БИОХИМИЯ, 2020, том 85, вып. 10, с. 1383–1397

УДК 571.27

НЕТоз: молекулярные механизмы, роль в физиологии и патологии

Обзор

© 2020 Н.В. Воробьева 1*, Б.В. Черняк 2

Московский государственный университет имени М.В. Ломоносова, биологический факультет, 119991 Москва, Россия; электронная почта: nvvorobjeva@mail.ru

НИИ физико-химической биологии имени А.Н. Белозерского, Московский государственный университет имени М.В. Ломоносова, 119991 Москва, Россия

Поступила в редакцию 20.06.2020
После доработки 16.07.2020
Принята к публикации 16.07.2020

DOI: 10.31857/S0320972520100061

КЛЮЧЕВЫЕ СЛОВА: нейтрофил, нейтрофильные внеклеточные ловушки, НЕТоз, NADPH-оксидаза, активные формы кислорода, митохондриальная пора, COVID-19.

Аннотация

НЕТоз – это программа образования нейтрофильных внеклеточных ловушек или NET (neutrophil extracellular traps), состоящих из модифицированного хроматина и связанных с ним бактерицидных белков гранул и цитоплазмы. НЕТоз могут вызывать различные патогены, антитела и иммунные комплексы, цитокины, микрокристаллы и другие физиологические стимулы. Индукция НЕТоза зависит от активных форм кислорода (АФК), основным источником которых служит NADPH-оксидаза. Активация NADPH-оксидазы зависит от повышения концентрации Са2+ в цитоплазме и в некоторых случаях от генерации АФК в митохондриях. В процессе НЕТоза происходит выход компонентов гранул в цитозоль, модификация гистонов, ведущая к деконденсации хроматина, разрушение ядерной оболочки, а также образование пор в плазматической мембране. В обзоре обсуждаются основные представления о механизмах НЕТоза, а также роль НЕТоза в патогенезе некоторых заболеваний, включая COVID-19.

Сноски

* Адресат для корреспонденции.

Финансирование

Работа выполнена при финансовой поддержке РФФИ (грант 17-00-00088).

Благодарности

Авторы выражают благодарность сотрудникам НИИ ФХБ им. А.Н. Белозерского МГУ О.Ю. Плетюшкиной, И.И. Галкину, С.А. Голышеву, Р.А. Зиновкину и А.С. Приходько, принявших активное участие в экспериментальной работе, посвященной изучению НЕТоза, дегрануляции и окислительного взрыва нейтрофилов человека. Мы также от всего сердца благодарим Владимира Петровича Скулачева, который инициировал наши работы в области митохондриологии, и поздравляем нашего дорогого учителя с 85-летним юбилеем.

Конфликт интересов

Авторы заявляют об отсутствии конфликта интересов.

Соблюдение этических норм

Настоящая статья не содержит описания каких-либо исследований с использованием животных в качестве объектов.

Список литературы

1. Takei, H., Araki, A., Watanabe, H., Ichinose, A., and Sendo, F. (1996) Rapid killing of human neutrophils by the potent activator phorbol 12-myristate 13-acetate (PMA) accompanied by changes different from typical apoptosis or necrosis, J. Leukoc. Biol., 59, 229-240, doi: 10.1002/jlb.59.2.229.

2. Brinkmann, V., Reichard, U., Goosmann, C., Fauler, B., Uhlemann, Y., Weiss, D. S., Weinrauch, Y., and Zychlinsky, A. (2004) Neutrophil extracellular traps kill bacteria, Science, 303, 1532-1535, doi: 10.1126/science.1092385.

3. Steinberg, B. E., and Grinstein, S. (2007) Unconventional roles of the NADPH oxidase: signaling, ion homeostasis, and cell death, Sci. STKE, 379, pe11, doi: 10.1126/stke.3792007pe11.

4. Vorobjeva, N. V., and Pinegin, B. V. (2014) Neutrophil extracellular traps: mechanisms of formation and role in health and disease, Biochemistry (Moscow), 79, 1286-1296, doi: 10.1134/S0006297914120025.

5. Ravindran, M., Khan, M. A., and Palaniyar, N. (2019) Neutrophil extracellular trap formation: physiology, pathology, and pharmacology, Biomolecules, 9, 365, doi: 10.3390/biom9080365.

6. Yousefi, S., Simon, D., Stojkov, D., Karsonova, A., Karaulov, A., and Simon, H. U. (2020) In vivo evidence for extracellular DNA trap formation, Cell Death Dis., 11, 300, doi: 10.1038/s41419-020-2497-x.

7. Rada, B. (2017) Neutrophil extracellular traps and microcrystals, J. Immunol. Res., 2017, 2896380, doi: 10.1155/2017/2896380.

