuchi T. Cerebral microvessel responses ­to focal ischemia. J Cereb Blood Flow Metab. 2003;23:879–894. ­doi: 10.1097/01. WCB.0000078322.96027.78.
  37. Rossi D.J., Brady J.D., Mohr C. Astrocyte metabolism and signaling during brain ischemia. Nat Neurosci. 2007;10:1377–1386. ­doi: 10.1038/nn2004.
  38. Selman L., Hansen S. Structure and function of collectin liver 1 (CL-L1) and collectin 11 (CL-11, CL-K1). Immunobiology. 2012;217:851–863. doi: 10.1016/j.imbio.2011.12.008.
  39. Takahashi K., Ohtani K., Larvie M., Moyo P., Chigweshe L., Van Cott E.M., et al. Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC). J Thromb Thrombolysis. 2014;38:331–338. doi: 10.1007/s11239-013-1042-5.
  40. Farrar C.A., Tran D., Li K., Wu W., Peng Q., Schwaeble W., et al. Collectin-11 detects stress-induced L-fucose pattern to trigger renal epithelial injury. J Clin Invest. 2016;126:1911–1925. doi: 10.1172/JCI83000.
  41. Watford W.T., Wright J.R., Hester C.G., Jiang H., Frank M.M. Surfactant protein A regulates complement activation. J Immunol. 2001;167:6593–6600.
  42. Wright J.R. Immunoregulatory functions of surfactant proteins. Nat Rev Immunol. 2005;5:58–68. doi: 10.1038/nri1528.
  43. Hein E., Garred P. The lectin pathway of complement and biocompatibility. Adv Exp Med Biol. 2015;865:77–92. doi: 10.1007/978-3-319-18603-0_5.
  44. Bratcher P.E., Gaggar A. Characterization and prevention ­of the adsorption of surfactant protein D to polypropylene. PLoS One. 2013;8:e73467. doi: 10.1371/journal.pone.0073467.
  45. Fan Q., Wang Y.E., Zhao X., Loo J.S., Zuo Y.Y. Adverse biophysical effects of hydroxyapatite nanoparticles on natural pulmonary surfactant. ACS Nano. 2011;5:6410–6416. doi: 10.1021/nn2015997.
  46. Hu F., Zhong Q., Gong J., Qin Y., Cui L., Yuan H. Serum surfactant protein D is associated with atherosclerosis of the carotid artery in patients ­on maintenance hemodialysis. Clin Lab. 2016;62:97–104.
  47. La Bonte L.R., Pavlov V.I., Tan Y.S., Takahashi K., Takahashi M., Banda N.K., et al. Mannose-binding lectin-associated serine protease-1 is a significant contributor to coagulation in a murine model ­of occlusive thrombosis. J Immunol. 2012;188:885–891. ­doi: 10.4049/jimmunol.1102916.
  48. Krarup A., Gulla K.C., Gál P., Hajela K., Sim R.B. The action ­of MBLassociated serine protease 1 (MASP1) on factor XIII and fibrinogen. Biochim Biophys Acta. 2008;1784:1294–1300. ­doi: 10.1016/j.bbapap.2008.03.020.
  49. Megyeri M., Makó V., Beinrohr L., Doleschall Z., Prohászka Z., Cervenak L., et al. Complement protease MASP-1 activates human endothelial cells: PAR4 activation is a link between complement and endothelial function. J Immunol. 2009;183:3409–3416. ­doi: 10.4049/jimmunol.0900879.
  50. Dobó J., Schroeder V., Jenny L., Cervenak L., Závodszky P., Gál P. Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation. Mol Immunol. 2014;61:69–78. doi: 10.1016/j.molimm.2014.05.013.
  51. Paréj K., Dobó J., Závodszky P., Gál P. The control of the complement lectin pathway activation revisited: both C1-inhibitor and antithrombin are likely physiological inhibitors, while α2-macroglobulin is not. Mol Immunol. 2013;54:415–422. doi: 10.1016/j.molimm.2013.01.009.
