Нейтрофильные внеклеточные ловушки (НВЛ) при заболеваниях почек: роль в патогенезе и возможности НВЛ-регулирующей терапии

Чрезмерные неконтролируемые воспалительные и иммунные реакции часто приводят к развитию острых и хронических форм повреждения различных органов, в том числе и почек. Нейтрофилы – это клетки врождённой иммунной системы, которые являются первыми клеточными эффекторами в защите хозяина от множества патогенов, включая бактерии, грибы и простейшие. Как наиболее многочисленные лейкоциты, присутствующие в крови человека, нейтрофилы рано мигрируют в очаги воспаления или повреждения тканей, где играют значительную роль в развитии воспаления, рекрутировании иммунных клеток, удалении патогенов и восстановлении тканей. Нейтрофилы, кроме того, продуцируют провоспалительные цитокины и высвобождают в процессе, названном нетоз, сетчатые структуры, состоящие из ДНК и гранулярных белков, известные как нейтрофильные внеклеточные ловушки (НВЛ). НВЛ потенциально токсичны, способствуют активации аутоиммунных процессов, повреждению эндотелия сосудов, следовательно повреждению клубочков и сформированию фиброза почек. Данные многочисленных исследований показывают, что дисбаланс между продукцией и клиренсом НВЛ пагубно сказывается на функционировании почек. Следовательно, стратегии, направленные на модуляцию процессов, связанных с НВЛ, могут иметь благоприятное прогностическое значение. В обзоре обсуждается роль нетоза в патогенезе заболеваний почек, приведены ассоциированные с НВЛ механизмы повреждения тканей и терапевтические возможности НВЛ-регулирующей терапии.

1. Tecklenborg J, Clayton D, Siebert S, Coley SM. The role of the immune system in kidney disease. Clin Exp Immunol 2018;192:142–150. https://doi.org/10.1111/cei.13119

2. Kato S, Chmielewski M, Honda H et al. Aspects of immune dysfunction in end-stage renal disease. Clin J Am Soc Nephrol 2008;3:1526–1533. https://doi.org/10.2215/CJN.00950208

3. Mastroianni-Kirsztajn G, Hornig N, Schlumberger W. Autoantibodies in renal diseases–Clinical significance and recent developments in serological detection. Front Immunol 2015;6:221. https://doi.org/10.3389/fimmu.2015.00221

4. Meng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol 2014;10:493–503. https://doi.org/10.1038/nrneph.2014.114

5. Brinkmann V, Reichard U, Goosmann C et al. Neutrophil extracellular traps kill bacteria. Science 2004;303:1532–1535. https://doi.org/10.1126/science.1092385

6. Mulay SR, Linkermann A, Anders HJ. Necroinflammation in Kidney Disease. J Am Soc Nephrol 2016;27:27–39. https://doi.org/10.1681/ASN.2015040405

7. Nakazawa D, Kumar SV, Marschner J et al. Histones and Neutrophil Extracellular Traps Enhance Tubular Necrosis and Remote Organ Injury in Ischemic AKI. J Am Soc Nephrol 2017;28:1753–1768. https://doi.org/10.1681/ASN.2016080925

8. Schönermarck U, Csernok E, Gross WL. Pathogenesis of anti-neutrophil cytoplasmic antibody-associated vasculitis: Challenges and solutions 2014. Nephrol Dial Transplant 2015;30:i46– i52. https://doi.org/10.1093/ndt/gfu398

9. Delgado-Rizo V, Martínez-Guzmán MA, Iñiguez-Gutierrez L et al. Neutrophil Extracellular Traps and Its Implications in Inflammation: An Overview. Front Immunol 2017;8:81. https://doi.org/10.3389/fimmu.2017.00081

10. Clancy DM, Henry CM, Sullivan GP, Martin SJ. Neutrophil extracellular traps can serve as platforms for processing and activation of IL-1 family cytokines. FEBS J 2017;284:1712–1725. https://doi.org/10.1111/febs.14075

11. Fuchs TA, Abed U, Goosmann C et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007;176:231–241. https://doi.org/10.1083/jcb.200606027

12. Yipp BG, Kubes P. NETosis: How vital is it? Blood 2013;122:2784–2794. https://doi.org/10.1182/blood-2013-04-457671

13. Jorgensen I, Rayamajhi M, Miao EA. Programmed cell death as a defence against infection. Nat Rev Immunol 2017;17:151–164. https://doi.org/10.1038/nri.2016.147