8. Pinegin, B., Vorobjeva, N., and Pinegin, V. (2015) Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity, Autoimmun. Rev., 14, 633-640, doi: 10.1016/j.autrev.2015.03.002.

9. Remijsen, Q., Vanden Berghe, T., Wirawan, E., Asselbergh, B., Parthoens, E., De Rycke, R., Noppen, S., Delforge, M., Willems, J., and Vandenabeele, P. (2011) Neutrophil extracellular trap cell death requires both autophagy and superoxide generation, Cell Res., 21, 290-304, doi: 10.1038/cr.2010.150.

10. Germic, N., Stojkov, D., Oberson, K., Yousefi, S., Simon, H. U. (2017) Neither eosinophils nor neutrophils require ATG5-dependent autophagy for extracellular DNA trap formation, Immunology, 152, 517-525, doi: 10.1111/imm.12790.

11. Desai, J., Kumar, S. V., Mulay, S. R., Konrad, L., Romoli, S., et al. (2016) PMA and crystal-induced neutrophil extracellular trap formation involves RIPK1-RIPK3-MLKL signaling, Eur. J. Immunol., 46, 223-229, doi: 10.1002/eji.201545605.

12. Schreiber, A., Rousselle, A., Becker, J. U., von Mässenhausen, A., Linkermann, A., and Kettritz, R. (2017) Necroptosis controls NET generation and mediates complement activation, endothelial damage, and autoimmune vasculitis, Proc. Natl. Acad. Sci. USA, 114, E9618-E9625, doi: 10.1073/pnas.1708247114.

13. D’Cruz, A. A., Speir, M., Bliss-Moreau, M., Dietrich, S., Wang, S., et al. (2018) The pseudokinase MLKL activates PAD4-dependent NET formation in necroptotic neutrophils, Sci. Signal., 11, eaao1716, doi: 10.1126/scisignal.aao1716.

14. Pinegin, B., Vorobjeva, N., Pashenkov, M., and Chernyak, B. (2018) The role of mitochondrial ROS in antibacterial immunity, J. Cell. Physiol., 233, 3745-3754, doi: 10.1002/jcp.26117.

15. Vorobjeva, N., Prikhodko, A., Galkin, I., Pletjushkina, O., Zinovkin, R., Sud’ina, G., Chernyak, B., and Pinegin, B. (2017) Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro, Eur. J. Cell. Biol., 96, 254-265, doi: 10.1016/j.ejcb.2017.03.003.

16. Vorobjeva, N., Galkin, I., Pletjushkina, O., Golyshev, S., Zinovkin, R., Prikhodko, A., Pinegin, V., Kondratenko, I., Pinegin, B., and Chernyak, B. (2020) Mitochondrial permeability transition pore is involved in oxidative burst and NETosis of human neutrophils, Biochim. Biophys. Acta Mol. Basis. Dis., 1866, 165664, doi: 10.1016/j.bbadis.2020.165664.

17. Von Köckritz-Blickwede, M., Goldmann, O., Thulin, P., Heinemann, K., Norrby-Teglund, A., Rohde, M., and Medina, E. (2008) Phagocytosis-independent antimicrobial activity of mast cells by means of extracellular trap formation, Blood, 111, 3070-3080, doi: 10.1182/blood-2007-07-104018.

18. Morshed, M., Hlushchuk, R., Simon, D., Walls, A. F., Obata-Ninomiya, K., Karasuyama, H., Djonov, V., Eggel, A., Kaufmann, T., Simon, H. U., and Yousefi, S. (2014) NADPH oxidase-independent formation of extracellular DNA traps by basophils, J. Immunol., 192, 5314-5323, doi: 10.4049/jimmunol.1303418.

19. Granger, V., Faille, D., Marani, V., Noël, B., Gallais, Y., Szely, N., Flament, H., Pallardy, M., Chollet-Martin, S., and de Chaisemartin, L. (2017) Human blood monocytes are able to form extracellular traps, J. Leukoc. Biol., 102, 775-781, doi: 10.1189/jlb.3MA0916-411R.

20. Chow, O. A., von Köckritz-Blickwede, M., Bright, A. T., Hensler, M. E., Zinkernagel, A. S., Cogen, A. L., Gallo, R. L., Monestier, M., Wang, Y., Glass, C. K., and Nizet, V. (2010) Statins enhance formation of phagocyte extracellular traps. Statins enhance formation of phagocyte extracellular traps, Cell. Host Microbe, 8, 445-454, doi: 10.1016/j.chom.2010.10.005.

21. Zhang, X., Zhuchenko, O., Kuspa, A., and Soldati, T. (2016) Social amoebae trap and kill bacteria by casting DNA nets, Nat. Commun., 7, 10938, doi: 10.1038/ncomms10938.

