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.
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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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).
Brinkmann, V. et al. Neutrophil extracellular traps kill bacteria. Science 303, 1532–1535 (2004).
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).
Leppkes, M. et al. Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis. Nat.Commun. 7, 10973 (2016).
Jimenez-Alcazar, M. et al. Host DNases prevent vascular occlusion by neutrophil extracellular traps. Science 358, 1202–1206 (2017).
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).
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).
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).
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).
McDonald, B. et al. Platelets and neutrophil extracellular traps collaborate to promote intravascular coagulation during sepsis in mice. Blood 129, 1357–1367 (2017).
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).
Cedervall, J. et al. Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice. Oncoimmunology 6, e1320009 (2017).
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).
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).
Fadini, G. P. et al. NETosis delays diabetic wound healing in mice and humans. Diabetes 65, 1061–1071 (2016).
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).
Huang, H. et al. Damage-associated molecular pattern-activated neutrophil extracellular trap exacerbates sterile inflammatory liver injury. Hepatology 62, 600–614 (2015).
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).
Ward, P. A. & Grailer, J. J. Acute lung injury and the role of histones. Transl Respir. Med. 2, 1 (2014).
Luo, L. et al. Proinflammatory role of neutrophil extracellular traps in abdominal sepsis. Am. J. Physiol. Lung Cell. Mol. Physiol. 307, L586–L596 (2014).
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).
Thomas, G. M. et al. Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119, 6335–6343 (2012).
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).
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).
Gupta, S. & Kaplan, M. J. The role of neutrophils and NETosis in autoimmune and renal diseases. Nat. Rev. Nephrol. 12, 402–413 (2016).
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).
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).
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).
Pisetsky, D. S. & Fairhurst, A. M. The origin of extracellular DNA during the clearance of dead and dying cells. Autoimmunity 40, 281–284 (2007).
Huang, L. et al. Eosinophils mediate protective immunity against secondary nematode infection. J. Immunol. 194, 283–290 (2015).
Yousefi, S. et al. Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense. Nat. Med. 14, 949–953 (2008).
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).
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).
Yousefi, S. et al. Basophils exhibit antibacterial activity through extracellular trap formation. Allergy 70, 1184–1188 (2015).
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).
von Kockritz-Blickwede, M. et al. Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation. Blood 111, 3070–3080 (2008).
Reinwald, C. et al. Reply to “Neutrophils are not required for resolution of acute gouty arthritis in mice”. Nat. Med. 22, 1384–1386 (2016).
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).
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).
Li, L. et al. Mouse macrophages capture and kill Giardia lamblia by means of releasing extracellular trap. Dev. Comp. Immunol. 88, 206–212 (2018).
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).
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).
Je, S. et al. Mycobacterium massiliense induces macrophage extracellular traps with facilitating bacterial growth. PLOS ONE 11, e0155685 (2016).
Liu, P. et al. Escherichia coli and Candida albicans induced macrophage extracellular trap-like structures with limited microbicidal activity. PLOS ONE 9, e90042 (2014).
Czaikoski, P. G. et al. Neutrophil extracellular traps induce organ damage during experimental and clinical sepsis. PLOS ONE 11, e0148142 (2016).
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).
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).
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).
Hahn, J. et al. Neutrophils and neutrophil extracellular traps orchestrate initiation and resolution of inflammation. Clin. Exp. Rheumatol. 34, 6–8 (2016).
Lipp, P. et al. Less neutrophil extracellular trap formation in term newborns than in adults. Neonatology 111, 182–188 (2017).
Munoz, L. E. et al. Nanoparticles size-dependently initiate self-limiting NETosis-driven inflammation. Proc. Natl Acad. Sci. USA 113, E5856–E5865 (2016).
Schauer, C. et al. Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines. Nat. Med. 20, 511–517 (2014).
Kienhofer, D. et al. Experimental lupus is aggravated in mouse strains with impaired induction of neutrophil extracellular traps. JCI Insight 2, 92920 (2017).
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).
Martinod, K. et al. Peptidylarginine deiminase 4 promotes age-related organ fibrosis. J. Exp. Med. 214, 439–458 (2017).
