The role of neutrophils and neutrophil extracellular traps in renal diseases of bacterial origin

Czech version

Authors: Krivošíková Katarína ¹; Tóthová Ubomíra ²; Kovalčíková Gaál Alexandra ^1,2; Podracká Udmila ¹
Authors‘ workplace: Detská klinika, Lekárska fakulta Univerzity Komenského a Národného ústavu detských chorôb, Bratislava ¹; Ústav molekulárnej biomedicíny, Lekárska fakulta Univerzity Komenského, Bratislava ²
Published in: Čes-slov Pediat 2023; 78 (4): 231-237.
Category: Review
doi: https://doi.org/10.55095/CSPediatrie2023/040

Overview

Neutrophils are a central component of the innate immune system. In recent years, neutrophils have gained considerable attention due to their newly discovered biological effector functions and their involvement in various pathological conditions. Neutrophils represent the first line of the immune system defense and act as a physical and chemical barrier against pathogens. Activated neutrophils can release contents – decondensed chromatin along with antimicrobial granular proteins creating neutrophil extracellular traps (NETs). The NET formation is triggered by the contact with various pro-inflammatory stimuli, including microorganisms, cytokines, immune complexes, and others. Currently, we know two basic mechanisms of NET formation. The classical way is one of the forms of programmed cell death dependent on NADPH-oxidase; it is the best described mechanism. The second way of NET formation is characterized by a rapid cellular response to an external stimulus, whereby the trap is released without breaking the cell membrane, so that the neutrophil is not killed. While NETs are very effective at eliminating pathogens, they can also cause serious damage if released in excess or removed inefficiently. This review provides a simple and comprehensible view of the role of neutrophils and the mechanism of NET formation depending on various stimuli, and also summarizes the current knowledge on the role of NETs in the pathophysiology of urinary tract infections and hemolytic uremic syndrome induced by E. coli infection.

Keywords:

inflammation – Urinary tract infections – innate immunity – STEC-HUS – kidney injury

Sources

1. Burn GL, Foti A, Marsman G, et al. The Neutrophil. Immunity 2021; 54: 1377–1391.

2. Bardoel BW, Kenny EF, Sollberger G, Zychlinsky A. The balancing act of neutrophils. Cell Host Microbe 2014; 15: 526–536.

3. Brinkmann V, Reichard U, Goosmann C, et al. Neutrophil extracellular traps kill bacteria. Science 2004; 303: 1532–1535.

4. S alazar-Gonzalez H, Zepeda-Hernandez A, Melo Z, et al. Neutrophil extracellular traps in the establishment and progression of renal diseases. Medicina 2019; 55: 431.

5. S epe V, Libetta C, Gregorini M, Rampino T. The innate immune system in human kidney inflammaging. J Nephrol 2022; 35: 381–395.

6. T ecklenborg J, Clayton D, Siebert S, Coley SM. The role of the immune system in kidney disease. Clin Exp Immunol 2018; 192: 142–150.

7. M astroianni-Kirsztajn G, Hornig N, Schlumberger W. Autoantibodies in renal diseases - clinical significance and recent developments in serological detection. Front Immunol 2015; 6: 221.

8. M eng XM, Nikolic-Paterson DJ, Lan HY. Inflammatory processes in renal fibrosis. Nat Rev Nephrol 2014; 10: 493–503.

9. K ubelkova K, Macela A. Innate immune recognition: an issue more complex than expected. Front Cell Infect Microbiol 2019; 9: 241.

10. N auseef WM, Borregaard N. Neutrophils at work. Nat Immunol 2014; 15: 602–611.

11. K obayashi SD, Malachowa N, DeLeo FR. Neutrophils and bacterial immune evasion. J Innate Immun 2018; 10: 432–441.

12. K olaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol 2013; 13: 159–175.

13. P ittman K, Kubes P. Damage-associated molecular patterns control neutrophil recruitment. J Innate Immun 2013; 5: 315–323.

14. D ömer D, Walther T, Möller S, et al. Neutrophil extracellular traps activate proinflammatory functions of human neutrophils. Front Immunol 2021; 12: 636954.

15. D elgado-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.

16. Vorobjeva NV. Neutrophil extracellular traps: new aspects. Moscow Univ Biol Sci Bull 2020; 75: 173–188.

17. U eki S, Konno Y, Takeda M, et al. Eosinophil extracellular trap cell death- -derived DNA traps: Their presence in secretions and functional attributes. J Allergy Clin Immunol 2016; 137: 258–267.

18. Y ousefi S, Morshed M, Amini P, et al. Basophils exhibit antibacterial activity through extracellular trap formation. Allergy 2015; 70: 1184–1188.

19. von Köckritz-Blickwede M, Goldmann O, Thulin P, et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 2008; 111: 3070–3080.

20. L i L, Li X, Li G, et al. Mouse macrophages capture and kill Giardia lamblia by means of releasing extracellular trap. Dev Comp Immunol 2018; 88: 206–212.

21. R awat S, Vrati S, Banerjee A. Neutrophils at the crossroads of acute viral infections and severity. Mol Aspects Med 2021; 81: 100996.

22. T akeuchi O, Akira S. Pattern recognition receptors and inflammation. Cell 2010; 140: 805–820.

23. Papayannopoulos V. Neutrophil extracellular traps in immunity and disease. Nat Rev Immunol 2018; 18: 134–147.

24. N eubert E, Meyer D, Rocca F, et al. Chromatin swelling drives neutrophil extracellular trap release. Nat Commun 2018; 9: 3767.

25. F uchs TA , Abed U, Goosmann C, et al. Novel cell death program leads to neutrophil extracellular traps. J Cell Biol 2007; 176: 231–241.

