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Extracellular DNA traps in inflammation, injury and healing

Abstract

Following strong activation signals, several types of immune cells reportedly release chromatin and granular proteins into the extracellular space, forming DNA traps. This process is especially prominent in neutrophils but also occurs in other innate immune cells such as macrophages, eosinophils, basophils and mast cells. Initial reports demonstrated that extracellular traps belong to the bactericidal and anti-fungal armamentarium of leukocytes, but subsequent studies also linked trap formation to a variety of human diseases. These pathological roles of extracellular DNA traps are now the focus of intensive biomedical research. The type of pathology associated with the release of extracellular DNA traps is mainly determined by the site of trap formation and the way in which these traps are further processed. Targeting the formation of aberrant extracellular DNA traps or promoting their efficient clearance are attractive goals for future therapeutic interventions, but the manifold actions of extracellular DNA traps complicate these approaches.

Key points

  • Extracellular traps survey ducts and vessels under normal physiological conditions, immobilize and sequester pathogens during host defence and shield viable tissue from necrotic areas in the context of massive tissue injury.

  • Extracellular traps tend to aggregate and form larger functional units endowed with a plethora of enzymatic activities that can modify biomolecules at the site of inflammation.

  • Extracellular traps participate in both the initiation and in the resolution of inflammation.

  • Extracellular traps that escape clearance in the body might challenge immune tolerance and serve as autoantigen repositories that trigger the onset and promote the chronicity of autoimmune diseases.

  • Interfering with the formation or clearance of extracellular traps might create novel therapeutic interventions for inflammation and tissue injury.

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Fig. 1: Types of NETs and aggregate NETs.
Fig. 2: Microscopic visualization of NETs.
Fig. 3: Cell composition over time during an inflammatory response.
Fig. 4: NETs in renal disease.

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References

  1. Branzk, N. et al. Neutrophils sense microbe size and selectively release neutrophil extracellular traps in response to large pathogens. Nat. Immunol. 15, 1017–1025 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).

    CAS  PubMed  Google Scholar 

  3. Urban, C. F., Reichard, U., Brinkmann, V. & Zychlinsky, A. Neutrophil extracellular traps capture and kill Candida albicans yeast and hyphal forms. Cell. Microbiol. 8, 668–676 (2006).

    CAS  PubMed  Google Scholar 

  4. Leppkes, M. et al. Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat.Commun. 7, 10973 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jimenez-Alcazar, M. et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358, 1202–1206 (2017).

    CAS  PubMed  Google Scholar 

  6. Zhu, L. et al. High level of neutrophil extracellular traps correlates with poor prognosis of severe influenza A infection. J. Infect. Dis. 217, 428–437 (2018).

    CAS  PubMed  Google Scholar 

  7. Arumugam, S., Girish Subbiah, K., Kemparaju, K. & Thirunavukkarasu, C. Neutrophil extracellular traps in acrolein promoted hepatic ischemia reperfusion injury: therapeutic potential of NOX2 and p38MAPK inhibitors. J. Cell. Physiol. 233, 3244–3261 (2018).

    CAS  PubMed  Google Scholar 

  8. Schreiber, A. et al. Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis. Proc. Natl Acad. Sci. USA 114, E9618–E9625 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Nakazawa, D. et al. Histones and neutrophil extracellular traps enhance tubular necrosis and remote organ injury in ischemic AKI. J. Am. Soc. Nephrol. 28, 1753–1768 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. McDonald, B. et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 129, 1357–1367 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Korabecna, M. & Tesar, V. NETosis provides the link between activation of neutrophils on hemodialysis membrane and comorbidities in dialyzed patients. Inflamm. Res. 66, 369–378 (2017).

    CAS  PubMed  Google Scholar 

  12. Cedervall, J. et al. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice. Oncoimmunology 6, e1320009 (2017).

    PubMed  PubMed Central  Google Scholar 

  13. Boettcher, M. et al. Degradation of extracellular DNA by DNase1 significantly reduces testicular damage after testicular torsion in rats. Urology 109, 223.e1–223.e7 (2017).

    Google Scholar 

  14. White, P. C., Chicca, I. J., Cooper, P. R., Milward, M. R. & Chapple, I. L. Neutrophil extracellular traps in periodontitis: a web of intrigue. J. Dent. Res. 95, 26–34 (2016).

    CAS  PubMed  Google Scholar 

  15. Fadini, G. P. et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 65, 1061–1071 (2016).

    CAS  PubMed  Google Scholar 

  16. Aleyd, E., Al, M., Tuk, C. W., van der Laken, C. J. & van Egmond, M. IgA complexes in plasma and synovial fluid of patients with rheumatoid arthritis induce neutrophil extracellular traps via FcalphaRI. J. Immunol. 197, 4552–4559 (2016).

    CAS  PubMed  Google Scholar 

  17. Huang, H. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62, 600–614 (2015).

    CAS  PubMed  Google Scholar 

  18. Grabcanovic-Musija, F. et al. Neutrophil extracellular trap (NET) formation characterises stable and exacerbated COPD and correlates with airflow limitation. Respir. Res. 16, 59 (2015).

    PubMed  PubMed Central  Google Scholar 

  19. Ward, P. A. & Grailer, J. J. Acute lung injury and the role of histones. Transl Respir. Med. 2, 1 (2014).

    PubMed  PubMed Central  Google Scholar 

  20. Luo, L. et al. Proinflammatory role of neutrophil extracellular traps in abdominal sepsis. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L586–L596 (2014).

    CAS  Google Scholar 

  21. Berkes, E., Oehmke, F., Tinneberg, H. R., Preissner, K. T. & Saffarzadeh, M. Association of neutrophil extracellular traps with endometriosis-related chronic inflammation. Eur. J. Obstet. Gynecol. Reprod. Biol. 183, 193–200 (2014).

    CAS  PubMed  Google Scholar 

  22. Thomas, G. M. et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119, 6335–6343 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Knight, J. S., Carmona-Rivera, C. & Kaplan, M. J. Proteins derived from neutrophil extracellular traps may serve as self-antigens and mediate organ damage in autoimmune diseases. Front. Immunol. 3, 380 (2012).

    PubMed  PubMed Central  Google Scholar 

  24. Narasaraju, T. et al. Excessive neutrophils and neutrophil extracellular traps contribute to acute lung injury of influenza pneumonitis. Am. J. Pathol. 179, 199–210 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Okubo, K. et al. Macrophage extracellular trap formation promoted by platelet activation is a key mediator of rhabdomyolysis-induced acute kidney injury. Nat. Med. 24, 232–238 (2018).

    CAS  PubMed  Google Scholar 

  27. von Brühl, M.-L. et al. Monocytes, neutrophils, and platelets cooperate to initiate and propagate venous thrombosis in mice in vivo. J. Exp. Med. 209, 819–835 (2012).

    Google Scholar 

  28. Pisetsky, D. S. & Jiang, N. The generation of extracellular DNA in SLE: the role of death and sex. Scand. J. Immunol. 64, 200–204 (2006).

    CAS  PubMed  Google Scholar 

  29. Pisetsky, D. S. & Fairhurst, A. M. The origin of extracellular DNA during the clearance of dead and dying cells. Autoimmunity 40, 281–284 (2007).

    CAS  PubMed  Google Scholar 

  30. Huang, L. et al. Eosinophils mediate protective immunity against secondary nematode infection. J. Immunol. 194, 283–290 (2015).