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).
Kenny, E. F. et al. Diverse stimuli engage different neutrophil extracellular trap pathways. eLife 6, e24437 (2017).
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).
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).
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).
Delaleu, N. et al. Sjogren’s syndrome patients with ectopic germinal centers present with a distinct salivary proteome. Rheumatology (Oxford) 55, 1127–1137 (2016).
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).
Sakkas, L. I., Daoussis, D., Liossis, S. N. & Bogdanos, D. P. The infectious basis of ACPA-positive rheumatoid arthritis. Front. Microbiol. 8, 1853 (2017).
Mulay, S. R. et al. Calcium oxalate crystals induce renal inflammation by NLRP3-mediated IL-1beta secretion. J. Clin. Invest. 123, 236–246 (2013).
Damby, D. E. et al. Volcanic ash activates the NLRP3 inflammasome in murine and human macrophages. Front. Immunol. 8, 2000 (2017).
Biermann, M. H. et al. Oxidative burst-dependent NETosis is implicated in the resolution of necrosis-associated sterile inflammation. Front. Immunol. 7, 557 (2016).
Rewa, O. & Bagshaw, S. M. Acute kidney injury-epidemiology, outcomes and economics. Nat. Rev. Nephrol. 10, 193–207 (2014).
Rosen, S. & Stillman, I. E. Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation. J. Am. Soc. Nephrol. 19, 871–875 (2008).
Sharfuddin, A. A. & Molitoris, B. A. Pathophysiology of ischemic acute kidney injury. Nat. Rev. Nephrol. 7, 189–200 (2011).
Jang, H. R. & Rabb, H. Immune cells in experimental acute kidney injury. Nat. Rev. Nephrol. 11, 88–101 (2015).
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).
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).
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).
Grams, M. E. & Rabb, H. The distant organ effects of acute kidney injury. Kidney Int. 81, 942–948 (2012).
Rohrbach, A. S., Slade, D. J., Thompson, P. R. & Mowen, K. A. Activation of PAD4 in NET formation. Front. Immunol. 3, 360 (2012).
Ham, A. et al. Peptidyl arginine deiminase-4 activation exacerbates kidney ischemia-reperfusion injury. Am. J. Physiol. Renal Physiol. 307, F1052–F1062 (2014).
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).
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).
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).
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).
Menzies, R. I., Tam, F. W., Unwin, R. J. & Bailey, M. A. Purinergic signaling in kidney disease. Kidney Int. 91, 315–323 (2017).
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).
Carestia, A., Kaufman, T. & Schattner, M. Platelets: new bricks in the building of neutrophil extracellular traps. Front. Immunol. 7, 271 (2016).
Fuchs, T. A. et al. Extracellular DNA traps promote thrombosis. Proc. Natl Acad. Sci. USA 107, 15880–15885 (2010).
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).
Caudrillier, A. et al. Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury. J. Clin. Invest. 122, 2661–2671 (2012).
Brill, A. et al. Neutrophil extracellular traps promote deep vein thrombosis in mice. J. Thromb. Haemost. 10, 136–144 (2012).
Chen, G. et al. Heme-induced neutrophil extracellular traps contribute to the pathogenesis of sickle cell disease. Blood 123, 3818–3827 (2014).
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).
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).
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).
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).
Dalbeth, N., Merriman, T. R. & Stamp, L. K. Gout. Lancet 388, 2039–2052 (2016).
Ungar, H. Experimental production of urate calculi in the urinary tract of white rats. Br. J. Exp. Pathol. 26, 363–366 (1945).
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).
Pieterse, E. et al. Blood-borne phagocytes internalize urate microaggregates and prevent intravascular NETosis by urate crystals. Sci. Rep. 6, 38229 (2016).
Apel, F., Zychlinsky, A. & Kenny, E. F. The role of neutrophil extracellular traps in rheumatic diseases. Nat. Rev. Rheumatol. 14, 467–475 (2018).
Schorn, C. et al. Sodium overload and water influx activate the NALP3 inflammasome. J. Biol. Chem. 286, 35–41 (2011).