22. Hawes, M., Allen, C., Turgeon, B. G., Curlango-Rivera, G., Minh Tran, T., Huskey, D. A., and Xiong, Z. (2016) Root border cells and their role in lant defense, Annu. Rev. Phytopathol., 54, 143-161, doi: 10.1146/annurev-phyto-080615-100140.

23. Fuchs, T. A., Abed, U., Goosmann, C., Hurwitz, R., Schulze, I., Wahn, V., Weinrauch, Y., Brinkmann, V., and Zychlinsky, A. (2007) Novel cell death program leads to neutrophil extracellular traps, J. Cell. Biol., 176, 231-241, doi: 10.1083/jcb.200606027.

24. Lu, D. J., Furuya, W., and Grinstein, S. (1993) Involvement of multiple kinases in neutrophil activation, Blood Cells, 19, 343-351.

25. Hakkim, A., Fuchs, T. A., Martinez, N. E., Hess, S., Prinz, H., Zychlinsky, A., and Waldmann, H. (2011) Activation of the Raf-MEK-ERK pathway is required for neutrophil extracellular trap formation, Nat. Chem. Biol., 7, 75-77, doi: 10.1038/nchembio.496.

26. Fonseca, Z., Díaz-Godínez, C., Mora, N., Alemán, O. R., Uribe-Querol, E., Carrero, J. C., and Rosales, C. (2018). Entamoeba histolytica induce signaling via Raf/MEK/ERK for neutrophil extracellular trap (NET) formation, Front. Cell. Infect. Microbiol., 8, 226, doi: 10.3389/fcimb.2018.00226.

27. Steinberg, S. F. (2015) Mechanisms for redox-regulation of protein kinase C, Front. Pharmacol., 6, 128, doi: 10.3389/fphar.2015.00128.

28. Trevelin, S. C., and Lopes, L. R. (2015) Protein disulfide isomerase and Nox: new partners in redox signaling, Curr. Pharm. Des., 21, 5951-5963, doi: 10.2174/1381612821666151029112523.

29. Dikalova, A. E., Bikineyeva, A. T., Budzyn, K., Nazarewicz, R. R., McCann, L., Lewis, W., Harrison, D. G., and Dikalov, S. I. (2010) Therapeutic targeting of mitochondrial superoxide in hypertension, Circ. Res., 107, 106-116, doi: 10.1161/CIRCRESAHA.109.214601.

30. Nazarewicz, R. R., Dikalova, A. E., Bikineyeva, A., and Dikalov, S. I. (2013) Nox2 as a potential target of mitochondrial superoxide and its role in endothelial oxidative stress, Am. J. Physiol. Heart Circ. Physiol., 305, H1131-1140, doi: 10.1152/ajpheart.00063.2013.

31. Kröller-Schön, S., Steven, S., Kossmann, S., Scholz, A., Daub, S., et al. (2014) Molecular mechanisms of the crosstalk between mitochondria and NADPH oxidase through reactive oxygen species-studies in white blood cells and in animal models, Antioxid. Redox Signal., 20, 247-266, doi: 10.1089/ars.2012.4953.

32. Douda, D. N., Khan, M. A., Grasemann, H., and Palaniyar, N. (2015) SK3 channel and mitochondrial ROS mediate NADPH oxidase-independent NETosis induced by calcium influx, Proc. Natl. Acad. Sci. USA, 112, 2817-2822, doi: 10.1073/pnas.1414055112.

33. Lood, C., Blanco, L. P., Purmalek, M. M., Carmona-Rivera, C., De Ravin, S. S., et al. (2016) Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease, Nat. Med., 22, 146-153, doi: 10.1038/nm.4027.

34. Kenny, E. F., Herzig, A., Krüger, R., Muth, A., Mondal, S., Thompson, P. R., Brinkmann, V., Bernuth, H. V., and Zychlinsky, A. (2017) Diverse stimuli engage different neutrophil extracellular trap pathways, Elife, 6, pii: e24437, doi: 10.7554/eLife.24437.

35. Vorobjeva, N. V., and Chernyak, B. V. (2020) NADPH oxidase modulates Ca2+-dependent formation of neutrophil extracellular traps, Vestn. Mosk. Univ. Ser. 16. Biol., 75 (in press).

36. Tintinger, G. R., Theron, A. J., Steel, H. C., and Anderson, R. (2001) Accelerated calcium influx and hyperactivation of neutrophils in chronic granulomatous disease, Clin. Exp. Immunol., 123, 254-263, doi: 10.1046/j.1365-2249.2001.01447.x.

37. Bernardi, P., Rasola, A., Forte, M., and Lippe, G. (2015) The mitochondrial permeability transition pore: channel formation by F-ATP synthase, integration in signal transduction, and role in pathophysiology, Physiol. Rev., 95, 1111-1155, doi: 10.1152/physrev.00001.2015.