    CAS  PubMed  Google Scholar 

  31. Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 14, 949–953 (2008).

    CAS  PubMed  Google Scholar 

  32. Ueki, S. et al. Eosinophil extracellular trap cell death-derived DNA traps: their presence in secretions and functional attributes. J. Allergy Clin. Immunol. 137, 258–267 (2016).

    CAS  PubMed  Google Scholar 

  33. Schorn, C. et al. Monosodium urate crystals induce extracellular DNA traps in neutrophils, eosinophils, and basophils but not in mononuclear cells. Front. Immunol. 3, 277 (2012).

    PubMed  PubMed Central  Google Scholar 

  34. Yousefi, S. et al. Basophils exhibit antibacterial activity through extracellular trap formation. Allergy 70, 1184–1188 (2015).

    CAS  PubMed  Google Scholar 

  35. Crivellato, E., Travan, L. & Ribatti, D. Mast cells and basophils: a potential link in promoting angiogenesis during allergic inflammation. Int. Arch. Allergy Immunol. 151, 89–97 (2010).

    CAS  PubMed  Google Scholar 

  36. von Kockritz-Blickwede, M. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 111, 3070–3080 (2008).

    Google Scholar 

  37. Reinwald, C. et al. Reply to “Neutrophils are not required for resolution of acute gouty arthritis in mice”. Nat. Med. 22, 1384–1386 (2016).

    CAS  PubMed  Google Scholar 

  38. An, Y. et al. Aflatoxin B1 induces reactive oxygen species-mediated autophagy and extracellular trap formation in macrophages. Front. Cell. Infect. Microbiol. 7, 53 (2017).

    PubMed  PubMed Central  Google Scholar 

  39. Sharma, R., O’Sullivan, K. M., Holdsworth, S. R., Bardin, P. G. & King, P. T. Visualizing macrophage extracellular traps using confocal microscopy. J. Vis. Exp. https://doi.org/10.3791/56459 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Li, L. et al. Mouse macrophages capture and kill Giardia lamblia by means of releasing extracellular trap. Dev. Comp. Immunol. 88, 206–212 (2018).

    CAS  PubMed  Google Scholar 

  41. Wong, K. W. & Jacobs, W. R. Jr. Mycobacterium tuberculosis exploits human interferon gamma to stimulate macrophage extracellular trap formation and necrosis. J. Infect. Dis. 208, 109–119 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Doster, R. S., Rogers, L. M., Gaddy, J. A. & Aronoff, D. M. Macrophage extracellular traps: a scoping review. J. Innate Immun. 10, 3–13 (2018).

    CAS  PubMed  Google Scholar 

  43. Je, S. et al. Mycobacterium massiliense induces macrophage extracellular traps with facilitating bacterial growth. PLOS ONE 11, e0155685 (2016).

    PubMed  PubMed Central  Google Scholar 

  44. Liu, P. et al. Escherichia coli and Candida albicans induced macrophage extracellular trap-like structures with limited microbicidal activity. PLOS ONE 9, e90042 (2014).

    PubMed  PubMed Central  Google Scholar 

  45. Czaikoski, P. G. et al. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLOS ONE 11, e0148142 (2016).

    PubMed  PubMed Central  Google Scholar 

  46. Papayannopoulos, V., Metzler, K. D., Hakkim, A. & Zychlinsky, A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J. Cell Biol. 191, 677–691 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Urban, C. F. et al. Neutrophil extracellular traps contain calprotectin, a cytosolic protein complex involved in host defense against Candida albicans. PLOS Pathog. 5, e1000639 (2009).

    PubMed  PubMed Central  Google Scholar 

  48. Jiménez-Alcázar, M. et al. Impaired DNase1-mediated degradation of neutrophil extracellular traps is associated with acute thrombotic microangiopathies. J. Thromb. Haemost. 13, 732–742 (2015).

    PubMed  Google Scholar 

  49. Hahn, J. et al. Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation. Clin. Exp. Rheumatol. 34, 6–8 (2016).

    PubMed  Google Scholar 

  50. Lipp, P. et al. Less neutrophil extracellular trap formation in term newborns than in adults. Neonatology 111, 182–188 (2017).

    CAS  PubMed  Google Scholar 

  51. Munoz, L. E. et al. Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation. Proc. Natl Acad. Sci. USA 113, E5856–E5865 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).

    CAS  PubMed  Google Scholar 

  53. Kienhofer, D. et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight 2, 92920 (2017).

    PubMed  Google Scholar 

  54. Hahn, J. et al. Aggregated neutrophil extracellular traps resolve inflammation by proteolysis of cytokines and chemokines and protection from antiproteases. FASEB J. 33, 1401–1414 (2019).

    CAS  PubMed  Google Scholar 

  55. Martinod, K. et al. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214, 439–458 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Lood, C. et al. Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease. Nat. Med. 22, 146–153 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Kenny, E. F. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife 6, e24437 (2017).

    PubMed  PubMed Central  Google Scholar 

  58. Juneau, R. A., Pang, B., Weimer, K. E., Armbruster, C. E. & Swords, W. E. Nontypeable Haemophilus influenzae initiates formation of neutrophil extracellular traps. Infect. Immun. 79, 431–438 (2011).

    CAS  PubMed  Google Scholar 

  59. Jones, E. A., McGillivary, G. & Bakaletz, L. O. Extracellular DNA within a nontypeable Haemophilus influenzae-induced biofilm binds human beta defensin-3 and reduces its antimicrobial activity. J. Innate Immun. 5, 24–38 (2013).

    CAS  PubMed  Google Scholar 

  60. Thornton, R. B. et al. Neutrophil extracellular traps and bacterial biofilms in middle ear effusion of children with recurrent acute otitis media—a potential treatment target. PLOS ONE 8, e53837 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Delaleu, N. et al. Sjogren’s syndrome patients with ectopic germinal centers present with a distinct salivary proteome. Rheumatology (Oxford) 55, 1127–1137 (2016).

    CAS  Google Scholar 

  62. England, B. R., Thiele, G. M. & Mikuls, T. R. Anticitrullinated protein antibodies: origin and role in the pathogenesis of rheumatoid arthritis. Curr. Opin. Rheumatol. 29, 57–64 (2017).

    CAS  PubMed  Google Scholar 

  63. Sakkas, L. I., Daoussis, D., Liossis, S. N. & Bogdanos, D. P. The infectious basis of ACPA-positive rheumatoid arthritis. Front. Microbiol. 8, 1853 (2017).

    PubMed  PubMed Central  Google Scholar 

  64. Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J. Clin. Invest. 123, 236–246 (2013).

    CAS  PubMed  Google Scholar 

  65. Damby, D. E. et al. Volcanic ash activates the NLRP3 inflammasome in murine and human macrophages. Front. Immunol. 8, 2000 (2017).

    PubMed  Google Scholar 

  66. Biermann, M. H. et al. Oxidative burst-dependent NETosis is implicated in the resolution of necrosis-associated sterile inflammation. Front. Immunol. 7, 557 (2016).

    PubMed  PubMed Central  Google Scholar 

  67. Rewa, O. & Bagshaw, S. M. Acute kidney injury-epidemiology, outcomes and economics. Nat. Rev. Nephrol. 10, 193–207 (2014).