Mitroulis, I. et al. Neutrophil extracellular trap formation is associated with IL-1beta and autophagy-related signaling in gout. PLOS ONE 6, e29318 (2011).
Heineke, M. H. et al. New insights in the pathogenesis of immunoglobulin A vasculitis (Henoch-Schonlein purpura). Autoimmun. Rev. 16, 1246–1253 (2017).
Brogan, P. & Eleftheriou, D. Vasculitis update: pathogenesis and biomarkers. Pediatr. Nephrol. 33, 187–198 (2018).
Kawasaki, K. et al. Factor XIII in Henoch-Schonlein purpura with isolated gastrointestinal symptoms. Pediatr. Int. 48, 413–415 (2006).
Semeraro, F. et al. Extracellular histones promote thrombin generation through platelet-dependent mechanisms: involvement of platelet TLR2 and TLR4. Blood 118, 1952–1961 (2011).
Massberg, S. et al. Reciprocal coupling of coagulation and innate immunity via neutrophil serine proteases. Nat. Med. 16, 887–896 (2010).
Petersen, L. C., Bjorn, S. E. & Nordfang, O. Effect of leukocyte proteinases on tissue factor pathway inhibitor. Thromb. Haemost. 67, 537–541 (1992).
Maugeri, N. et al. Human polymorphonuclear leukocytes produce and express functional tissue factor upon stimulation. J. Thromb. Haemost. 4, 1323–1330 (2006).
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).
Ozturk, K. & Ekinci, Z. Is neutrophil-to-lymphocyte ratio valid to predict organ involvement in Henoch-Schonlein purpura? Rheumatol. Int. 36, 1147–1148 (2016).
George, J. N. & Nester, C. M. Syndromes of thrombotic microangiopathy. N. Engl. J. Med. 371, 654–666 (2014).
Brocklebank, V., Wood, K. M. & Kavanagh, D. Thrombotic microangiopathy and the kidney. Clin. J. Am. Soc. Nephrol. 13, 300–317 (2018).
Exeni, R. A. et al. Pathogenic role of inflammatory response during Shiga toxin-associated hemolytic uremic syndrome (HUS). Pediatr. Nephrol. 33, 2057–2071 (2018).
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).
Ramos, M. V. et al. Induction of neutrophil extracellular traps in Shiga toxin-associated hemolytic uremic syndrome. J. Innate Immun. 8, 400–411 (2016).
Gloude, N. J. et al. Circulating dsDNA, endothelial injury, and complement activation in thrombotic microangiopathy and GVHD. Blood 130, 1259–1266 (2017).
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).
Marder, W. et al. Placental histology and neutrophil extracellular traps in lupus and pre-eclampsia pregnancies. Lupus Sci. Med. 3, e000134 (2016).
Leffler, J. et al. Decreased neutrophil extracellular trap degradation in Shiga toxin-associated haemolytic uraemic syndrome. J. Innate Immun. 9, 12–21 (2017).
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).
Singer, M. et al. The Third International Consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315, 801–810 (2016).
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).
Ma, S. et al. Sepsis-induced acute kidney injury: a disease of the microcirculation. Microcirculation 26, e12483 (2019).
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).
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).
Kovach, M. A. & Standiford, T. J. The function of neutrophils in sepsis. Curr. Opin. Infect. Dis. 25, 321–327 (2012).
Fani, F. et al. Recent advances in the pathogenetic mechanisms of sepsis-associated acute kidney injury. J. Nephrol. 31, 351–359 (2018).
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).
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).
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).
Meng, W. et al. Depletion of neutrophil extracellular traps in vivo results in hypersusceptibility to polymicrobial sepsis in mice. Crit. Care 16, R137 (2012).
Martinod, K. et al. PAD4-deficiency does not affect bacteremia in polymicrobial sepsis and ameliorates endotoxemic shock. Blood 125, 1948–1956 (2015).
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).
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).
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).
Clark, S. R. et al. Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood. Nat. Med. 13, 463–469 (2007).
Sreeramkumar, V. et al. Neutrophils scan for activated platelets to initiate inflammation. Science 346, 1234–1238 (2014).