26. P ilsczek 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.

27. Y ipp 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.

28. Y ousefi S, Mihalache C, Kozlowski E, et al. Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps. Cell Death Differ 2009; 16: 1438–1444.

29. Bandari B, Sindgikar SP, Kumar SS, et al. Renal scarring following urinary tract infections in children. Sudan J Paediatr 2019; 19: 25–30.

30. S haikh N, Ewing AL, Bhatnagar S, Hoberman A. Risk of renal scarring in children with a first urinary tract infection: a systematic review. Pediatrics 2010; 126: 1084–1091.

31. M asajtis-Zagajewska A, Nowicki M. New markers of urinary tract infection. Clin Chim Acta 2017; 471: 286–291.

32. Ronald A. The etiology of urinary tract infection: traditional and emerging pathogens. Am J Med 2002; 113 (Suppl 1A): 14s–19s.

33. R agnarsdóttir B, Fischer H, Godaly G, et al. TLR- and CXCR1-dependent innate immunity: insights into the genetics of urinary tract infections. Eur J Clin Invest 2008; 38 (Suppl 2): 12–20.

34. R agnarsdóttir B, Svanborg C. Susceptibility to acute pyelonephritis or asymptomatic bacteriuria: host-pathogen interaction in urinary tract infections. Pediatr Nephrol 2012; 27: 2017–2029.

35. Weichhart T, Haidinger M, Hörl WH, Säemann MD. Current concepts of molecular defence mechanisms operative during urinary tract infection. Eur J Clin Invest 2008; 38 Suppl 2: 29–38.

36. Vorobjeva NV, Chernyak BV. NETosis: Molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc) 2020; 85: 1178–1190.

37. García Moreira V, Prieto García B, de la Cera Martínez T, Alvarez Menéndez FV. Elevated transrenal DNA (cell-free urine DNA) in patients with urinary tract infection compared to healthy controls. Clin Biochem 2009; 42: 729–731.

38. C elec P, Vlková B, Lauková L, et al. Cell-free DNA: the role in pathophysiology and as a biomarker in kidney diseases. Expert Rev Mol Med 2018; 20: e1.

39. Y u Y, Kwon K, Tsitrin T, et al. Characterization of early-phase neutrophil extracellular traps in urinary tract infections. PLoS Pathog 2017; 13: e1006151.

40. Y u Y, Sikorski P, Bowman-Gholston C, et al. Diagnosing inflammation and infection in the urinary system via proteomics. J Transl Med 2015; 13: 111.

41. K rivošíková K, Šupčíková N, Gaál Kovalčíková A, et al. Neutrophil extracellular traps in urinary tract infection. Front Pediatr 2023; 11.

42. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014; 371: 654–666.

43. T alarico V, Aloe M, Monzani A, et al. Hemolytic uremic syndrome in children. Minerva Pediatr 2016; 68: 441–455.

44. S andvig K. Shiga toxins. Toxicon 2001; 39: 1629–1635.

45. F ernandez GC, Lopez MF, Gomez SA, et al. Relevance of neutrophils in the murine model of haemolytic uraemic syndrome: mechanisms involved in Shiga toxin type 2-induced neutrophilia. Clin Exp Immunol 2006; 146: 76–84.

46. L effler J, Prohászka Z, Mikes B, et al. Decreased neutrophil extracellular trap degradation in Shiga toxin-associated haemolytic uraemic syndrome. J Innate Immun 2017; 9: 12–21.

47. R amos 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.

48. F eitz WJC, Suntharalingham S, Khan M, et al. Shiga toxin 2a induces NETosis via NOX-dependent pathway. Biomedicines 2021; 9.

49. F uchs TA , Brill A, Duerschmied D, et al. Extracellular DNA traps promote thrombosis. Proc Natl Acad Sci U S A 2010; 107: 15880–15885.

50. C lark 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.

51. Wang G, Ma N, Meng L, et al. Activation of the phosphatidylinositol 3-kinase/ Akt pathway is involved in lipocalin-2-promoted human pulmonary artery smooth muscle cell proliferation. Mol Cell Biochem 2015; 410: 207–213.

52. L effler J, Martin M, Gullstrand B, et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J Immunol 2012; 188: 3522–3531.

53. L ocatelli M, Buelli S, Pezzotta A, et al. Shiga toxin promotes podocyte injury in experimental hemolytic uremic syndrome via activation of the alternative pathway of complement. J Am Soc Nephrol 2014; 25: 1786–1798.

54. Westra D, Volokhina EB, van der Molen RG, et al. Serological and genetic complement alterations in infection-induced and complement-mediated hemolytic uremic syndrome. Pediatr Nephrol 2017; 32: 297–309.

55. L andoni VI, Pittaluga JR, Carestia A, et al. Neutrophil extracellular traps induced by Shiga toxin and lipopolysaccharide-treated platelets exacerbate endothelial cell damage. Front Cell Infect Microbiol 2022; 12: 897019.

56. T erlizzi V, Castellani C, Taccetti G, Ferrari B. Dornase alfa in cystic fibrosis: indications, comparative studies and effects on lung clearance index. Ital J Pediatr 2022; 48: 141.

57. K una P, Jenkins M, O’Brien CD, Fahy WA. AZD9668, a neutrophil elastase inhibitor, plus ongoing budesonide/formoterol in patients with COPD. Respir Med 2012; 106: 531–539.

58. S hute JK, Calzetta L, Cardaci V, et al. Inhaled nebulised unfractionated heparin improves lung function in moderate to very severe COPD: A pilot study. Pulm Pharmacol Ther 2018; 48: 88–96.

59. Zhu D, Lu Y, Wang Y, Wang Y. PAD 4 and its inhibitors in cancer progression and prognosis. Pharmaceutics 2022; 14.