Pediatric Hematology/Oncology and ImmunopathologyPediatric Hematology/Oncology and ImmunopathologyВопросы гематологии/онкологии и иммунопатологии в педиатрии1726-17082414-9314Fund Doctors, Innovations, Science for Children85210.24287/1726-1708-2024-23-1-211-218LITERATURE REVIEWОБЗОР ЛИТЕРАТУРЫConditions for the implementation of the phenomenon of programmed death of neutrophils with the appearance of DNA extracellular traps during thrombus formationУсловия реализации феномена запрограммированной гибели нейтрофилов с появлением внеклеточных ДНК-ловушек при тромбообразованииhttps://orcid.org/0000-0003-4720-7319SveshnikovaA. N.СвешниковаА. Н.
Russian Federation

Anastasia N. Sveshnikova, Dr. Sci. in Physics and Mathematics, Head of the Laboratory

Laboratory of Cellular Biology and Translational Medicine

117997; 1 Samory Mashela St.; Moscow

Анастасия Никитична Свешникова, д-р физ.-мат. наук, заведующая лабораторией

лаборатория клеточной биологии и трансляционной медицины

117997; ул. Саморы Машела, 1; Москва

a.sveshnikova@physics.msu.ruhttps://orcid.org/0009-0000-4828-4063AdamanskayaE. A.АдаманскаяЕ. А.
Russian Federation

Moscow

Москва

https://orcid.org/0000-0002-8128-7757PanteleevM. A.ПантелеевМ. А.
Russian Federation

Moscow

Москва

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian FederationФГБУ «Национальный медицинский исследовательский центр детской гематологии, онкологии и иммунологии им. Дмитрия Рогачева» Минздрава РоссииM.V. Lomonosov Moscow State UniversityФГБОУ ВО «Московский государственный университет им. М.В. Ломоносова»Center for Theoretical Problems of Physical and Chemical Pharmacology, Russian Academy of SciencesФГБУН «Центр теоретических проблем физико-химической фармакологии» РАН190420242312112181904202419042024Copyright ©; 2024, «D. Rogachev NMRCPHOI»Copyright ©; 2024, ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России2024«D. Rogachev NMRCPHOI»ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава Россииhttps://creativecommons.org/licenses/by/4.0https://hemoncim.com/jour/article/view/852

   The formation of DNA extracellular traps of neutrophils (NET-osis) is a mechanism of programmed cell death of leukocytes, which initially has antibacterial and antifungal functions. The ability of neutrophils to become activated upon contact with activated platelets and, in turn, to activate the contact coagulation pathway via DNA traps plays a central role in venous thrombosis and disseminated intravascular coagulation in COVID-19. At the same time, the intracellular signaling that controls NET-osis is extremely poorly understood even for the simplest cases, when this process is caused by lipopolysaccharides of the bacterial cell wall. In this review, we consider the case of NET-osis in thrombosis, for which there are even more questions. We focused on the conditions for NET-osis observation and features in different scenarios.

   Формирование внеклеточных ДНК-ловушек нейтрофилов (NET-оз) – механизм запрограммированной клеточной смерти лейкоцитов, имеющий исходно антибактериальную и противогрибковую функции. Способность нейтрофилов активироваться при контакте с активированными тромбоцитами и, в свою очередь, активировать контактный путь свертывания с помощью ДНК-ловушек играет центральную роль в венозных тромбозах и диссеминированном внутрисосудистом свертывании крови при COVID-19. При этом внутриклеточная сигнализация, управляющая NET-озом, является крайне плохо понятной даже для простейших случаев, когда этот процесс вызывается липополисахаридами бактериальной стенки. В настоящем обзоре мы рассматриваем случай NET-оза при тромбозе, для которого вопросов еще больше. Внимание сосредоточено на условиях наблюдения NET-оза и особенностях его протекания при разных сценариях.