  52. Jenny L., Dobó J., Gál P., Schroeder V. MASP-1 of the complement system promotes clotting via prothrombin activation. Mol Immunol. 2015;65:398–405. doi: 10.1016/j.molimm.2015.02.014.
  53. Mosnier L.O., Bouma B.N. Regulation of fibrinolysis by thrombin activatable fibrinolysis inhibitor, an unstable carboxypeptidase B that unites the pathways of coagulation and fibrinolysis. Arterioscler Thromb Vasc Biol. 2006;26:2445–2453. doi: 10.1161/01.ATV.0000244680.14653.9a.
  54. Speth C., Rambach G., Würzner R., Lass-Flörl C., Kozarcanin H., Hamad O.A., et al. Complement and platelets: mutual interference in the immune network. Mol Immunol. 2015;67:108–118. ­doi: 10.1016/j.molimm.2015.03.244.
  55. de la Rosa X., Cervera A., Kristoffersen A.K., Valdés C.P., Varma H.M., Justicia C. et al. Mannose-binding lectin promotes local microvascular thrombosis after transient brain ischemia in mice. Stroke. 2014;45:1453–1459.
  56. Endo Y., Matsushita M., Fujita T. The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol. 2011;43:705–712. doi:10.1016/j.biocel.2011.02.003.
  57. Endo Y., Nakazawa N., Iwaki D., Takahashi M., Matsushita M., Fujita T. Interactions of ficolin and mannose-binding lectin with fibrinogen/fibrin augment the lectin complement pathway. J Innate Immun. 2010;2:33–42. doi: 10.1159/000227805.
  58. Tanio M., Kondo S., Sugio S., Kohno T. Trivalent recognition unit ­of innate immunity system: crystal structure of trimeric human M-ficolin fibrinogen-like domain. J Biol Chem. 2007;282:3889–3895. ­doi: 10.1074/jbc.M608627200.
  59. Meroni P.L., Borghi M.O., Raschi E., Tedesco F. Pathogenesis ­of antiphospholipid syndrome: understanding the antibodies. Nat Rev Rheumatol. 2011;7:330–339. doi: 10.1038/nrrheum.2011.52.
  60. Fischetti F., Durigutto P., Pellis V., Debeus A., Macor P., Bulla R., ­et al. Thrombus formation induced by antibodies to beta2-glycoprotein I is complement dependent and requires a priming factor. Blood. 2005;106:2340–2346. doi: 10.1182/blood-2005-03-1319.
  61. Pierangeli S.S., Girardi G., Vega-Ostertag M., Liu X., Espinola R.G., Salmon J. Requirement of activation of complement C3 and C5 ­for antiphospholipid antibody-mediated thrombophilia. Arthritis Rheum. 2005;52:2120–2124. doi: 10.1002/art.21157.
  62. Russell D.A., Wijeyaratne S.M., Gough M.J. Relationship of carotid plaque echomorphology to presenting symptom. Eur J Vasc Endovasc Surg. 2010;39:134–138. doi: 10.1016/j.ejvs.2009.11.003.
  63. Hellings W.E., Peeters W., Moll F.L., Piers S.R., van Setten J., Van der Spek P.J., et al. Composition of carotid atherosclerotic plaque is associated with cardiovascular outcome: a prognostic study. Circulation. 2010;121:1941–1950. doi: 10.1161/CIRCULATIONAHA.109.887497.
  64. Spagnoli L.G., Mauriello A., Sangiorgi G., Fratoni S., Bonanno E., Schwartz R.S., et al. Extracranial thrombotically active carotid plaque as a risk factor for ischemic stroke. JAMA. 2004;292:1845–1852. ­doi: 10.1001/jama.292.15.1845.
  65. Verhoeven B., Hellings W.E., Moll F.L., de Vries J.P., de Kleijn D.P., ­de Bruin P., et al. Carotid atherosclerotic plaques in patients with transient ischemic attacks and stroke have unstable characteristics compared with plaques in asymptomatic and amaurosis fugax patients. J Vasc Surg. 2005;42:1075–1081. doi: 10.1016/j.jvs.2005.08.009.