14. Petretto A, Bruschi M, Pratesi F et al. Neutrophil extracellular traps (NET) induced by different stimuli: A comparative proteomic analysis. PLoS ONE 2019;14:e0218946. https://doi.org/10.1371/journal.pone.0218946

15. Leshner M, Wang S, Lewis C et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front Immunol 2012;3:307. https://doi.org/10.3389/fimmu.2012.00307

16. Wang Y, Li M, Stadler S et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J Cell Biol 2009;184:205–213. https://doi.org/10.1083/jcb.200806072

17. Keshari RS, Jyoti A, Dubey M et al. Cytokines induced neutrophil extracellular traps formation: Implication for the inflammatory disease condition. PLoS ONE 2012;7:e48111. https://doi.org/10.1371/journal.pone.0048111

18. Neeli I, Radic M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release. Front Immunol 2013;4:38. https://doi.org/10.3389/fimmu.2013.00038

19. Wang Y, Wang Y, Wu J et al. PRAK Is Required for the Formation of Neutrophil Extracellular Traps. Front Immunol 2019;4:1252. https://doi.org/10.3389/fimmu.2019.01252

20. 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. https://doi.org/10.1038/nm1565

21. Yipp BG, Petri B, Salina D et al. Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat Med 2012;18:1386–1393. https://doi.org/10.1038/nm.2847

22. Pilsczek FH, Salina D, Poon KK et al. A novel mechanism of rapid nuclear neutrophil extracellular trap formation in response to Staphylococcus aureus. J Immunol 2010;185:7413–7425. https://doi.org/10.4049/jimmunol.1000675

23. Itakura A, McCarty OJ. Pivotal role for the mTOR pathway in the formation of neutrophil extracellular traps via regulation of autophagy. Am J Physiol-Cell Physiol 2013;305:C348–C354. https://doi.org/10.1152/ajpcell.00108.2013

24. Park SY, Shrestha S, Youn YJ et al. Autophagy Primes Neutrophils for Neutrophil Extracellular Trap Formation during Sepsis. Am J Respir Crit Care Med 2017;196:577–589. https://doi.org/10.1164/rccm.201603-0596OC

25. McInturff AM, Cody MJ, Elliott EA et al. Mammalian target of rapamycin regulates neutrophil extracellular trap formation via induction of hypoxia-inducible factor 1 alpha. Blood 2012;120:3118–3125. https://doi.org/10.1182/blood-2012-01-405993

26. Sawhney S, Fraser SD. Epidemiology of AKI: Utilizing Large Databases to Determine the Burden of AKI. Adv Chronic Kidney Dis 2017;24:194–204. https://doi.org/10.1053/j.ackd.2017.05.001

27. Ham A, Rabadi M, Kim M et al. Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. Am J Physiol Ren Physiol 2014;307:F1052–F1062. https://doi.org/10.1152/ajprenal.00243.2014

28. Raup-Konsavage WM, Wang Y, Wang WW et al. Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int 2018;93:365–374. https://doi.org/10.1016/j.kint.2017.08.014

29. Jansen MP, Emal D, Teske GJ et al. Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps. Kidney Int 2017;91:352–364. https://doi.org/10.1016/j.kint.2016.08.006

30. Ramos MV, Mejias MP, Sabbione F et al. Induction of Neutrophil Extracellular Traps in Shiga Toxin-Associated Hemolytic Uremic Syndrome. J Innate Immun 2016;8:400–411. https://doi.org/10.1159/000445770

31. Mistry P, Kaplan MJ. Cell death in the pathogenesis of systemic lupus erythematosus and lupus nephritis. Clin Immunol 2017;185:59–73. https://doi.org/10.1016/j.clim.2016.08.010

32. Hakkim A, Fürnrohr BG, Amann K et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc Natl Acad Sci USA 2010;107:9813–9818. https://doi.org/10.1073/pnas.0909927107

33. Lood C, Blanco LP, Purmalek MM et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat Med 2016;22:146–153. https://doi.org/10.1038/nm.4027

34. Bonaventura A, Liberale L, Carbone F et al. The Pathophysiological Role of Neutrophil Extracellular Traps in Inflammatory Diseases. Thromb Haemost 2018;118:6–27. https://doi.org/10.1160/TH17-09-0630