38. Dumas, J. F., Argaud, L., Cottet-Rousselle, C., Vial, G., Gonzalez, C., Detaille, D., Leverve, X., and Fontaine, E. (2009) Effect of transient and permanent permeability transition pore opening on NAD(P)H localization in intact cells, J. Biol. Chem., 284, 15117-15125, doi: 10.1074/jbc.M900926200.

39. Kroemer, G., Dallaporta, B., and Resche-Rigon, M. (1998) The mitochondrial death/life regulator in apoptosis and necrosis, Annu. Rev. Physiol., 60, 619-642, doi: 10.1146/annurev.physiol.60.1.619.

40. Scorrano, L., Ashiya, M., Buttle, K., Weiler, S., Oakes, S. A., Mannella, C. A., and Korsmeyer, S. J. (2002) A distinct pathway remodels mitochondrial cristae and mobilizes cytochrome c during apoptosis, Dev. Cell, 2, 55-67, doi: 10.1016/S1534-5807(01)00116-2.

41. Griffiths, E. J., and Halestrap, A. P. (1995) Mitochondrial non-specific pores remain closed during cardiac ischaemia, but open upon reperfusion, Biochem. J., 307, 93-98, doi: 10.1042/bj3070093.

42. Metzler, K. D., Goosmann, C., Lubojemska, A., Zychlinsky, A., and Papayannopoulos, V. (2014) A myeloperoxidase-containing complex regulates neutrophil elastase release and actin dynamics during NETosis, Cell. Rep., 8, 883-896, doi: 10.1016/j.celrep.2014.06.044.

43. Papayannopoulos, V., Metzler, K. D., Hakkim, A., and Zychlinsky, A. (2010) Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps, J. Cell. Biol., 191, 677-691, doi: 10.1083/jcb.201006052.

44. Metzler, K. D., Fuchs, T. A., Nauseef, W. M., Reumaux, D., Roesler, J., Schulze, I., Wahn, V., Papayannopoulos, V., and Zychlinsky, A. (2011) Myeloperoxidase is required for neutrophil extracellular trap formation: implications for innate immunity, Blood, 117, 953-959, doi: 10.1182/blood-2010-06-290171.

45. Repnik, U., Hafner Česen, M., and Turk, B. (2014) Lysosomal membrane permeabilization in cell death: concepts and challenges, Mitochondrion, 19 Pt. A, 49-57, doi: 10.1016/j.mito.2014.06.006.

46. Li, P., Li, M., Lindberg, M. R., Kennett, M. J., Xiong, N., and Wang, Y. (2010) PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps, J. Exp. Med., 207, 1853-1862, doi: 10.1084/jem.20100239.

47. Neeli, I., Dwivedi, N., Khan, S., and Radic, M. (2009) Regulation of extracellular chromatin release from neutrophils, J. Innate Immun., 1, 194-201, doi: 10.1159/000206974.

48. Amulic, B., Knackstedt, S. L., Abu Abed, U., Deigendesch, N., Harbort, C. J., Caffrey, B. E., Brinkmann, V., Heppner, F. L., Hinds, P. W., and Zychlinsky, A. (2017) Cell-cycle proteins control production of neutrophil extracellular traps, Dev. Cell, 43, 449-462.e5, doi: 10.1016/j.devcel.2017.10.013.

49. Kambara, H., Liu, F., Zhang, X., Liu, P., Bajrami, B., Teng, Y., Zhao, L., Zhou, S., Yu, H., Zhou, W., Silberstein, L. E., Cheng, T., Han, M., Xu, Y., and Luo, H. R. (2018) Gasdermin D exerts anti-inflammatory effects by promoting neutrophil death, Cell Rep., 22, 2924-2936, doi: 10.1016/j.celrep.2018.02.067.

50. Sollberger, G., Choidas, A., Burn, G. L., Habenberger, P., Di Lucrezia, R., Kordes, S., Menninger, S., Eickhoff, J., Nussbaumer, P., Klebl, B., Krüger, R., Herzig, A., and Zychlinsky, A. (2018) Gasdermin D plays a vital role in the generation of neutrophil extracellular traps, Sci. Immunol., 3, eaar6689, doi: 10.1126/sciimmunol.aar6689.

51. Chen, K. W., Monteleone, M., Boucher, D., Sollberger, G., Ramnath, D., Condon, N. D., von Pein, J. B., Broz, P., Sweet, M. J., and Schroder, K. (2018) Noncanonical inflammasome signaling elicits gasdermin D-dependent neutrophil extracellular traps, Sci. Immunol., 3, eaar6676, doi: 10.1126/sciimmunol.aar6676.

52. Rogers, C., Fernandes-Alnemri, T., Mayes, L., Alnemri, D., Cingolani, G., and Alnemri, E. S. (2017) Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death, Nat. Commun., 8, 14128, doi: 10.1038/ncomms14128.