  66. Hovland A., Jonasson L., Garred P., Yndestad A., Aukrust P., Lappegård K.T., et al. The complement system and toll-like receptors as integrated players in the pathophysiology ­of atherosclerosis. Atherosclerosis. 2015;241:480–494. doi: 10.1016/j.atherosclerosis.2015.05.038.
  67. Bhakdi S., Torzewski M., Paprotka K., Schmitt S., Barsoom H., Suriyaphol P., et al. Possible protective role for C-reactive protein ­in atherogenesis: complement activation by modified lipoproteins halts before detrimental terminal sequence. Circulation. 2004;109:1870–1876. doi: 10.1161/01.CIR.0000124228.08972.26.
  68. Speidl W.S., Kastl S.P., Huber K., Wojta J. Complement ­in atherosclerosis: friend or foe? J Thromb Haemost. 2011;9:428–440. doi:10.1111/j.1538-7836.2010.04172.x.
  69. Haskard D.O., Boyle J.J., Mason J.C. The role of complement ­in atherosclerosis. Curr Opin Lipidol. 2008;19:478–482. doi: 10.1097/MOL.0b013e32830f4a06.
  70. Torzewski M., Bhakdi S. Complement and atherosclerosis-united ­to the point of no return? Clin Biochem. 2013;46:20–25. ­doi: 10.1016/j.clinbiochem.2012.09.012.
  71. Best L.G., Davidson M., North K.E., MacCluer J.W., Zhang Y., Lee E.T., et al. Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: the Strong Heart Study. Circulation. 2004;109:471–475. doi: 10.1161/01.CIR.0000109757.95461.10.
  72. Madsen H.O., Videm V., Svejgaard A., Svennevig J.L., Garred P. Association of mannose-binding-lectin deficiency with severe atherosclerosis. Lancet. 1998;352:959–960. doi: 10.1016/S0140-6736(05)61513-9.
  73. Øhlenschlaeger T., Garred P., Madsen H.O., Jacobsen S. Mannose-binding lectin variant alleles and the risk of arterial thrombosis ­in systemic lupus erythematosus. N Engl J Med. 2004;351:260–267. doi: 10.1056/NEJMoa033122.
  74. Káplár M., Sweni S., Kulcsár J., Cogoi B., Esze R., Somodi S., et al. Mannose-binding lectin levels and carotid intima-media thickness in type 2 diabetic patients. J Diabetes Res. 2016;2016:8132925. doi:10.1155/2016/8132925.
  75. Keller T.T., van Leuven S.I., Meuwese M.C., Wareham N.J., Luben R., Stroes E.S., et al. Serum levels of mannose-binding lectin and ­the risk of future coronary artery disease in apparently healthy men and women. Arterioscler Thromb Vasc Biol. 2006;26:2345–2350. ­doi: 10.1161/01.ATV.0000240517.69201.77.
  76. Rugonfalvi-Kiss S., Dósa E., Madsen H.O., Endrész V., Prohászka Z., Laki J., et al. High rate of early restenosis after carotid eversion endarterectomy in homozygous carriers of the normal mannose-binding lectin genotype. Stroke. 2005;36:944–948. doi: 10.1161/01.STR.0000160752.67422.18.
  77. Vengen I.T., Madsen H.O., Garred P., Platou C., Vatten L., Videm V. Mannosebinding lectin deficiency is associated with myocardial infarction: the HUNT2 study in Norway. PLoS One. 2012;7:e42113. doi: 10.1371/journal.pone.0042113.
  78. Longhi L., Orsini F., De Blasio D., Fumagalli S., Ortolano F., Locatelli M., ­et al. Mannose-binding lectin is expressed after clinical and experimental traumatic brain injury and its deletion is protective. Crit Care Med. 2014;42:1910–1918. doi: 10.1097/CCM.0000000000000399.
  79. De Blasio D., Fumagalli S., Longhi L., Orsini F., Palmioli A., Stravalaci M., et al. Pharmacological inhibition of mannose-binding lectin ameliorates neurobehavioral dysfunction following experimental traumatic brain injury

Похожие статьи

Бионика Медиа