    CAS  PubMed  Google Scholar 

  68. Rosen, S. & Stillman, I. E. Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation. J. Am. Soc. Nephrol. 19, 871–875 (2008).

    PubMed  Google Scholar 

  69. Sharfuddin, A. A. & Molitoris, B. A. Pathophysiology of ischemic acute kidney injury. Nat. Rev. Nephrol. 7, 189–200 (2011).

    CAS  PubMed  Google Scholar 

  70. Jang, H. R. & Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol. 11, 88–101 (2015).

    CAS  PubMed  Google Scholar 

  71. Jansen, M. P. et al. Release of extracellular DNA influences renal ischemia reperfusion injury by platelet activation and formation of neutrophil extracellular traps. Kidney Int. 91, 352–364 (2017).

    CAS  PubMed  Google Scholar 

  72. Raup-Konsavage, W. M. et al. Neutrophil peptidyl arginine deiminase-4 has a pivotal role in ischemia/reperfusion-induced acute kidney injury. Kidney Int. 93, 365–374 (2018).

    CAS  PubMed  Google Scholar 

  73. Cedervall, J. et al. Neutrophil extracellular traps accumulate in peripheral blood vessels and compromise organ function in tumor-bearing animals. Cancer Res. 75, 2653–2662 (2015).

    CAS  PubMed  Google Scholar 

  74. Grams, M. E. & Rabb, H. The distant organ effects of acute kidney injury. Kidney Int. 81, 942–948 (2012).

    PubMed  Google Scholar 

  75. Rohrbach, A. S., Slade, D. J., Thompson, P. R. & Mowen, K. A. Activation of PAD4 in NET formation. Front. Immunol. 3, 360 (2012).

    PubMed  PubMed Central  Google Scholar 

  76. Ham, A. et al. Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol. 307, F1052–F1062 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Rabadi, M., Kim, M., D’Agati, V. & Lee, H. T. Peptidyl arginine deiminase-4-deficient mice are protected against kidney and liver injury after renal ischemia and reperfusion. Am. J. Physiol. Renal Physiol. 311, F437–F449 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Biron, B. M. et al. PAD4 deficiency leads to decreased organ dysfunction and improved survival in a dual insult model of hemorrhagic shock and sepsis. J. Immunol. 200, 1817–1828 (2018).

    CAS  PubMed  Google Scholar 

  79. Li, H. et al. Divergent roles for kidney proximal tubule and granulocyte PAD4 in ischemic AKI. Am. J. Physiol. Renal Physiol. 314, F809–F819 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Rabadi, M. et al. ATP induces PAD4 in renal proximal tubule cells via P2X7 receptor activation to exacerbate ischemic AKI. Am. J. Physiol. Renal Physiol. 314, F293–F305 (2018).

    PubMed  Google Scholar 

  81. Menzies, R. I., Tam, F. W., Unwin, R. J. & Bailey, M. A. Purinergic signaling in kidney disease. Kidney Int. 91, 315–323 (2017).

    CAS  PubMed  Google Scholar 

  82. Mulay, S. R., Kumar, S. V., Lech, M., Desai, J. & Anders, H.-J. How kidney cell death induces renal necroinflammation. Semin. Nephrol. 36, 162–173 (2016).

    CAS  PubMed  Google Scholar 

  83. Carestia, A., Kaufman, T. & Schattner, M. Platelets: new bricks in the building of neutrophil extracellular traps. Front. Immunol. 7, 271 (2016).

    PubMed  PubMed Central  Google Scholar 

  84. Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Martinod, K. et al. Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice. Proc. Natl Acad. Sci. USA 110, 8674–8679 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  86. Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  88. Chen, G. et al. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123, 3818–3827 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Maueroder, C. et al. Menage-a-trois: the ratio of bicarbonate to CO2 and the pH regulate the capacity of neutrophils to form NETs. Front. Immunol. 7, 583 (2016).

    PubMed  PubMed Central  Google Scholar 

  90. Madhi, R., Rahman, M., Taha, D., Morgelin, M. & Thorlacius, H. Targeting peptidylarginine deiminase reduces neutrophil extracellular trap formation and tissue injury in severe acute pancreatitis. J. Cell. Physiol. 234, 11850–11860 (2018).

    PubMed  Google Scholar 

  91. Merza, M. et al. Neutrophil extracellular traps induce trypsin activation, inflammation, and tissue damage in mice with severe acute pancreatitis. Gastroenterology 149, 1920–1931 (2015).

    CAS  PubMed  Google Scholar 

  92. Korhonen, J. T., Dudeja, V., Dawra, R., Kubes, P. & Saluja, A. Neutrophil extracellular traps provide a grip on the enigmatic pathogenesis of acute pancreatitis. Gastroenterology 149, 1682–1685 (2015).

    PubMed  Google Scholar 

  93. Dalbeth, N., Merriman, T. R. & Stamp, L. K. Gout. Lancet 388, 2039–2052 (2016).

    CAS  PubMed  Google Scholar 

  94. Ungar, H. Experimental production of urate calculi in the urinary tract of white rats. Br. J. Exp. Pathol. 26, 363–366 (1945).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Ganzoni, A. & Stoll, E. Acute urate nephropathy. Kidney failure in unripe cell lymphatic leukemia during treatment with vincristine sulfate [German]. Z. Klin. Med. 158, 313–336 (1965).

    CAS  PubMed  Google Scholar 

  96. Pieterse, E. et al. Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals. Sci. Rep. 6, 38229 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Apel, F., Zychlinsky, A. & Kenny, E. F. The role of neutrophil extracellular traps in rheumatic diseases. Nat. Rev. Rheumatol. 14, 467–475 (2018).

    CAS  PubMed  Google Scholar 

  98. Schorn, C. et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 286, 35–41 (2011).

    CAS  PubMed  Google Scholar 

  99. Mitroulis, I. et al. Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLOS ONE 6, e29318 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Heineke, M. H. et al. New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schonlein purpura). Autoimmun. Rev. 16, 1246–1253 (2017).

    CAS  PubMed  Google Scholar 

  101. Brogan, P. & Eleftheriou, D. Vasculitis update: pathogenesis and biomarkers. Pediatr. Nephrol. 33, 187–198 (2018).

    PubMed  Google Scholar 

  102. Kawasaki, K. et al. Factor XIII in Henoch-Schonlein purpura with isolated gastrointestinal symptoms. Pediatr. Int. 48, 413–415 (2006).

    PubMed  Google Scholar 

  103. Semeraro, F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118, 1952–1961 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).

    CAS  PubMed  Google Scholar 

  105. Petersen, L. C., Bjorn, S. E. & Nordfang, O. Effect of leukocyte proteinases on tissue factor pathway inhibitor. Thromb. Haemost. 67, 537–541 (1992).

    CAS  PubMed  Google Scholar 

  106. Maugeri, N. et al. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J. Thromb. Haemost. 4, 1323–1330 (2006).

    CAS  PubMed  Google Scholar 

  107. Makay, B., Gucenmez, O. A., Duman, M. & Unsal, E. The relationship of neutrophil-to-lymphocyte ratio with gastrointestinal bleeding in Henoch-Schonlein purpura. Rheumatol. Int. 34, 1323–1327 (2014).