35. Villanueva E, Yalavarthi S, Berthier CC et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J Immunol 2011;187:538–552. https://doi.org/10.4049/jimmunol.1100450

36. Yasutomo K, Horiuchi T, Kagami S et al. Mutation of DNASE1 in people with systemic lupus erythematosus. Nat Genet 2001;28:313–314. https://doi.org/10.1038/91070

37. Guo R, Tu Y, Xie S et al. A Role for Receptor-Interacting Protein Kinase-1 in Neutrophil Extracellular Trap Formation in Patients with Systemic Lupus Erythematosus: A Preliminary Study. Cell Physiol Biochem 2018;45:2317–2328. https://doi.org/10.1159/000488179

38. Barnado A, Crofford LJ, Oates JC. At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases. J Leukoc Biol 2016;99:265–278. https://doi.org/10.1189/jlb.5BT0615-234R

39. Carmona-Rivera C, Zhao W, Yalavarthi S, Kaplan MJ. Neutrophil extracellular traps induce endothelial dysfunction in systemic lupus erythematosus through the activation of matrix metalloproteinase-2. Ann Rheum Dis 2015;74:1417–1424. https://doi.org/10.1136/annrheumdis-2013-204837

40. Lande R, Ganguly D, Facchinetti V et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci Transl Med 2011;3:73ra19. https://doi.org/10.1126/scitranslmed.3001180

41. Schett G, Smole J, Zimmermann C et al. The autoimmune response to chromatin antigens in systemic lupus erythematosus: Autoantibodies against histone H1 are a highly specific marker for SLE associated with increased disease activity. Lupus 2002;11:704–715. https://doi.org/10.1191/0961203302lu247oa

42. Denny MF, Yalavarthi S, Zhao W et al. A distinct subset of proinflammatory neutrophils isolated from patients with systemic lupus erythematosus induces vascular damage and synthesizes type I IFNs. J Immunol 2010;184:3284–3297. https://doi.org/10.4049/jimmunol.0902199

43. Lindau D, Mussard J, Rabsteyn A et al. TLR9 independent interferon α production by neutrophils on NETosis in response to circulating chromatin, a key lupus autoantigen. Annals of the rheumatic diseases 2014;73:12:2199–2207. http://dx.doi.org/10.1136/annrheumdis-2012-203041

44. Simon D, Simon HU, Yousefi S. Extracellular DNA traps in allergic, infectious, and autoimmune diseases. Allergy 2013;68:409–416. https://doi.org/10.1111/all.12111

45. Frangou E, Chrysanthopoulou A, Mitsios A et al. REDD1/ autophagy pathway promotes thromboinflammation and fibrosis in human systemic lupus erythematosus (SLE) through NETs decorated with tissue factor (TF) and interleukin-17A (IL-17A) Ann Rheum Dis 2019;78:238–248. https://doi.org/10.1136/annrheumdis-2018-213181

46. Xiao H, Schreiber A, Heeringa P et al. Alternative complement pathway in the pathogenesis of disease mediated by anti-neutrophil cytoplasmic autoantibodies. Am J Pathol 2007;170:52–64. https://doi.org/10.2353/ajpath.2007.060573

47. Kessenbrock K, Krumbholz M, Schönermarck U et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat Med 2009;15:623–625. https://doi.org/10.1038/nm.1959

48. Söderberg D, Kurz T, Motamedi A et al. Increased levels of neutrophil extracellular trap remnants in the circulation of patients with small vessel vasculitis, but an inverse correlation to anti-neutrophil cytoplasmic antibodies during remission. Rheumatology (Oxford) 2015;54:2085–2094. https://doi.org/10.1093/rheumatology/kev217

49. Kallenberg CG. Pathogenesis of ANCA-associated vasculitides. Ann Rheum Dis 2011;70(Suppl. 1):i59–i63. https://doi.org/10.1136/ard.2010.138024

50. Söderberg D, Segelmark M. Neutrophil Extracellular Traps in ANCA-Associated Vasculitis. Front Immunol 2016;7:256. https://doi.org/10.3389/fimmu.2016.00256

51. Kraaij T, Kamerling SWA, van Dam LS et al. Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA. Kidney Int 2018;94:139–149. https://doi.org/10.1016/j.kint.2018.01.013

52. O’Sullivan KM, Lo CY, Summers SA et al. Renal participation of myeloperoxidase in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. Kidney Int 2015;88:1030– 1046. https://doi.org/10.1038/ki.2015.202

