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Platelet thrombus formation in eHUS is prevented by anti-MBL2


Autoři: R. I. Kushak aff001;  D. C. Boyle aff001;  I. A. Rosales aff001;  J. R. Ingelfinger aff001;  G. L. Stahl aff002;  M. Ozaki aff002;  R. B. Colvin aff001;  E. F. Grabowski aff001
Působiště autorů: Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, United States of America aff002;  Department of Emergency and Critical Care Medicine, St. Marianna University School of Medicine, Kawasaki, Japan aff003
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0220483

Souhrn

E. coli associated Hemolytic Uremic Syndrome (epidemic hemolytic uremic syndrome, eHUS) caused by Shiga toxin-producing bacteria is characterized by thrombocytopenia, microangiopathic hemolytic anemia, and acute kidney injury that cause acute renal failure in up to 65% of affected patients. We hypothesized that the mannose-binding lectin (MBL) pathway of complement activation plays an important role in human eHUS, as we previously demonstrated that injection of Shiga Toxin-2 (Stx-2) led to fibrin deposition in mouse glomeruli that was blocked by co-injection of the anti-MBL-2 antibody 3F8. However, the markers of platelet thrombosis in affected mouse glomeruli were not delineated. To investigate the effect of 3F8 on markers of platelet thrombosis, we used kidney sections from our mouse model (MBL-2+/+ Mbl-A/C-/-; MBL2 KI mouse). Mice in the control group received PBS, while mice in a second group received Stx-2, and those in a third group received 3F8 and Stx-2. Using double immunofluorescence (IF) followed by digital image analysis, kidney sections were stained for fibrin(ogen) and CD41 (marker for platelets), von-Willebrand factor (marker for endothelial cells and platelets), and podocin (marker for podocytes). Electron microscopy (EM) was performed on ultrathin sections from mice and human with HUS. Injection of Stx-2 resulted in an increase of both fibrin and platelets in glomeruli, while administration of 3F8 with Stx-2 reduced both platelet and fibrin to control levels. EM studies confirmed that CD41-positive objects observed by IF were platelets. The increases in platelet number and fibrin levels by injection of Stx-2 are consistent with the generation of platelet-fibrin thrombi that were prevented by 3F8.

Klíčová slova:

Electron microscopy – Fibrin – Glomeruli – Kidneys – Lectins – Mouse models – Platelets – Complement activation


Zdroje

1. Chandler WL, Jelacic S, Boster DR, Ciol MA, Williams GD, Watkins SL, et al. Prothrombotic coagulation abnormalities preceding the hemolytic–uremic syndrome. N Engl J Med 2002;346:23–32. doi: 10.1056/NEJMoa011033 11777999

2. George JN, Nester CM. Syndromes of Thrombotic Microangiopathy. N Engl J Med 2014;371:654–666. doi: 10.1056/NEJMra1312353 25119611

3. Bell BP, Goldoft M, Griffin PM, Davis MA, Gordon DC, Tarr PI, et al. A multistate outbreak of Escherichia coli O157:H7-associated bloody diarrhea and hemolytic uremic syndrome from hamburgers: the Washington experience. JAMA 1994;272:1349–1353. 7933395

4. Pennington H. Escherichia coli O157. Lancet 2010;376:1428–1435. doi: 10.1016/S0140-6736(10)60963-4 20971366

5. Buchholz U, Bernard H, Werber D, Böhmer MM, Remschmidt C, Wilking H, et al. German outbreak of Escherichia coli O104:H4 associated with sprouts. N Engl J Med 2011;365:1763–1770. doi: 10.1056/NEJMoa1106482 22029753

6. Tesh VL, Burris JA, Owens JW, Gordon VM, Wadolkowski EA, O'Brien AD, et al. Comparison of the relative toxicities of Shiga-like toxins type I and type II for mice. Infect Immun. 1993;61:3392–3402. 8335369

7. Tesh VL. Induction of apoptosis by Shiga toxins. Future Microbiol. 2010; 5:431–453. doi: 10.2217/fmb.10.4 20210553

8. Jenssen GR, Vold L, Hovland E, Bangstad HJ, Nygård K, Bjerre A. Clinical features, therapeutic interventions and long-term aspects of hemolytic-uremic syndrome in Norwegian children: a nationwide retrospective study from 1999–2008. BMC Infect Dis. 2016;16:285. doi: 10.1186/s12879-016-1627-7 27297224

9. Rodríguez de Córdoba S, Hidalgo MS, Pinto S, Tortajada A. Genetics of atypical hemolytic uremic syndrome (aHUS). Semin Thromb Hemost. 2014;40:422–430. doi: 10.1055/s-0034-1375296 24799305

10. Noris M, Remuzzi G. Atypical hemolytic-uremic syndrome. N Engl J Med. 2009;361:1676–1687. doi: 10.1056/NEJMra0902814 19846853