    CAS  PubMed  Google Scholar 

  108. Ozturk, K. & Ekinci, Z. Is neutrophil-to-lymphocyte ratio valid to predict organ involvement in Henoch-Schonlein purpura? Rheumatol. Int. 36, 1147–1148 (2016).

    PubMed  Google Scholar 

  109. George, J. N. & Nester, C. M. Syndromes of thrombotic microangiopathy. N. Engl. J. Med. 371, 654–666 (2014).

    CAS  PubMed  Google Scholar 

  110. Brocklebank, V., Wood, K. M. & Kavanagh, D. Thrombotic microangiopathy and the kidney. Clin. J. Am. Soc. Nephrol. 13, 300–317 (2018).

    CAS  PubMed  Google Scholar 

  111. Exeni, R. A. et al. Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr. Nephrol. 33, 2057–2071 (2018).

    PubMed  Google Scholar 

  112. Fuchs, T. A., Kremer Hovinga, J. A., Schatzberg, D., Wagner, D. D. & Lämmle, B. Circulating DNA and myeloperoxidase indicate disease activity in patients with thrombotic microangiopathies. Blood 120, 1157–1164 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Ramos, M. V. et al. Induction of neutrophil extracellular traps in Shiga toxin-associated hemolytic uremic syndrome. J. Innate Immun. 8, 400–411 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Gloude, N. J. et al. Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD. Blood 130, 1259–1266 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Celec, P., Vlkova, B., Laukova, L., Babickova, J. & Boor, P. Cell-free DNA: the role in pathophysiology and as a biomarker in kidney diseases. Expert Rev. Mol. Med. 20, e1 (2018).

    PubMed  Google Scholar 

  116. Marder, W. et al. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci. Med. 3, e000134 (2016).

    PubMed  PubMed Central  Google Scholar 

  117. Leffler, J. et al. Decreased neutrophil extracellular trap degradation in Shiga toxin-associated haemolytic uraemic syndrome. J. Innate Immun. 9, 12–21 (2017).

    CAS  PubMed  Google Scholar 

  118. Leffler, J. et al. Neutrophil extracellular traps that are not degraded in systemic lupus erythematosus activate complement exacerbating the disease. J. Immunol. 188, 3522–3531 (2012).

    CAS  PubMed  Google Scholar 

  119. Singer, M. et al. The Third International Consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315, 801–810 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Dellepiane, S., Marengo, M. & Cantaluppi, V. Detrimental cross-talk between sepsis and acute kidney injury: new pathogenic mechanisms, early biomarkers and targeted therapies. Crit. Care 20, 61 (2016).

    PubMed  PubMed Central  Google Scholar 

  121. Ma, S. et al. Sepsis-induced acute kidney injury: a disease of the microcirculation. Microcirculation 26, e12483 (2019).

    PubMed  Google Scholar 

  122. Shen, X. F., Cao, K., Jiang, J. P., Guan, W. X. & Du, J. F. Neutrophil dysregulation during sepsis: an overview and update. J. Cell. Mol. Med. 21, 1687–1697 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Fialkow, L., Wang, Y. & Downey, G. P. Reactive oxygen and nitrogen species as signaling molecules regulating neutrophil function. Free Radic. Biol. Med. 42, 153–164 (2007).

    CAS  PubMed  Google Scholar 

  124. Kovach, M. A. & Standiford, T. J. The function of neutrophils in sepsis. Curr. Opin. Infect. Dis. 25, 321–327 (2012).

    CAS  PubMed  Google Scholar 

  125. Fani, F. et al. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J. Nephrol. 31, 351–359 (2018).

    CAS  PubMed  Google Scholar 

  126. Langenberg, C., Gobe, G., Hood, S., May, C. N. & Bellomo, R. Renal histopathology during experimental septic acute kidney injury and recovery. Crit. Care Med. 42, e58–e67 (2014).

    CAS  PubMed  Google Scholar 

  127. Takasu, O. et al. Mechanisms of cardiac and renal dysfunction in patients dying of sepsis. Am. J. Respir. Crit. Care Med. 187, 509–517 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  128. McDonald, B., Urrutia, R., Yipp, B. G., Jenne, C. N. & Kubes, P. Intravascular neutrophil extracellular traps capture bacteria from the bloodstream during sepsis. Cell Host Microbe 12, 324–333 (2012).

    CAS  PubMed  Google Scholar 

  129. Meng, W. et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit. Care 16, R137 (2012).

    PubMed  PubMed Central  Google Scholar 

  130. Martinod, K. et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood 125, 1948–1956 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Bystrzycka, W. et al. Influence of different bacteria strains isolated from septic children on release and degradation of extracellular traps by neutrophils from healthy adults. Adv. Exp. Med. Biol. 1108, 1–12 (2018).

    PubMed  Google Scholar 

  132. Lefrancais, E., Mallavia, B., Zhuo, H., Calfee, C. S. & Looney, M. R. Maladaptive role of neutrophil extracellular traps in pathogen-induced lung injury. JCI Insight 3, 98178 (2018).

    PubMed  Google Scholar 

  133. Biron, B. M. et al. Cl-amidine prevents histone 3 citrullination and neutrophil extracellular trap formation, and improves survival in a murine sepsis model. J. Innate Immun. 9, 22–32 (2017).

    CAS  PubMed  Google Scholar 

  134. Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13, 463–469 (2007).

    CAS  PubMed  Google Scholar 

  135. Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Tanaka, K. et al. In vivo characterization of neutrophil extracellular traps in various organs of a murine sepsis model. PLOS ONE 9, e111888 (2014).

    PubMed  PubMed Central  Google Scholar 

  137. Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  138. Xu, J., Zhang, X., Monestier, M., Esmon, N. L. & Esmon, C. T. Extracellular histones are mediators of death through TLR2 and TLR4 in mouse fatal liver injury. J. Immunol. 187, 2626–2631 (2011).

    CAS  PubMed  Google Scholar 

  139. Liaw, P. C., Ito, T., Iba, T., Thachil, J. & Zeerleder, S. DAMP and DIC: the role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 30, 257–261 (2016).

    CAS  PubMed  Google Scholar 

  140. Jochum, M., Lander, S., Heimburger, N. & Fritz, H. Effect of human granulocytic elastase on isolated human antithrombin III. Hoppe-Seyler’s Z. Physiol. Chem. 362, 103–112 (1981).

    CAS  Google Scholar 

  141. Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  142. Mahajan, A., Herrmann, M. & Munoz, L. E. Clearance deficiency and cell death pathways: a model for the pathogenesis of SLE. Front. Immunol. 7, 35 (2016).

    PubMed  PubMed Central  Google Scholar 

  143. Neeli, I., Khan, S. N. & Radic, M. Histone deimination as a response to inflammatory stimuli in neutrophils. J. Immunol. 180, 1895–1902 (2008).

    CAS  PubMed  Google Scholar 

  144. Wang, L. & Law, H. K. W. Immune complexes suppressed autophagy in glomerular endothelial cells. Cell. Immunol. 328, 1–8 (2018).

    CAS  PubMed  Google Scholar 

  145. Giannakakis, K. & Faraggiana, T. Histopathology of lupus nephritis. Clin. Rev. Allergy Immunol. 40, 170–180 (2011).

    PubMed  Google Scholar 

  146. Schwartzman-Morris, J. & Putterman, C. Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis. Clin. Dev. Immunol. 2012, 604892 (2012).