53. Gadola SD, Gross WL. Vasculitis in 2011: The renaissance of granulomatous inflammation in AAV. Nat Rev Rheumatol 2012;8:74–76. https://doi.org/10.1038/nrrheum.2011.218

54. Yoshida M, Yamada M, Sudo Y et al. Myeloperoxidase anti-neutrophil cytoplasmic antibody affinity is associated with the formation of neutrophil extracellular traps in the kidney and vasculitis activity in myeloperoxidase anti-neutrophil cytoplasmic antibody-associated microscopic polyangiitis. Nephrology (Carlton) 2016;21:624–629. https://doi.org/10.1111/nep.12736

55. Nakazawa D, Shida H, Tomaru U et al. Enhanced formation and disordered regulation of NETs in myeloperoxidase-ANCA-associated microscopic polyangiitis. J Am Soc Nephrol 2014;25:990–997. https://doi.org/10.1681/ASN.2013060606

56. Pieterse E, Rother N, Garsen M et al. Neutrophil Extracellular Traps Drive Endothelial-to-Mesenchymal Transition. Arterioscler. Thromb Vasc Biol 2017;37:1371–1379. https://doi.org/10.1161/ATVBAHA.117.309002

57. Fuchs TA, Brill A, Duerschmied D et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci USA 2010;107:15880–15885. https://doi.org/10.1073/pnas.1005743107

58. Kumar SV, Kulkarni OP, Mulay SR et al. Neutrophil extracellular trap-related extracellular histones cause vascular necrosis in severe GN. J Am Soc Nephrol 2015;26:2399–2413. https://doi.org/10.1681/ASN.2014070673

59. Hasler P, Giaglis S, Hahn S. Neutrophil extracellular traps in health and disease. Swiss Med Wkly 2016;146:w14352. https://doi.org/10.4414/smw.2016.14352

60. Allam R, Darisipudi MN, Tschopp J, Anders HJ. Histones trigger sterile inflammation by activating the NLRP3 inflammasome. Eur J Immunol 2013;43:3336–3342. https://doi.org/10.1002/eji.201243224

61. Allam R, Scherbaum CR, Darisipudi MN et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J Am Soc Nephrol 2012;23:1375–1388. https://doi.org/10.1681/ASN.2011111077

62. Xu J, Zhang X, Pelayo R et al. Extracellular histones are major mediators of death in sepsis. Nat Med 2009;15:1318–1321. https://doi.org/10.1038/nm.2053

63. Semeraro F, Ammollo CT, Morrissey JH et al. Extracellular histones promote thrombin generation through plateletdependent mechanisms: Involvement of platelet TLR2 and TLR4. Blood 2011;118:1952–1961. https://doi.org/10.1182/blood-2011-03-343061

64. Cruz-Solbes AS, Youker K. Epithelial to Mesenchymal Transition (EMT) and Endothelial to Mesenchymal Transition (EndMT): Role and Implications in Kidney Fibrosis. Results Probl Cell Differ 2017;60:345–372. https://doi.org/10.1007/978-3319-51436-9_13

65. Dejana E, Orsenigo F, Lampugnani MG. The role of adherens junctions and VE-cadherin in the control of vascular permeability. J Cell Sci 2008;121:2115–2122. https://doi.org/10.1242/jcs.017897

66. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med 2013;5:178ra140. https://doi.org/10.1126/scitranslmed.3005580

67. Suurmond J, Diamond B. Autoantibodies in systemic autoimmune diseases: Specificity and pathogenicity. J Clin Investig 2015;125:2194–2202. https://doi.org/10.1172/JCI78084

68. Sokolove J, Zhao X, Chandra PE, Robinson WH. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum 2011;63:53–62. https://doi.org/10.1002/art.30081

69. Raghavan M, Bjorkman PJ. Fc receptors and their interactions with immunoglobulins. Annu Rev Cell Dev Biol 1996;12:181– 220. https://doi.org/10.1146/annurev.cellbio.12.1.181

70. Lefkowith JB, Gilkeson GS. Nephritogenic autoantibodies in lupus: Current concepts and continuing controversies. Arthritis Rheum 1996;39:894–903. https://doi.org/10.1002/art.1780390605