53. Rogers, C., Erkes, D. A., Nardone, A., Aplin, A. E., Fernandes-Alnemri, T., and Alnemri, E. S. (2019) Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation, Nat. Commun., 10, 1689, doi: 10.1038/s41467-019-09397-2.

54. Maueröder, C., Mahajan, A., Paulus, S., Gößwein, S., Hahn, J., Kienhöfer, D., Biermann, M. H., Tripal, P., Friedrich, R. P., Munoz, L. E., Neurath, M. F., Becker, C., Schett, G. A., Herrmann, M., and Leppkes, M. (2016) Ménage-à-Trois: the ratio of bicarbonate to CO2 and the pH regulate the capacity of neutrophils to form NETs, Front. Immunol., 7, 583, doi: 10.3389/fimmu.2016.00583.

55. Naah de Souza, C., Breda, L. C. D., Khan, M. A., de Almeida, S. R., Câmara, N. O. S., Sweezey, N., and Palaniyar, N. (2017) Alkaline pH promotes NADPH oxidase-independent neutrophil extracellular trap formation: a matter of mitochondrial reactive oxygen species generation and citrullination and cleavage of histone, Front. Immunol., 8, 1849, doi: 10.3389/fimmu.2017.01849.

56. Behnen, M., Möller, S., Brozek, A., Klinger, M., and Laskay, T. (2017) Extracellular acidification inhibits the ROS-dependent formation of neutrophil extracellular traps, Front. Immunol., 8, 184, doi: 10.3389/fimmu.2017.00184.

57. Lodge, K. M., Cowburn, A. S., Li, W., and Condliffe, A. M. (2020) The impact of hypoxia on neutrophil degranulation and consequences for the host, Int. J. Mol. Sci., 21, 1183, doi: 10.3390/ijms21041183.

58. Branitzki-Heinemann, K., Möllerherm, H., Völlger, L., Husein, D. M., de Buhr, N., Blodkamp, S., Reuner, F., Brogden, G., Naim, H. Y., and von Köckritz-Blickwede, M. (2016) Formation of neutrophil extracellular traps under low oxygen level, Front. Immunol., 7, 518, doi: 10.3389/fimmu.2016.00518.

59. Nadesalingam, A., Chen, J. H. K., Farahvash, A., Khan, M. A. (2018) Hypertonic saline suppresses NADPH oxidase-dependent neutrophil extracellular trap formation and promotes apoptosis, Front. Immunol., 9, 359, doi: 10.3389/fimmu.2018.00359.

60. Domingo-Gonzalez, R., Martínez-Colón, G. J., Smith, A. J., Smith, C. K., Ballinger, M. N., Xia, M., Murray, S., Kaplan, M. J., Yanik, G. A., and Moore, B. B. (2016) Inhibition of neutrophil extracellular trap formation after stem cell transplant by prostaglandin E2, Am. J. Respir. Crit. Care Med., 193, 186-197, doi: 10.1164/rccm.201501-0161OC.

61. Shishikura, K., Horiuchi, T., Sakata, N., Trinh, D. A., Shirakawa, R., Kimura, T., Asada, Y., and Horiuchi, H. (2016) Prostaglandin E2 inhibits neutrophil extracellular trap formation through production of cyclic AMP, Br. J. Pharmacol., 173, 319-331, doi: 10.1111/bph.13373.

62. Healy, L. D., Puy, C., Fernández, J. A., Mitrugno, A., Keshari, R. S., Taku, N. A., Chu, T. T., Xu, X., Gruber, A., Lupu, F., Griffin, J. H., and McCarty, O. J. T. (2017) Activated protein C inhibits neutrophil extracellular trap formation in vitro and activation in vivo, J. Biol. Chem., 292, 8616-8629, doi: 10.1074/jbc.M116.768309.

63. Saitoh, T., Komano, J., Saitoh, Y., Misawa, T., Takahama, M., Kozaki, T., Uehata, T., Iwasaki, H., Omori, H., Yamaoka, S., Yamamoto, N., and Akira, S. (2012) Neutrophil extracellular traps mediate a host defense response to human immunodeficiency virus-1, Cell Host Microbe, 12, 109-116, doi: 10.1016/j.chom.2012.05.015.

64. Yost, C. C., Schwertz, H., Cody, M. J., Wallace, J. A., Campbell, R. A., et al. (2016) Neonatal NET-inhibitory factor and related peptides inhibit neutrophil extracellular trap formation, J. Clin. Invest., 126, 3783-3798, doi: 10.1172/JCI83873.

65. Hahn, S., Giaglis, S., Chowdhury, C. S., Hösli, I., and Hasler, P. (2013) Modulation of neutrophil NETosis: interplay between infectious agents and underlying host physiology, Semin. Immunopathol., 35, 439-453, doi: 10.1007/s00281-013-0380-x.