    PubMed  PubMed Central  Google Scholar 

  147. Yu, Y. & Su, K. Neutrophil extracellular traps and systemic lupus erythematosus. J. Clin. Cell. Immunol. 4, 139 (2013).

    PubMed  PubMed Central  Google Scholar 

  148. Clarke, S. H. Anti-Sm B cell tolerance and tolerance loss in systemic lupus erythematosus. Immunol. Res. 41, 203–216 (2008).

    CAS  PubMed  Google Scholar 

  149. Kalinina, O., Louzoun, Y., Wang, Y., Utset, T. & Weigert, M. Origins and specificity of auto-antibodies in Sm+ SLE patients. J. Autoimmun. 90, 94–104 (2018).

    CAS  PubMed  Google Scholar 

  150. Abramson, S. B., Given, W. P., Edelson, H. S. & Weissmann, G. Neutrophil aggregation induced by sera from patients with active systemic lupus erythematosus. Arthritis Rheum. 26, 630–636 (1983).

    CAS  PubMed  Google Scholar 

  151. Courtney, P. A. et al. Increased apoptotic peripheral blood neutrophils in systemic lupus erythematosus: relations with disease activity, antibodies to double stranded DNA, and neutropenia. Ann. Rheum. Dis. 58, 309–314 (1999).

    CAS  Google Scholar 

  152. Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  153. Villanueva, E. et al. Netting neutrophils induce endothelial damage, infiltrate tissues, and expose immunostimulatory molecules in systemic lupus erythematosus. J. Immunol. 187, 538–552 (2011).

    CAS  PubMed  Google Scholar 

  154. Lande, R. et al. Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus. Sci. Transl Med. 3, 73ra19 (2011).

    PubMed  PubMed Central  Google Scholar 

  155. Gestermann, N. et al. Netting neutrophils activate autoreactive B cells in lupus. J. Immunol. 200, 3364–3371 (2018).

    CAS  PubMed  Google Scholar 

  156. Lorenz, G. & Anders, H. J. Neutrophils, dendritic cells, toll-like receptors, and interferon-alpha in lupus nephritis. Semin. Nephrol. 35, 410–426 (2015).

    CAS  PubMed  Google Scholar 

  157. Yu, Y. et al. Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation. Curr. Mol. Med. 15, 401–410 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  158. Dieker, J. et al. Circulating apoptotic microparticles in systemic lupus erythematosus patients drive the activation of dendritic cell subsets and prime neutrophils for NETosis. Arthritis Rheumatol. 68, 462–472 (2016).

    CAS  PubMed  Google Scholar 

  159. Rother, N., Pieterse, E., Lubbers, J., Hilbrands, L. & van der Vlag, J. Acetylated histones in apoptotic microparticles drive the formation of neutrophil extracellular traps in active lupus nephritis. Front. Immunol. 8, 1136 (2017).

    PubMed  PubMed Central  Google Scholar 

  160. Fuchs, T. A. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176, 231–241 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  162. Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  163. Lunec, J., Herbert, K., Blount, S., Griffiths, H. R. & Emery, P. 8-Hydroxydeoxyguanosine. A marker of oxidative DNA damage in systemic lupus erythematosus. FEBS Lett. 348, 131–138 (1994).

    CAS  PubMed  Google Scholar 

  164. Campbell, A. M., Kashgarian, M. & Shlomchik, M. J. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci. Transl Med. 4, 157ra141 (2012).

    PubMed  PubMed Central  Google Scholar 

  165. Knight, J. S. et al. Peptidylarginine deiminase inhibition reduces vascular damage and modulates innate immune responses in murine models of atherosclerosis. Circ. Res. 114, 947–956 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  166. Knight, J. S. 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. 74, 2199–2206 (2015).

    CAS  PubMed  Google Scholar 

  167. Knight, J. S. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. Clin. Invest. 123, 2981–2993 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  168. Gordon, R. A. et al. Lupus and proliferative nephritis are PAD4 independent in murine models. JCI Insight 2, 92926 (2017).

    PubMed  Google Scholar 

  169. Leffler, J. et al. Degradation of neutrophil extracellular traps co-varies with disease activity in patients with systemic lupus erythematosus. Arthritis Res. Ther. 15, R84 (2013).

    PubMed  PubMed Central  Google Scholar 

  170. van der Linden, M., Westerlaken, G. H. A., van der Vlist, M., van Montfrans, J. & Meyaard, L. Differential signalling and kinetics of neutrophil extracellular trap release revealed by quantitative live imaging. Sci. Rep. 7, 6529 (2017).

    PubMed  PubMed Central  Google Scholar 

  171. Westhorpe, C. L. et al. In vivo imaging of inflamed glomeruli reveals dynamics of neutrophil extracellular trap formation in glomerular capillaries. Am. J. Pathol. 187, 318–331 (2017).

    CAS  PubMed  Google Scholar 

  172. Petry, F., Berkel, A. I. & Loos, M. Multiple identification of a particular type of hereditary C1q deficiency in the Turkish population: review of the cases and additional genetic and functional analysis. Hum. Genet. 100, 51–56 (1997).

    CAS  PubMed  Google Scholar 

  173. Hair, P. S., Enos, A. I., Krishna, N. K. & Cunnion, K. M. Inhibition of immune complex complement activation and neutrophil extracellular trap formation by peptide inhibitor of complement C1. Front. Immunol. 9, 558 (2018).

    PubMed  PubMed Central  Google Scholar 

  174. Gaipl, U. S. et al. Cooperation between C1q and DNase I in the clearance of necrotic cell-derived chromatin. Arthritis Rheum. 50, 640–649 (2004).

    CAS  PubMed  Google Scholar 

  175. Majetschak, M. Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J. Leukoc. Biol. 89, 205–219 (2011).

    CAS  PubMed  Google Scholar 

  176. Barrera-Vargas, A. et al. Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus. Ann. Rheum. Dis. 77, 944–950 (2018).

    CAS  PubMed  Google Scholar 

  177. Soderberg, D. & Segelmark, M. Neutrophil extracellular traps in ANCA-associated vasculitis. Front. Immunol. 7, 256 (2016).

    PubMed  PubMed Central  Google Scholar 

  178. Cossarizza, A. et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur. J. Immunol. 47, 1584–1797 (2017).

    CAS  PubMed  Google Scholar 

  179. Poli, C. et al. IL-26 confers proinflammatory properties to extracellular DNA. J. Immunol. 198, 3650–3661 (2017).

    CAS  PubMed  Google Scholar 

  180. Schreiber, A. et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J. Am. Soc. Nephrol. 20, 289–298 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  181. Kolaczkowska, E. et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat. Commun. 6, 6673 (2015).

    CAS  PubMed  Google Scholar 

  182. Kusunoki, Y. et al. Peptidylarginine deiminase inhibitor suppresses neutrophil extracellular trap formation and MPO-ANCA production. Front. Immunol. 7, 227 (2016).

    PubMed  PubMed Central  Google Scholar 

  183. Lood, C. & Hughes, G. C. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford) 56, 638–643 (2017).

    CAS  Google Scholar 

  184. Panda, R. et al. Neutrophil extracellular traps contain selected antigens of anti-neutrophil cytoplasmic antibodies. Front. Immunol. 8, 439 (2017).