11. Noris M, Mescia F, Remuzzi G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol. 2012; 8:622–633. doi: 10.1038/nrneph.2012.195 22986360

12. Fakhouri F, Loirat C. Anticomplement Treatment in Atypical and Typical Hemolytic Uremic Syndrome. Semin Hematol. 2018;55:150–158. doi: 10.1053/j.seminhematol.2018.04.009 30032752

13. Kielstein JT, Beutel G, Fleig S, Steinhoff J, Meyer TN, Hafer C et al. Best supportive care and therapeutic plasma exchange with or without eculizumab in Shiga toxin-producing E. coli O104:H4 induced haemolytic–uraemic syndrome: an analysis of the German STEC–HUS registry. Nephrol Dial Transpl 2012; 27: 3807–3815.

14. Lapeyraque AL, Malina M, Fremeaux-Bacchi V, Boppel T, Kirschfink M, Oualha M et al. Eculizumab in Severe Shiga-Toxin- Associated HUS. N Engl J Med. 2011; 364:2561–2563. doi: 10.1056/NEJMc1100859 21612462

15. Rosbjerg A, Genster N, Pilely K, Gal P, Pál G, Halvorsen B, et al. Complementary Roles of the Classical and Lectin Complement Pathways in the Defense against Aspergillus fumigatus. Front Immunol. 2016;7:473. doi: 10.3389/fimmu.2016.00473 27857715

16. Pilely K, Rosbjerg A, Genster N, Gal P, Pál G, Halvorsen B et al. Cholesterol Crystals Activate the Lectin Complement Pathway via Ficolin-2 and Mannose-Binding Lectin: Implications for the Progression of Atherosclerosis. J Immunol. 2016;196:5064–5074. doi: 10.4049/jimmunol.1502595 27183610

17. Orsini F, Villa P, Parrella S, Zangari R, Zanier ER, 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 22879370

18. Pavlov VI, Tan YS, McClure EE, La Bonte LR, Zou C, Gorsuch WB et al. Human mannose-binding lectin inhibitor prevents myocardial injury and arterial thrombogenesis in a novel animal model. Am J Pathol. 2015;185:347–355. doi: 10.1016/j.ajpath.2014.10.015 25482922

19. Ali YM, Lynch NJ, Haleem KS, Fujita T, Endo Y, Hansen S et al. The lectin pathway of complement activation is a critical component of the innate immune response to pneumococcal infection. PLoS Pathog. 2012;8:e1002793.1. doi: 10.1371/journal.ppat.1002793 22792067

20. Ozaki M, Kang Y, Tan YS, Pavlov VI, Liu B, Boyle DC, et al. Human mannose-binding lectin inhibitor prevents Shiga toxin-induced renal injury. Kidney Int. 2016;90:774–782. doi: 10.1016/j.kint.2016.05.011 27378476

21. Kushak RI, Ozaki M, Rosales IA, Boyle DC, Colvin RB, Ingelfinger JR et al. Both platelets and fibrin deposition are increased in the glomeruli of mice after treatment with Shiga toxin-2. Kidney Int. 2017;92:1556–1557.

22. Zhao H, Wakamiya N, Suzuki Y, Hamonko MT, Stahl GL. Identification of human mannose binding lectin (MBL) recognition sites for novel inhibitory antibodies. Hybrid Hybridomics. 2002;21:25–36. doi: 10.1089/15368590252917610 11991814

23. National Research Council (US) Committee for the Update of the Guide for the Care and Use of Laboratory Animals. Guide for the Care and Use of Laboratory Animals. 8th edition. National Academies Press (US); Washington (DC): 2011. doi: 10.1258/la.2010.010031 21123303

24. Hoyt E Jr, Hawkins RJV, et al. Chapter 2—Mouse Physiology A2—Fox, James G. The Mouse in Biomedical Research (Second Edition). M. T. Davisson, F. W. Quimby, Barthold S. W., C. E. Newcomer and A. L. Smith. Burlington, Academic Press 2007: 23–XVI.

25. Zhai X. Y., Birn Jensen KB H., Thomsen JS, Andreasen A et al. Digital three-dimensional reconstruction and ultrastructure of the mouse proximal tubule." J Am Soc Nephrol 2003;14: 611–619. doi: 10.1097/01.asn.0000051725.00406.0c 12595496

26. Grabowski EF, Curran MA, Van Cott EM. Assessment of a cohort of primarily pediatric patients with a presumptive diagnosis of type 1 von Willebrand disease with a novel high shear rate, non-citrated blood flow device. Thromb Res. 2012;129:18–24.