66. Hu, S., Liu, X., Gao, Y., Zhou, R., Wei, M., Dong, J., Yan, H., and Zhao, Y. (2019) Hepatitis B virus inhibits neutrophil extracellular trap release by modulating reactive oxygen species production and autophagy, J. Immunol., 202, 805-815, doi: 10.4049/jimmunol.1800871.

67. Galluzzi, L., Vitale, I., Aaronson, S. A., Abrams, J. M., Adam, D., et al. (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on cell death 2018, Cell. Death Differ., 25, 486-541, doi: 10.1038/s41418-017-0012-4.

68. Clark, S. R., Ma, A. C., Tavener, S. A., McDonald, B., Goodarzi, Z., et al. (2007) Platelet TLR4 activates neutrophil extracellular traps to ensnare bacteria in septic blood, Nat. Med., 13, 463-469, doi: 10.1038/nm1565.

69. Yipp, B. G., Petri, B., Salina, D., Jenne, C. N., Scott, B. N., et al. (2012) Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo, Nat. Med., 18, 1386-1393, doi: 10.1038/nm.2847.

70. Yousefi, S., Gold, J. A., Andina, N., Lee, J. J., Kelly, A. M., Kozlowski, E., Schmid, I., Straumann, A., Reichenbach, J., Gleich, G. J., and Simon, H. U. (2008) Catapult-like release of mitochondrial DNA by eosinophils contributes to antibacterial defense, Nat. Med., 14, 949-953, doi: 10.1038/nm.1855.

71. Yousefi, S., Mihalache, C., Kozlowski, E., Schmid, I., and Simon, H. U. (2009) Viable neutrophils release mitochondrial DNA to form neutrophil extracellular traps, Cell Death Dis., 16, 1438-1444, doi: 10.1038/cdd.2009.96.

72. Ingelsson, B., Söderberg, D., Strid, T., Söderberg, A., Bergh, A. C., Loitto, V., Lotfi, K., Segelmark, M., Spyrou, G., and Rosén, A. (2018) Lymphocytes eject interferogenic mitochondrial DNA webs in response to CpG and non-CpG oligodeoxynucleotides of class C, Proc. Natl. Acad. Sci. USA, 115, E478-E487, doi: 10.1073/pnas.1711950115.

73. Jin, X., Zhao, Y., Zhang, F., Wan, T., Fan, F., Xie, X., and Lin, Z. (2016) Neutrophil extracellular traps involvement in corneal fungal infection, Mol. Vis., 22, 944-952.

74. Shan, Q., Dwyer, M., Rahman, S., and Gadjeva, M. (2014) Distinct susceptibilities of corneal Pseudomonas aeruginosa clinical isolates to neutrophil extracellular trap-mediated immunity, Infect. Immun., 82, 4135-4143, doi: 10.1128/IAI.02169-14.

75. Sonawane, S., Khanolkar, V., Namavari, A., Chaudhary, S., Gandhi, S., et al. (2012) Ocular surface extracellular DNA and nuclease activity imbalance: a new paradigm for inflammation in dry eye disease, Invest. Ophthalmol. Vis. Sci., 53, 8253-8263, doi: 10.1167/iovs.12-10430.

76. Tibrewal, S., Ivanir, Y., Sarkar, J., Nayeb-Hashemi, N., Bouchard, C. S., Kim, E., and Jain, S. (2014) Hyperosmolar stress induces neutrophil extracellular trap formation: implications for dry eye disease, Invest. Ophthalmol. Vis. Sci., 55, 7961-7969, doi: 10.1167/iovs.14-15332.

77. An, S., Raju, I., Surenkhuu, B., Kwon, J. E., Gulati, S., Karaman, M., Pradeep, A., Sinha, S., Mun, C., and Jain, S. (2019) Neutrophil extracellular traps (NETs) contribute to pathological changes of ocular graft-vs.-host disease (oGVHD) dry eye: Implications for novel biomarkers and therapeutic strategies, Ocul. Surf., 17, 589-614, doi: 10.1016/j.jtos.2019.03.010.

78. De Bont, C. M., Stokman, M. E. M., Faas, P., Thurlings, R. M., Boelens, W. C., Wright, H. L., and Pruijn, G. J. (2020) Autoantibodies to neutrophil extracellular traps represent a potential serological biomarker in rheumatoid arthritis, J. Autoimmun., 102484, doi: 10.1016/j.jaut.2020.102484.

79. Brzheskiy, V. V., Efimova, E. L., Vorontsova, T. N., Alekseev, V. N., Gusarevich, O. G., et al. (2015) Results of a multicenter, randomized, double-masked, placebo-controlled clinical study of the efficacy and safety of visomitin eye drops in patients with dry eye syndrome, Adv. Ther., 32, 1263-1279, doi: 10.1007/s12325-015-0273-6.