    PubMed  PubMed Central  Google Scholar 

  185. Tsiveriotis, K., Tsirogianni, A., Pipi, E., Soufleros, K. & Papasteriades, C. Antineutrophil cytoplasmic antibodies testing in a large cohort of unselected greek patients. Autoimmune Dis. 2011, 626495 (2011).

    PubMed  PubMed Central  Google Scholar 

  186. Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15, 623–625 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Chen, H. H. et al. Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study. Ann. Rheum. Dis. 72, 1206–1211 (2013).

    PubMed  Google Scholar 

  188. Maresz, K. J. et al. Porphyromonas gingivalis facilitates the development and progression of destructive arthritis through its unique bacterial peptidylarginine deiminase (PAD). PLOS Pathog. 9, e1003627 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Quirke, A. M. et al. Heightened immune response to autocitrullinated Porphyromonas gingivalis peptidylarginine deiminase: a potential mechanism for breaching immunologic tolerance in rheumatoid arthritis. Ann. Rheum. Dis. 73, 263–269 (2014).

    CAS  PubMed  Google Scholar 

  190. Makrygiannakis, D. et al. Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells. Ann. Rheum. Dis. 67, 1488–1492 (2008).

    CAS  PubMed  Google Scholar 

  191. McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).

    CAS  PubMed  Google Scholar 

  192. Lee, J. et al. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology (Oxford) 56, 644–653 (2017).

    CAS  Google Scholar 

  193. Johansson, L. et al. Antibodies directed against endogenous and exogenous citrullinated antigens pre-date the onset of rheumatoid arthritis. Arthritis Res. Ther. 18, 127 (2016).

    PubMed  PubMed Central  Google Scholar 

  194. Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLOS ONE 7, e35296 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Corsiero, E., Pratesi, F., Prediletto, E., Bombardieri, M. & Migliorini, P. NETosis as source of autoantigens in rheumatoid arthritis. Front. Immunol. 7, 485 (2016).

    PubMed  PubMed Central  Google Scholar 

  196. Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra140 (2013).

    Google Scholar 

  197. Wang, W., Peng, W. & Ning, X. Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis. Int. J. Rheum. Dis. 21, 415–421 (2018).

    CAS  PubMed  Google Scholar 

  198. Papadaki, G. et al. Neutrophil extracellular traps exacerbate Th1-mediated autoimmune responses in rheumatoid arthritis by promoting DC maturation. Eur. J. Immunol. 46, 2542–2554 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  199. Lapponi, M. J. et al. Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J. Pharmacol. Exp. Ther. 345, 430–437 (2013).

    CAS  PubMed  Google Scholar 

  200. Hakkim, A. et al. Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation. Nat. Chem. Biol. 7, 75–77 (2011).

    CAS  PubMed  Google Scholar 

  201. Metzler, K. D. et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood 117, 953–959 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  202. Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A. & Papayannopoulos, V. A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis. Cell Rep. 8, 883–896 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  203. Rossaint, J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 123, 2573–2584 (2014).

    CAS  PubMed  Google Scholar 

  204. Healy, L. D. et al. Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo. J. Biol. Chem. 292, 8616–8629 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl Med. 8, 361ra138 (2016).

    PubMed  PubMed Central  Google Scholar 

  206. Macanovic, M. 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. 106, 243–252 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  207. 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. 43, 195–205 (2016).

    CAS  PubMed  Google Scholar 

  208. Basnakian, A. G. et al. Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. J. Am. Soc. Nephrol. 16, 697–702 (2005).

    CAS  PubMed  Google Scholar 

  209. Leshner, M. et al. PAD4 mediated histone hypercitrullination induces heterochromatin decondensation and chromatin unfolding to form neutrophil extracellular trap-like structures. Front. Immunol. 3, 307 (2012).

    PubMed  PubMed Central  Google Scholar 

  210. Davis, J. C. Jr. et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68–76 (1999).

    PubMed  Google Scholar 

  211. Garcia, R. J. et al. Attention deficit and hyperactivity disorder scores are elevated and respond to N-acetylcysteine treatment in patients with systemic lupus erythematosus. Arthritis Rheum. 65, 1313–1318 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  212. Lai, Z.-W. et al. N-Acetylcysteine reduces disease activity by blocking mammalian target of rapamycin in T cells from systemic lupus erythematosus patients: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 64, 2937–2946 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  213. Jones, J. E., Causey, C. P., Knuckley, B., Slack-Noyes, J. L. & Thompson, P. R. Protein arginine deiminase 4 (PAD4): current understanding and future therapeutic potential. Curr. Opin. Drug Discov. Devel. 12, 616–627 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Muller, S. & Radic, M. Citrullinated autoantigens: from diagnostic markers to pathogenetic mechanisms. Clin. Rev. Allergy Immunol. 49, 232–239 (2015).

    CAS  PubMed  Google Scholar 

  215. Hemmers, S., Teijaro, J. R., Arandjelovic, S. & Mowen, K. A. PAD4-mediated neutrophil extracellular trap formation is not required for immunity against influenza infection. PLOS ONE 6, e22043 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Ma, A. C. & Kubes, P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J. Thromb. Haemost. 6, 415–420 (2008).

    CAS  PubMed  Google Scholar 

  217. Chen, K. et al. Endocytosis of soluble immune complexes leads to their clearance by FcgammaRIIIB but induces neutrophil extracellular traps via FcgammaRIIA in vivo. Blood 120, 4421–4431 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  218. Kraaij, T. et al. A novel method for high-throughput detection and quantification of neutrophil extracellular traps reveals ROS-independent NET release with immune complexes. Autoimmun. Rev. 15, 577–584 (2016).

    CAS  PubMed  Google Scholar 

  219. Bilyy, R. et al. Neutrophil extracellular traps form a barrier between necrotic and viable areas in acute abdominal inflammation. Front. Immunol. 7, 424 (2016).

    PubMed  PubMed Central  Google Scholar 

  220. Khan, M. A. et al. JNK activation turns on LPS- and gram-negative bacteria-induced NADPH oxidase-dependent suicidal NETosis. Sci. Rep. 7, 3409 (2017).

    PubMed  PubMed Central  Google Scholar 

  221. Bjornsdottir, H. et al. Phenol-soluble modulin alpha peptide toxins from aggressive Staphylococcus aureus induce rapid formation of neutrophil extracellular traps through a reactive oxygen species-independent pathway. Front. Immunol. 8, 257 (2017).

    PubMed  PubMed Central  Google Scholar 

  222. Chen, S. T. et al. CLEC5A is a critical receptor in innate immunity against Listeria infection. Nat. Commun. 8, 299 (2017).

    PubMed  PubMed Central  Google Scholar 

  223. Ramos-Kichik, V. et al. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis 89, 29–37 (2009).

    PubMed  Google Scholar 

  224. Yamamoto, T., Kida, Y., Sakamoto, Y. & Kuwano, K. Mpn491, a secreted nuclease of Mycoplasma pneumoniae, plays a critical role in evading killing by neutrophil extracellular traps. Cell. Microbiol. 19, e12666 (2017).

    Google Scholar 

  225. Mitiku, F. et al. The major membrane nuclease MnuA degrades neutrophil extracellular traps induced by Mycoplasma bovis. Vet. Microbiol. 218, 13–19 (2018).

    CAS  PubMed  Google Scholar 

  226. Byrd, A. S. et al. NETosis in neonates: evidence of a reactive oxygen species-independent pathway in response to fungal challenge. J. Infect. Dis. 213, 634–639 (2016).