Tanaka, K. et al. In vivo characterization of neutrophil extracellular traps in various organs of a murine sepsis model. PLOS ONE 9, e111888 (2014).
Allam, R. et al. Histones from dying renal cells aggravate kidney injury via TLR2 and TLR4. J. Am. Soc. Nephrol. 23, 1375–1388 (2012).
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).
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).
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).
Hakkim, A. et al. Impairment of neutrophil extracellular trap degradation is associated with lupus nephritis. Proc. Natl Acad. Sci. USA 107, 9813–9818 (2010).
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).
Neeli, I., Khan, S. N. & Radic, M. Histone deimination as a response to inflammatory stimuli in neutrophils. J. Immunol. 180, 1895–1902 (2008).
Wang, L. & Law, H. K. W. Immune complexes suppressed autophagy in glomerular endothelial cells. Cell. Immunol. 328, 1–8 (2018).
Giannakakis, K. & Faraggiana, T. Histopathology of lupus nephritis. Clin. Rev. Allergy Immunol. 40, 170–180 (2011).
Schwartzman-Morris, J. & Putterman, C. Gender differences in the pathogenesis and outcome of lupus and of lupus nephritis. Clin. Dev. Immunol. 2012, 604892 (2012).
Yu, Y. & Su, K. Neutrophil extracellular traps and systemic lupus erythematosus. J. Clin. Cell. Immunol. 4, 139 (2013).
Clarke, S. H. Anti-Sm B cell tolerance and tolerance loss in systemic lupus erythematosus. Immunol. Res. 41, 203–216 (2008).
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).
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).
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).
Bennett, L. et al. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197, 711–723 (2003).
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).
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).
Gestermann, N. et al. Netting neutrophils activate autoreactive B cells in lupus. J. Immunol. 200, 3364–3371 (2018).
Lorenz, G. & Anders, H. J. Neutrophils, dendritic cells, toll-like receptors, and interferon-alpha in lupus nephritis. Semin. Nephrol. 35, 410–426 (2015).
Yu, Y. et al. Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation. Curr. Mol. Med. 15, 401–410 (2015).
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).
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).
Fuchs, T. A. et al. Novel cell death program leads to neutrophil extracellular traps. J. Cell Biol. 176, 231–241 (2007).
Li, P. et al. PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. J. Exp. Med. 207, 1853–1862 (2010).
Wang, Y. et al. Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. J. Cell Biol. 184, 205–213 (2009).
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).
Campbell, A. M., Kashgarian, M. & Shlomchik, M. J. NADPH oxidase inhibits the pathogenesis of systemic lupus erythematosus. Sci. Transl Med. 4, 157ra141 (2012).
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).
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).
Knight, J. S. et al. Peptidylarginine deiminase inhibition is immunomodulatory and vasculoprotective in murine lupus. J. Clin. Invest. 123, 2981–2993 (2013).
Gordon, R. A. et al. Lupus and proliferative nephritis are PAD4 independent in murine models. JCI Insight 2, 92926 (2017).
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).
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).
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).
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).
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).
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).
Majetschak, M. Extracellular ubiquitin: immune modulator and endogenous opponent of damage-associated molecular pattern molecules. J. Leukoc. Biol. 89, 205–219 (2011).
Barrera-Vargas, A. et al. Differential ubiquitination in NETs regulates macrophage responses in systemic lupus erythematosus. Ann. Rheum. Dis. 77, 944–950 (2018).
Soderberg, D. & Segelmark, M. Neutrophil extracellular traps in ANCA-associated vasculitis. Front. Immunol. 7, 256 (2016).
Cossarizza, A. et al. Guidelines for the use of flow cytometry and cell sorting in immunological studies. Eur. J. Immunol. 47, 1584–1797 (2017).
Poli, C. et al. IL-26 confers proinflammatory properties to extracellular DNA. J. Immunol. 198, 3650–3661 (2017).
Schreiber, A. et al. C5a receptor mediates neutrophil activation and ANCA-induced glomerulonephritis. J. Am. Soc. Nephrol. 20, 289–298 (2009).
Kolaczkowska, E. et al. Molecular mechanisms of NET formation and degradation revealed by intravital imaging in the liver vasculature. Nat. Commun. 6, 6673 (2015).