80. Martinod, K., and Wagner, D. D. (2014) Thrombosis: tangled up in NETs, Blood, 123, 2768-2776, doi: 10.1182/blood-2013-10-463646.

81. Moschonas, I. C., and Tselepis, A. D. (2019) The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis, Atherosclerosis, 288, 9-16, doi: 10.1016/j.atherosclerosis.2019.06.919.

82. Martinod, K., Demers, M., Fuchs, T. A., Wong, S. L., Brill, A., Gallant, M., Hu, J., Wang, Y., and Wagner, D. D. (2013) Neutrophil histone modification by peptidylarginine deiminase 4 is critical for deep vein thrombosis in mice, Proc. Natl. Acad. Sci. USA, 110, 8674-8679, doi: 10.1073/pnas.1301059110.

83. Zucoloto, A. Z., and Jenne, C. N. (2019) Platelet-neutrophil interplay: insights into neutrophil extracellular trap (NET)-driven coagulation in infection, Front. Cardiovasc. Med., 6, 85, doi: 10.3389/fcvm.2019.00085.

84. Novotny, J., Oberdieck, P., Titova, A., Pelisek, J., Chandraratne, S., et al. (2020) Thrombus NET content is associated with clinical outcome in stroke and myocardial infarction, Neurology, 94, e2346-e2360, doi: 10.1212/WNL.0000000000009532.

85. Warnatsch, A., Ioannou, M., Wang, Q., and Papayannopoulos, V. (2015) Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis, Science, 349, 316-320, doi: 10.1126/science.aaa8064.

86. Tsourouktsoglou, T. D., Warnatsch, A., Ioannou, M., Hoving, D., Wang, Q., and Papayannopoulos, V. (2020) Histones, DNA, and citrullination promote neutrophil extracellular trap inflammation by regulating the localization and activation of TLR4, Cell Rep., 31, 107602, doi: 10.1016/j.celrep.2020.107602.

87. Snoderly, H. T., Boone, B. A., and Bennewitz, M. F. (2019) Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment, Breast Cancer Res., 21, 145, doi: 10.1186/s13058-019-1237-6.

88. Breitbach, C. J., De Silva, N. S., Falls, T. J., Aladl, U., Evgin, L., et al. (2011) Targeting tumor vasculature with an oncolytic virus, Mol. Ther., 19, 886-894, doi: 10.1038/mt.2011.26.

89. Leppkes, M., Maueroder, C., Hirth, S., Nowecki, S., Gunther, C., et al. (2016) Externalized decondensed neutrophil chromatin occludes pancreatic ducts and drives pancreatitis, Nat. Commun., 7, 10973, doi: 10.1038/ncomms10973.

90. Muñoz, L. E., Boeltz, S., Bilyy, R., Schauer, C., Mahajan, A., et al. (2019) Neutrophil extracellular traps initiate gallstone formation, Immunity, 51, 443-450.e4, doi: 10.1016/j.immuni.2019.07.002.

91. Twaddell, S. H., Baines, K. J., Grainge, C., and Gibson, P. G. (2019) The emerging role of neutrophil extracellular traps in respiratory disease, Chest, 156, 774-782, doi: 10.1016/j.chest.2019.06.012.

92. Ebrahimi, F., Giaglis, S., Hahn, S., Blum, C. A., Baumgartner, C., Kutz, A., van Breda, S. V., Mueller, B., Schuetz, P., Christ-Crain, M., and Hasler, P. (2018) Markers of neutrophil extracellular traps predict adverse outcome in community-acquired pneumonia: secondary analysis of a randomised controlled trial, Eur. Respir. J., 51, 1701389, doi: 10.1183/13993003.01389-2017.

93. Vassallo, A., Wood, A. J., Subburayalu, J., Summers, C., and Chilvers, E. R. (2019) The counter-intuitive role of the neutrophil in the acute respiratory distress syndrome, Br. Med. Bull., 131, 43-55, doi: 10.1093/bmb/ldz024.

94. Uddin, M., Watz, H., Malmgren, A., and Pedersen, F. (2019) NETopathic inflammation in chronic obstructive pulmonary disease and severe asthma, Front. Immunol., 10, 47, doi: 10.3389/fimmu.2019.00047.

95. Toussaint, M., Jackson, D. J., Swieboda, D., Guedan, A., Tsourouktsoglou, T. D., et al. (2017). Host DNA released by NETosis promotes rhinovirusinduced type-2 allergic asthma exacerbation, Nat. Med., 23, 681-691, doi: 10.1038/nm.4332.

96. Choi, Y., Pham, D., Lee, D.-H., Lee, S.-H., Kim, S.-H., and Park, H.-S. (2018) Biological function of eosinophil extracellular traps in patients with severe eosinophilic asthma, Exp. Mol. Med., 50, 104, doi: 10.1038/s12276-018-0136-8.