    CAS  PubMed  Google Scholar 

  227. Hopke, A. et al. Neutrophil attack triggers extracellular trap-dependent candida cell wall remodeling and altered immune recognition. PLOS Pathog. 12, e1005644 (2016).

    PubMed  PubMed Central  Google Scholar 

  228. Halder, L. D. et al. Factor H binds to extracellular DNA traps released from human blood monocytes in response to Candida albicans. Front. Immunol. 7, 671 (2016).

    PubMed  Google Scholar 

  229. Hopke, A. & Wheeler, R. T. In vitro detection of neutrophil traps and post-attack cell wall changes in candida hyphae. Bio Protoc. 7, e2213 (2017).

    PubMed  PubMed Central  Google Scholar 

  230. Guimaraes-Costa, A. B. et al. Leishmania amazonensis promastigotes induce and are killed by neutrophil extracellular traps. Proc. Natl Acad. Sci. USA 106, 6748–6753 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  231. Guimaraes-Costa, A. B., Nascimento, M. T., Wardini, A. B., Pinto-da-Silva, L. H. & Saraiva, E. M. ETosis: a microbicidal mechanism beyond cell death. J. Parasitol. Res. 2012, 929743 (2012).

    PubMed  PubMed Central  Google Scholar 

  232. Hong, W., Juneau, R. A., Pang, B. & Swords, W. E. Survival of bacterial biofilms within neutrophil extracellular traps promotes nontypeable Haemophilus influenzae persistence in the chinchilla model for otitis media. J. Innate Immun. 1, 215–224 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  233. Vitkov, L., Klappacher, M., Hannig, M. & Krautgartner, W. D. Extracellular neutrophil traps in periodontitis. J. Periodont. Res. 44, 664–672 (2009).

    CAS  Google Scholar 

  234. Bhattacharya, M. et al. Staphylococcus aureus biofilms release leukocidins to elicit extracellular trap formation and evade neutrophil-mediated killing. Proc. Natl Acad. Sci. USA 115, 7416–7421 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  235. Pieterse, E., Rother, N., Yanginlar, C., Hilbrands, L. B. & van der Vlag, J. Neutrophils discriminate between lipopolysaccharides of different bacterial sources and selectively release neutrophil extracellular traps. Front. Immunol. 7, 484 (2016).

    PubMed  PubMed Central  Google Scholar 

  236. Martinelli, S. et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J. Biol. Chem. 279, 44123–44132 (2004).

    CAS  PubMed  Google Scholar 

  237. Gupta, A. K., Hasler, P., Holzgreve, W., Gebhardt, S. & Hahn, S. Induction of neutrophil extracellular DNA lattices by placental microparticles and IL-8 and their presence in preeclampsia. Hum. Immunol. 66, 1146–1154 (2005).

    CAS  PubMed  Google Scholar 

  238. Heeringa, P., Rutgers, A. & Kallenberg, C. G. M. The net effect of ANCA on neutrophil extracellular trap formation. Kidney Int. 94, 14–16 (2018).

    CAS  PubMed  Google Scholar 

  239. Hosseinzadeh, A., Thompson, P. R., Segal, B. H. & Urban, C. F. Nicotine induces neutrophil extracellular traps. J. Leukoc. Biol. 100, 1105–1112 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  240. Neeli, I. & Radic, M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release. Front. Immunol. 4, 38 (2013).

    PubMed  PubMed Central  Google Scholar 

  241. Pang, L., Hayes, C. P., Buac, K., Yoo, D. G. & Rada, B. Pseudogout-associated inflammatory calcium pyrophosphate dihydrate microcrystals induce formation of neutrophil extracellular traps. J. Immunol. 190, 6488–6500 (2013).

    CAS  PubMed  Google Scholar 

  242. Rada, B. Neutrophil extracellular traps and microcrystals. J. Immunol. Res. 2017, 2896380 (2017).

    PubMed  PubMed Central  Google Scholar 

  243. Li, Y., Cao, X., Liu, Y., Zhao, Y. & Herrmann, M. Neutrophil extracellular traps formation and aggregation orchestrate induction and resolution of sterile crystal-mediated inflammation. Front. Immunol. 9, 1559 (2018).

    PubMed  PubMed Central  Google Scholar 

  244. Desai, J. et al. PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling. Eur. J. Immunol. 46, 223–229 (2016).

    CAS  PubMed  Google Scholar 

  245. Sil, P. et al. P2Y6 receptor antagonist MRS2578 inhibits neutrophil activation and aggregated neutrophil extracellular trap formation induced by gout-associated monosodium urate crystals. J. Immunol. 198, 428–442 (2017).

    CAS  PubMed  Google Scholar 

  246. Chatfield, S. M. et al. Monosodium urate crystals generate nuclease-resistant neutrophil extracellular traps via a distinct molecular pathway. J. Immunol. 200, 1802–1816 (2018).

    CAS  PubMed  Google Scholar 

  247. Lewis, H. D. et al. Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation. Nat. Chem. Biol. 11, 189–191 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  248. Parker, H., Dragunow, M., Hampton, M. B., Kettle, A. J. & Winterbourn, C. C. Requirements for NADPH oxidase and myeloperoxidase in neutrophil extracellular trap formation differ depending on the stimulus. J. Leukoc. Biol. 92, 841–849 (2012).

    CAS  PubMed  Google Scholar 

  249. Patel, S. et al. Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation. Nitric Oxide 22, 226–234 (2010).

    CAS  PubMed  Google Scholar 

  250. Zheng, W. et al. PF-1355, a mechanism-based myeloperoxidase inhibitor, prevents immune complex vasculitis and anti-glomerular basement membrane glomerulonephritis. J. Pharmacol. Exp. Ther. 353, 288–298 (2015).

    CAS  PubMed  Google Scholar 

  251. Kirchner, T. et al. The impact of various reactive oxygen species on the formation of neutrophil extracellular traps. Mediators Inflamm. 2012, 849136 (2012).

    PubMed  PubMed Central  Google Scholar 

  252. Folco, E. J. et al. Neutrophil extracellular traps induce endothelial cell activation and tissue factor production through interleukin-1α and cathepsin G. Arterioscler. Thromb. Vasc. Biol. 38, 1901–1912 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  253. Okubo, K. et al. Lactoferrin suppresses neutrophil extracellular traps release in inflammation. EBioMedicine 10, 204–215 (2016).

    PubMed  PubMed Central  Google Scholar 

  254. Gupta, A. K., Giaglis, S., Hasler, P. & Hahn, S. Efficient neutrophil extracellular trap induction requires mobilization of both intracellular and extracellular calcium pools and is modulated by cyclosporine A. PLOS ONE 9, e97088 (2014).

    PubMed  PubMed Central  Google Scholar 

  255. Kirchner, T. et al. Flavonoids and 5-aminosalicylic acid inhibit the formation of neutrophil extracellular traps. Mediators Inflamm. 2013, 710239 (2013).

    PubMed  PubMed Central  Google Scholar 

  256. Frangou, E. 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. 78, 238–248 (2019).

    CAS  PubMed  Google Scholar 

  257. Kambas, K. et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLOS ONE 7, e45427 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  258. Yang, C. & Montgomery, M. Dornase alfa for cystic fibrosis. Cochrane Database Syst. Rev. 9, CD001127 (2018).