71. Bijl M, Dijstelbloem HM, Oost WW et al. IgG subclass distribution of autoantibodies differs between renal and extrarenal relapses in patients with systemic lupus erythematosus. Rheumatology (Oxford) 2002;41:62–67. https://doi.org/10.1093/rheumatology/41.1.62

72. Behnen M, Leschczyk C, Möller S et al. Immobilized immune complexes induce neutrophil extracellular trap release by human neutrophil granulocytes via FcγRIIIB and Mac-1. J Immunol 2014;193:1954–1965. https://doi.org/10.4049/jimmunol.1400478

73. de Bont CM, Boelens WC, Pruijn GJM. NETosis, complement, and coagulation: A triangular relationship. Cell Mol Immunol 2019;16:19–27. https://doi.org/10.1038/s41423-018-0024-0

74. Morgan BP. The membrane attack complex as an inflammatory trigger. Immunobiology 2016;221:747–751. doi: 10.1016/j.imbio.2015.04.006

75. Cedervall J, Dragomir A, Saupe F et al. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice. Oncoimmunology 2017;6:e1320009. https://doi.org/10.1080/2162402X.2017.1320009

76. Aliko A, Kamińska M, Falkowski K et al. Discovery of Novel Potential Reversible Peptidyl Arginine Deiminase Inhibitor. Int J Mol Sci 2019;20:2174. https://doi.org/10.3390/ijms20092174

77. Luo Y, Knuckley B, Lee YH et al. A fluoroacetamidine-based inactivator of protein arginine deiminase 4: Design, synthesis, and in vitro and in vivo evaluation. J Am Chem Soc 2006;128:1092–1093. https://doi.org/10.1021/ja0576233

78. Lewis HD, Liddle J, Coote JE et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat Chem Biol 2015;11:189–191. https://doi.org/10.1038/nchembio.1735

79. Knight JS, Subramanian V, O’Dell AA et al. Peptidylarginine deiminase inhibition disrupts NET formation and protects against kidney, skin and vascular disease in lupus-prone MRL/lpr mice. Ann Rheum Dis 2015;74:2199–2206. https://doi.org/10.1136/annrheumdis-2014-205365

80. Patel S, Kumar S, Jyoti A et al. Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation. Nitric Oxide 2010;22:226–234. https://doi.org/10.1016/j.niox.2010.01.001

81. McBride JM, Jiang J, Abbas AR et al. Safety and pharmacodynamics of rontalizumab in patients with systemic lupus erythematosus: Results of a phase I, placebo-controlled, doubleblind, dose-escalation study. Arthritis Rheum 2012;64:3666–3676. https://doi.org/10.1002/art.34632

82. Wahono CS, Rusmini H, Soelistyoningsih D et al. Effects of 1,25(OH)2D3 in immune response regulation of systemic lupus erithematosus (SLE) patient with hypovitamin D. Int J Clin Exp Med 2014;15:22–31

83. Robinson AB, Thierry-Palmer M, Gibson KL, Rabinovich CE. Disease activity, proteinuria, and vitamin D status in children with systemic lupus erythematosus and juvenile dermatomyositis. J Pediatr 2012;160:297–302. https://doi.org/10.1016/j.jpeds.2011.08.011

84. Karimzadeh H, Shirzadi M, Karimifar M. The effect of Vitamin D supplementation in disease activity of systemic lupus erythematosus patients with Vitamin D deficiency: A randomized clinical trial. J Res Med Sci 2017;22:4. https://doi.org/10.4103/17351995.199089

85. Macanovic M, Sinicropi D, Shak S et al. The treatment of systemic lupus erythematosus (SLE) in NZB/W F1 hybrid mice; studies with recombinant murine DNase and with dexamethasone. Clin Exp Immunol 1996;106:243–252. https://doi.org/10.1046/j.1365-2249.1996.d01-839.x

86. Yeh TM, Chang HC, Liang CC et al. Deoxyribonucleaseinhibitory antibodies in systemic lupus erythematosus. J Biomed Sci 2003;10:544–551. https://doi.org/10.1007/BF02256116

87. Peer V, Abu Hamad R, Berman S, Efrati S. Renoprotective Effects of DNAse-I Treatment in a Rat Model of Ischemia/Reperfusion-Induced Acute Kidney Injury. Am J Nephrol 2016;43:195–205. https://doi.org/10.1159/000445546

88. Uozumi R, Iguchi R, Masuda S et al. Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis. Mod Rheumatol 2019. https://doi.org/10.1080/14397595.2019.1602292