Kusunoki, Y. et al. Peptidylarginine deiminase inhibitor suppresses neutrophil extracellular trap formation and MPO-ANCA production. Front. Immunol. 7, 227 (2016).
Lood, C. & Hughes, G. C. Neutrophil extracellular traps as a potential source of autoantigen in cocaine-associated autoimmunity. Rheumatology (Oxford) 56, 638–643 (2017).
Panda, R. et al. Neutrophil extracellular traps contain selected antigens of anti-neutrophil cytoplasmic antibodies. Front. Immunol. 8, 439 (2017).
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).
Kessenbrock, K. et al. Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15, 623–625 (2009).
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).
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).
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).
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).
McInnes, I. B. & Schett, G. The pathogenesis of rheumatoid arthritis. N. Engl. J. Med. 365, 2205–2219 (2011).
Lee, J. et al. Nicotine drives neutrophil extracellular traps formation and accelerates collagen-induced arthritis. Rheumatology (Oxford) 56, 644–653 (2017).
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).
Sokolove, J. et al. Autoantibody epitope spreading in the pre-clinical phase predicts progression to rheumatoid arthritis. PLOS ONE 7, e35296 (2012).
Corsiero, E., Pratesi, F., Prediletto, E., Bombardieri, M. & Migliorini, P. NETosis as source of autoantigens in rheumatoid arthritis. Front. Immunol. 7, 485 (2016).
Khandpur, R. et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci. Transl Med. 5, 178ra140 (2013).
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).
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).
Lapponi, M. J. et al. Regulation of neutrophil extracellular trap formation by anti-inflammatory drugs. J. Pharmacol. Exp. Ther. 345, 430–437 (2013).
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).
Metzler, K. D. et al. Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity. Blood 117, 953–959 (2011).
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).
Rossaint, J. et al. Synchronized integrin engagement and chemokine activation is crucial in neutrophil extracellular trap-mediated sterile inflammation. Blood 123, 2573–2584 (2014).
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).
Park, J. et al. Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Sci. Transl Med. 8, 361ra138 (2016).
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).
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).
Basnakian, A. G. et al. Cisplatin nephrotoxicity is mediated by deoxyribonuclease I. J. Am. Soc. Nephrol. 16, 697–702 (2005).
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).
Davis, J. C. Jr. et al. Recombinant human Dnase I (rhDNase) in patients with lupus nephritis. Lupus 8, 68–76 (1999).
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).
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).
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).
Muller, S. & Radic, M. Citrullinated autoantigens: from diagnostic markers to pathogenetic mechanisms. Clin. Rev. Allergy Immunol. 49, 232–239 (2015).
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).
Ma, A. C. & Kubes, P. Platelets, neutrophils, and neutrophil extracellular traps (NETs) in sepsis. J. Thromb. Haemost. 6, 415–420 (2008).
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).
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).
Bilyy, R. et al. Neutrophil extracellular traps form a barrier between necrotic and viable areas in acute abdominal inflammation. Front. Immunol. 7, 424 (2016).
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).
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).
Chen, S. T. et al. CLEC5A is a critical receptor in innate immunity against Listeria infection. Nat. Commun. 8, 299 (2017).
Ramos-Kichik, V. et al. Neutrophil extracellular traps are induced by Mycobacterium tuberculosis. Tuberculosis 89, 29–37 (2009).
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).
Mitiku, F. et al. The major membrane nuclease MnuA degrades neutrophil extracellular traps induced by Mycoplasma bovis. Vet. Microbiol. 218, 13–19 (2018).
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).
Hopke, A. et al. Neutrophil attack triggers extracellular trap-dependent candida cell wall remodeling and altered immune recognition. PLOS Pathog. 12, e1005644 (2016).
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).
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).
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).
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).
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).
Vitkov, L., Klappacher, M., Hannig, M. & Krautgartner, W. D. Extracellular neutrophil traps in periodontitis. J. Periodont. Res. 44, 664–672 (2009).
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).
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).
Martinelli, S. et al. Induction of genes mediating interferon-dependent extracellular trap formation during neutrophil differentiation. J. Biol. Chem. 279, 44123–44132 (2004).