    PubMed  Google Scholar 

  259. Yalavarthi, S. et al. Release of neutrophil extracellular traps by neutrophils stimulated with antiphospholipid antibodies: a newly identified mechanism of thrombosis in the antiphospholipid syndrome. Arthritis Rheumatol. 67, 2990–3003 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  260. Dorward, D. A. et al. The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am. J. Pathol. 185, 1172–1184 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  261. Gray, R. D. et al. Activation of conventional protein kinase C (PKC) is critical in the generation of human neutrophil extracellular traps. J. Inflamm. (Lond.) 10, 12 (2013).

    CAS  Google Scholar 

  262. Van Avondt, K., Fritsch-Stork, R., Derksen, R. H. W. M. & Meyaard, L. Ligation of signal inhibitory receptor on leukocytes-1 suppresses the release of neutrophil extracellular traps in systemic lupus erythematosus. PLOS ONE 8, e78459 (2013).

    PubMed  PubMed Central  Google Scholar 

  263. Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15, 1318–1321 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  264. Neeli, I., Dwivedi, N., Khan, S. & Radic, M. Regulation of extracellular chromatin release from neutrophils. J. Innate Immun. 1, 194–201 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  265. Leemans, J. C., Kors, L., Anders, H.-J. & Florquin, S. Pattern recognition receptors and the inflammasome in kidney disease. Nat. Rev. Nephrol. 10, 398–414 (2014).

    CAS  PubMed  Google Scholar 

  266. Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).

    PubMed  PubMed Central  Google Scholar 

  267. Furumoto, Y. et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. 69, 148–160 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  268. van Bijnen, S. T. A., Wouters, D., van Mierlo, G. J., Muus, P. & Zeerleder, S. Neutrophil activation and nucleosomes as markers of systemic inflammation in paroxysmal nocturnal hemoglobinuria: effects of eculizumab. J. Thromb. Haemost. 13, 2004–2011 (2015).

    PubMed  Google Scholar 

  269. Wang, Y. et al. Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5. Proc. Natl Acad. Sci. USA 93, 8563–8568 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Huang, Y.-M., Wang, H., Wang, C., Chen, M. & Zhao, M.-H. Promotion of hypercoagulability in antineutrophil cytoplasmic antibody-associated vasculitis by C5a-induced tissue factor-expressing microparticles and neutrophil extracellular traps. Arthritis Rheumatol. 67, 2780–2790 (2015).

    PubMed  Google Scholar 

  271. Jayne, D. R. W. et al. Randomized trial of C5a receptor inhibitor avacopan in ANCA-associated vasculitis. J. Am. Soc. Nephrol. 28, 2756–2767 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  272. Pickering, M. C. et al. Eculizumab as rescue therapy in severe resistant lupus nephritis. Rheumatology (Oxford) 54, 2286–2288 (2015).

    Google Scholar 

  273. Kumar, P. S. et al. Peptide inhibitor of complement C1 modulates acute intravascular hemolysis of mismatched red blood cells in rats. Transfusion 56, 2133–2145 (2016).

    CAS  PubMed  Google Scholar 

  274. Furie, R. et al. Anifrolumab, an anti-interferon-α receptor monoclonal antibody, in moderate-to-severe systemic lupus erythematosus. Arthritis Rheumatol. 69, 376–386 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  275. Khamashta, M. et al. Sifalimumab, an anti-interferon-α monoclonal antibody, in moderate to severe systemic lupus erythematosus: a randomised, double-blind, placebo-controlled study. Ann. Rheum. Dis. 75, 1909–1916 (2016).

    CAS  PubMed  Google Scholar 

  276. Kalunian, K. C. et al. A phase II study of the efficacy and safety of rontalizumab (rhuMAb interferon-α) in patients with systemic lupus erythematosus (ROSE). Ann. Rheum. Dis. 75, 196–202 (2016).

    PubMed  Google Scholar 

  277. Baccala, R. et al. Anti-IFN-α/β receptor antibody treatment ameliorates disease in lupus-predisposed mice. J. Immunol. 189, 5976–5984 (2012).

    CAS  PubMed  Google Scholar 

  278. Ramani, K. et al. An essential role of interleukin-17 receptor signaling in the development of autoimmune glomerulonephritis. J. Leukoc. Biol. 96, 463–472 (2014).

    PubMed  PubMed Central  Google Scholar 

  279. Tang, S. et al. Neutrophil extracellular trap formation is associated with autophagy-related signalling in ANCA-associated vasculitis. Clin. Exp. Immunol. 180, 408–418 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  280. Handono, K. et al. Vitamin D prevents endothelial damage induced by increased neutrophil extracellular traps formation in patients with systemic lupus erythematosus. Acta Med. Indones. 46, 189–198 (2014).

    PubMed  Google Scholar 

  281. Wahono, C. S. 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. 7, 22–31 (2014).

    PubMed  PubMed Central  Google Scholar 

  282. Reynolds, J., Ray, D., Alexander, M. Y. & Bruce, I. Role of vitamin D in endothelial function and endothelial repair in clinically stable systemic lupus erythematosus. Lancet 385 (Suppl. 1), S83 (2015).

    PubMed  Google Scholar 

  283. Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015).

    CAS  PubMed  Google Scholar 

  284. Wan, T., Zhao, Y., Fan, F., Hu, R. & Jin, X. Dexamethasone inhibits S. aureus-induced neutrophil extracellular pathogen-killing mechanism, possibly through Toll-like receptor regulation. Front. Immunol. 8, 60 (2017).

    PubMed  PubMed Central  Google Scholar 

  285. Shishikura, K. et al. Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. Br. J. Pharmacol. 173, 319–331 (2016).

    CAS  PubMed  Google Scholar 

  286. Domingo-Gonzalez, R. et al. Inhibition of neutrophil extracellular trap formation after stem cell transplant by prostaglandin E2. Am. J. Respir. Crit. Care Med. 193, 186–197 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  287. Apostolidou, E. et al. Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever. Ann. Rheum. Dis. 75, 269–277 (2016).

    CAS  PubMed  Google Scholar 

  288. Smith, C. K. et al. Neutrophil extracellular trap-derived enzymes oxidize high-density lipoprotein: an additional proatherogenic mechanism in systemic lupus erythematosus. Arthritis Rheumatol. 66, 2532–2544 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  289. Sacre, K., Criswell, L. A. & McCune, J. M. Hydroxychloroquine is associated with impaired interferon-alpha and tumor necrosis factor-alpha production by plasmacytoid dendritic cells in systemic lupus erythematosus. Arthritis Res. Ther. 14, R155 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors’ work was partially supported by the German Research Foundation (DFG) (CRC1181 projects C03, A01 and Z02 and TRR241-B04), by the Innovative Medicines Initiative (IMI)-funded RTCure and by Ardea Biosciences, Inc.

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Nature Reviews Nephrology thanks P. Migliorini, and the other anonymous reviewer(s), for their contribution to the peer review of this work.

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All authors contributed equally to this review. M.H. researched data for the article.

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Correspondence to Martin Herrmann.

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Daniel, C., Leppkes, M., Muñoz, L.E. et al. Extracellular DNA traps in inflammation, injury and healing. Nat Rev Nephrol 15, 559–575 (2019). https://doi.org/10.1038/s41581-019-0163-2

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