27. Boyd B and Lingwood C. Verotoxin receptor glycolipid in human renal tissue. Nephron. 1989; 51:207–210. doi: 10.1159/000185286 2644572

28. Lingwood CA. Verotoxin-binding in human renal sections. Nephrol. 1994;66:21–28.

29. Porubsky S, Federico G, Müthing J, Jennemann R, Gretz N, Büttner S et al. Direct acute tubular damage contributes to Shiga toxin-mediated kidney failure. J Pathol. 2014;234:120–133. doi: 10.1002/path.4388 24909663

30. Eisenhauer PB, Chaturvedi P, Fine RE, Ritchie AJ, Pober JS, Cleary TG et al. Tumor necrosis factor alpha increases human cerebral endothelial cell Gb3 and sensitivity to Shiga toxin. Infect. Immun. 2001; 69:1889–1894. doi: 10.1128/IAI.69.3.1889-1894.2001 11179369

31. Stricklett PK, Hughes AK, Ergonul Z, Kohan DE. Molecular basis for up-regulation by inflammatory cytokines of Shiga toxin 1 cytotoxicity and globotriaosylceramide expression. J. Infec. Dis. 2002;186:976–982.

32. Grabowski EF, Kushak RI, Liu B, Ingelfinger JR. Shiga toxin downregulates tissue factor pathway inhibitor, modulating an increase in the expression of functional tissue factor on endothelium. Thromb Res. 2013;131:521–528. doi: 10.1016/j.thromres.2013.03.006 23642803

33. Grabowski EF, Liu B, Gerace MR, Kushak RI, Ingelfinger JR. Shiga toxin-1 Decreases Endothelial Cell Tissue Factor Pathway Inhibitor Not Co-localized with Tissue Factor on the Cell Membrane. Thromb Res. 2015;135:1214–1217. doi: 10.1016/j.thromres.2015.03.018 25864889

34. van Setten PA, Monnens LA, Verstraten RG, van den Heuvel LPvan Hinsbergh VW. Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood. 1996;88:174–183. 8704172

35. Karpman D, Papadopoulou D, Nilsson K, Sjögren AC, Mikaelsson C, Lethagen S. Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood. 200197:3100–3008.

36. Nestoridi E, Tsukurov O, Kushak RI, Ingelfinger JR, Grabowski EFet al. Shiga toxin enhances functional tissue factor on human glomerular endothelial cells: implications for the pathophysiology of hemolytic uremic syndrome. J Thromb Haemost. 2005;3:752–762. doi: 10.1111/j.1538-7836.2005.01205.x 15842359

37. Morigi M, Galbusera M, Gastoldi S, Locatelli M, Buelli S, Pezzotta A et al. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J Immunol. 2011187:172–180.

38. Thurman JM, Marians R, Emlen W, Wood S, Smith C, Akana H, et al. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin J Am Soc Nephrol. 2009;12:1920–1924.

39. Orth D, Khan AB, Naim A, Grif K, Brockmeyer J, Karch H et al. Shiga Toxin Activated and Binds Factor H: Evidence for an Active Role of complement in Hemolytic Uremic Syndrome. J Immunol. 2009; 182: 6394–6400. doi: 10.4049/jimmunol.0900151 19414792

40. Jenny L, Dobó J, Gál P, Pál G, Lam WA, Schroeder V. MASP-1 of the complement system enhances clot formation in a microvascular whole blood flow model. PLoS One. 2018; 11:13:e0191292.

41. Vakeva AP, Agah A, Rollins SA, Matis LA, Li L, Stahl GL. Myocardial infarction and apoptosis after myocardial ischemia and reperfusion: role of the terminal complement components and inhibition by anti-C5 therapy. Circulation. 1998; 97:2259–2267. doi: 10.1161/01.cir.97.22.2259 9631876

42. La Bonte LR, Pavlov VI, Tan YS, Takahashi K, Takahashi M, Banda NK 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 22156595

43. Huang J, Motto DG, Bundle DR, Sadler JE. Shiga toxin B subunits induce VWF secretion by human endothelial cells and thrombotic microangiopathy in ADAMTS13-deficient mice. Blood. 2010;116:3653–3659. doi: 10.1182/blood-2010-02-271957 20644116

44. Tsai HM, Chandler WL, Sarode R, Hoffman R, Jelacic S, Habeeb RL et al. von Willebrand factor and von Willebrand factor-cleaving metalloprotease activity in Escherichia coli O157:H7-associated hemolytic uremic syndrome. Pediatr Res. 2001;49:653–659. doi: 10.1203/00006450-200105000-00008 11328948

45. Nguyen TC, Cruz MA, Carcillo JA. Thrombocytopenia-Associated Multiple Organ Failure and Acute Kidney Injury. Crit Care Clin. 2015;31;661–674. doi: 10.1016/j.ccc.2015.06.004 26410136

46. Hosler GA, Cusumano AM, Hutchins GM. Thrombotic thrombocytopenic purpura and hemolytic uremic syndrome are distinct pathologic entities. A review of 56 autopsy cases. Arch Pathol Lab Med. 2003;127:834–839. doi: 10.1043/1543-2165(2003)127<834:TTPAHU>2.0.CO;2 12823037


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