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).
Heeringa, P., Rutgers, A. & Kallenberg, C. G. M. The net effect of ANCA on neutrophil extracellular trap formation. Kidney Int. 94, 14–16 (2018).
Hosseinzadeh, A., Thompson, P. R., Segal, B. H. & Urban, C. F. Nicotine induces neutrophil extracellular traps. J. Leukoc. Biol. 100, 1105–1112 (2016).
Neeli, I. & Radic, M. Opposition between PKC isoforms regulates histone deimination and neutrophil extracellular chromatin release. Front. Immunol. 4, 38 (2013).
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).
Rada, B. Neutrophil extracellular traps and microcrystals. J. Immunol. Res. 2017, 2896380 (2017).
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).
Desai, J. et al. PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling. Eur. J. Immunol. 46, 223–229 (2016).
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).
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).
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).
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).
Patel, S. et al. Nitric oxide donors release extracellular traps from human neutrophils by augmenting free radical generation. Nitric Oxide 22, 226–234 (2010).
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).
Kirchner, T. et al. The impact of various reactive oxygen species on the formation of neutrophil extracellular traps. Mediators Inflamm. 2012, 849136 (2012).
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).
Okubo, K. et al. Lactoferrin suppresses neutrophil extracellular traps release in inflammation. EBioMedicine 10, 204–215 (2016).
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).
Kirchner, T. et al. Flavonoids and 5-aminosalicylic acid inhibit the formation of neutrophil extracellular traps. Mediators Inflamm. 2013, 710239 (2013).
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).
Kambas, K. et al. Autophagy mediates the delivery of thrombogenic tissue factor to neutrophil extracellular traps in human sepsis. PLOS ONE 7, e45427 (2012).
Yang, C. & Montgomery, M. Dornase alfa for cystic fibrosis. Cochrane Database Syst. Rev. 9, CD001127 (2018).
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).
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).
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).
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).
Xu, J. et al. Extracellular histones are major mediators of death in sepsis. Nat. Med. 15, 1318–1321 (2009).
Neeli, I., Dwivedi, N., Khan, S. & Radic, M. Regulation of extracellular chromatin release from neutrophils. J. Innate Immun. 1, 194–201 (2009).
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).
Wolach, O. et al. Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms. Sci. Transl Med. 10, eaan8292 (2018).
Furumoto, Y. et al. Tofacitinib ameliorates murine lupus and its associated vascular dysfunction. Arthritis Rheumatol. 69, 148–160 (2017).
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).
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).
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).
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).
Pickering, M. C. et al. Eculizumab as rescue therapy in severe resistant lupus nephritis. Rheumatology (Oxford) 54, 2286–2288 (2015).
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).
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).
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).
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).
Baccala, R. et al. Anti-IFN-α/β receptor antibody treatment ameliorates disease in lupus-predisposed mice. J. Immunol. 189, 5976–5984 (2012).
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).
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).
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).
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).
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).
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).
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).
Shishikura, K. et al. Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP. Br. J. Pharmacol. 173, 319–331 (2016).
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).
Apostolidou, E. et al. Neutrophil extracellular traps regulate IL-1β-mediated inflammation in familial Mediterranean fever. Ann. Rheum. Dis. 75, 269–277 (2016).
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).
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).
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.
Nature Reviews Nephrology thanks P. Migliorini, and the other anonymous reviewer(s), for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Breakdown of striated muscle cells and the release of intracellular muscle components into the circulation that are potentially toxic.
Nonblanchable, haemorrhagic skin lesions resulting from the leakage of red blood cells into the skin.
- Microangiopathic haemolytic anaemia
Non-immune haemolytic anaemia that results from traumatic intravascular fragmentation of red blood cells.
- Malignant hypertension
Serious complication of high blood pressure characterized by progressive target organ damage.
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Elevation of the mitochondrial transmembrane potential (ΔΨm).
- Papillon–Lefévre syndrome
Autosomal recessive genetic disorder caused by a deficiency in cathepsin C and characterized by severe periodontitis and palmoplantar keratoderma.
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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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