97. Mehta, P., McAuley, D. F., Brown, M., Sanchez, E., Tattersall, R. S., and Manson, J. J., HLH Across Speciality Collaboration, UK (2020) COVID-19: con-sider cytokine storm syndromes and immunosuppression, Lancet, 395, 1033-1034, doi: 10.1016/S0140-6736(20)30628-0.

98. Zuo, Y., Yalavarthi, S., Shi, H., Gockman, K., Zuo, M., Madison, J. A., Blair, C. N., Weber, A., Barnes, B. J., Egeblad, M., Woods, R. J., Kanthi, Y., and Knight, J. S. (2020) Neutrophil extracellular traps in COVID-19, JCI insight, 138999. Advance online publication, doi: 10.1172/jci.insight.138999.

99. Yoshida, Y., Takeshita, S., Kawamura, Y., Kanai, T., Tsujita, Y., and Nonoyama, S. (2020) Enhanced formation of neutrophil extracellular traps in Kawasaki disease, Pediatr. Res., 87, 998-1004, doi: 10.1038/s41390-019-0710-3.

100. Barnes, B. J., Adrover, J. M., Baxter-Stoltzfus, A., Borczuk, A., Cools-Lartigue, J., et al. (2020) Targeting potential drivers of COVID-19: neutrophil extracellular traps, J. Exp. Med., 217, e20200652, doi: 10.1084/jem.20200652.

101. Gupta, S., and Kaplan, M. J. (2016) The role of neutrophils and NETosis in autoimmune and renal diseases, Nat. Rev. Nephrol., 12, 402-413, doi: 10.1038/nrneph.2016.71.

102. Fortner, K. A., Blanco, L. P., Buskiewicz, I., Huang, N., Gibson, P. C., et al. (2020) Targeting mitochondrial oxidative stress with MitoQ reduces NET formation and kidney disease in lupus-prone MRL-lpr mice, Lupus Sci. Med., 7, e000387, doi: 10.1136/lupus-2020-000387.

103. Khandpur, R., Carmona-Rivera, C., Vivekanandan-Giri, A., Gizinski, A., Yalavarthi, S., et al. (2013) NETs are a source of citrullinated autoantigens and stimulateinflammatory responses in rheumatoid arthritis, Sci. Transl. Med., 5, 178ra40, doi: 10.1126/scitranslmed.3005580.

104. Wang, W., Peng, W., and Ning, X. (2018) Increased levels of neutrophil extracellular trap remnants in the serum of patients with rheumatoid arthritis, Int. J. Rheum. Dis., 21, 415-421, doi: 10.1111/1756-185X.13226.

105. Carmona-Rivera, C., Carlucci, P. M., Moore, E., Lingampalli, N., Uchtenhagen, H., et al. (2017) Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis, Sci. Immunol., 2, eaag3358, doi: 10.1126/sciimmunol.aag3358.

106. Fousert, E., Toes, R., and Desai, J. (2020) Neutrophil extracellular traps (NETs) take the central stage in driving autoimmune responses, Cells, 9, 915, doi: 10.3390/cells9040915.

107. Schauer, C., Janko, C., Munoz, L. E., Zhao, Y., Kienhöfer, D., et al. (2014) Aggregated neutrophil extracellular traps limit inflammation by degrading cytokines and chemokines, Nat. Med., 20, 511-517, doi: 10.1038/nm.3547.

108. Tagami, T., Tosa, R., Omura, M., Fukushima, H., Kaneko, T., et al. (2014) Effect of a selective neutrophil elastase inhibitor on mortality and ventilator-free days in patients with increased extravascular lung water: a post hoc analysis of the PiCCO pulmonary edema study, J. Intensive Care, 2, 67, doi: 10.1186/s40560-014-0067-y.

109. Hu, J. J., Liu, X., Xia, S., Zhang, Z., Zhang, Y., et al. (2020) FDA-approved disulfiram inhibits pyroptosis by blocking gasdermin D pore formation, Nat. Immunol., 21, 736-745, doi: 10.1038/s41590-020-0669-6.

110. Papayannopoulos, V., Staab, D., and Zychlinsky, A. (2011) Neutrophil elastase enhances sputum solubilization in cystic fibrosis patients receiving DNase therapy, PLoS One, 6, e28526, doi: 10.1371/journal.pone.0028526.

111. Zakharova, V. V., Pletjushkina, O. Y., Galkin, I. I., Zinovkin, R. A., Chernyak, B. V., Krysko, D. V., Bachert, C., Krysko, O., Skulachev, V. P., and Popova, E. N. (2017) Low concentration of uncouplers of oxidative phosphorylation decreases the TNF-induced endothelial permeability and lethality in mice, Biochim. Biophys. Acta. Mol. Basis Dis., 1863, 968-977, doi: 10.1016/j.bbadis.2017.01.024.