neutrophilsDNA-trapsintracellular signalingthrombosisнейтрофилыДНК-ловушкивнутриклеточная сигнализациятромбозыThis work was supported by a grant from the Ministry of Science and higher education of the Russian Federation No. 075-15-2022-242Работа выполнена при поддержке гранта Министерства науки и высшего образования Российской Федерации № 075-15-2022-242Robb C.T., Dyrynda E.A., Gray R.D., Rossi A.G., Smith V.J. Invertebrate Extracellular Phagocyte Traps Show That Chromatin Is an Ancient Defence Weapon. Nat Commun 2014; 5: 4627. DOI: 10.1038/ncomms5627Daniel C., Leppkes M., Muñoz L.E., Schley G., Schett G., Herrmann M. Extracellular DNA Traps in Inflammation, Injury and Healing. Nat Rev Nephrol 2019; 15: 559–75. DOI: 10.1038/s41581-019-0163-2Palacios-Acedo A.L., Mège D., Crescence L., Dignat-George F., Dubois C., Panicot-Dubois L. Platelets, Thrombo-Inflammation, and Cancer: Collaborating With the Enemy. Front Immunol 2019; 10: 1805. DOI: 10.3389/fimmu.2019.01805Sveshnikova A.N., Ataullakhanov F.I., Panteleev M.A. Compartmentalized Calcium Signaling Triggers Subpopulation Formation upon Platelet Activation through PAR1. Mol BioSyst 2015; 11: 1052–60. DOI: 10.1039/c4mb00667dCaudrillier A., Kessenbrock K., Gilliss B.M., Nguyen J.X., Marques M.B., Monestier M., et al. Platelets Induce Neutrophil Extracellular Traps in Transfusion-Related Acute Lung Injury. J Clin Invest 2012; 122: 2661–71. DOI: 10.1172/JCI61303Golas A., Parhi P., Dimachkie Z.O., Siedlecki C.A., Vogler E.A. Surface-Energy Dependent Contact Activation of Blood Factor XII. Biomaterials 2010; 31: 1068–79. DOI:10.1016/j.biomaterials.2009.10.039Fuchs T.A., Brill A., Wagner D.D. Neutrophil Extracellular Trap (NET) Impact on Deep Vein Thrombosis. Arterioscler Thromb Vasc Biol 2012; 32: 1777–83. DOI: 10.1161/ATVBAHA.111.242859Brinkmann V., Reichard U., Goosmann C., Fauler B., Uhlemann Y., Weiss D.S., et al. Neutrophil Extracellular Traps Kill Bacteria. Science 2004; 303: 1532–5. DOI: 10.1126/science.1092385Rosales C. Neutrophil: A Cell with Many Roles in Inflammation or Several Cell Types? Front Physiol 2018; 9: 113.Kozlov S.O., Kudryavtsev I.V., Grudinina N.A., Kostevich V.A., Panasenko O.M., Sokolov A.V., Vasilyev V.B. Activated producing HOCL neutrophils revealed by flow cytometry and confocal microscopy with celestine blue B. Acta Biomedica Scientifica 2016; 1 (3(2)): 86–91. DOI: 10.12737/article_590823a4895537.04307905 (In Russ.)Козлов С.О., Кудрявцев И.В., Грудинина Н.А., Костевич В.А., Панасенко О.М., Соколов А.В., Васильев В.Б. Активированные нейтрофилы, продуцирующие HOCL, выявляющиеся при проточной цитометрии и конфокальной микроскопии с помощью целестинового синего В. Acta Biomedica Scientifica 2016; 1 (3(2)): 86–91. DOI: 10.12737/article_590823a4895537.04307905.Bratton D.L., Henson P.M. Neutrophil Clearance: When the Party Is over, Clean-up Begins. Trends Immunol 2011; 32: 350–7. DOI: 10.1016/j.it.2011.04.009Hoffbrand V., Vyas P., Campo E., Haferlach T., Gomez K. Color Atlas of Clinical Hematology: Molecular and Cellular Basis of Disease. John Wiley & Sons; 2019. ISBN 978-1-119-05701-7.Borregaard N., Sørensen O.E., Theilgaard-Mönch K. Neutrophil Granules: A Library of Innate Immunity Proteins. Trends Immunol 2007; 28: 340–5. DOI:10.1016/j.it.2007.06.002Pogorelov V., Kozinets G., Diaghileva O., Lugovskaya S., Protsenko D., Sarycheva T. Hematological atlas. Laboratory physician's desk manual. Litres; 2022. ISBN 978-5-04-256439-0. (In Russ.)Погорелов В., Козинец Г., Дягилева О., Луговская С., Проценко Д., Сарычева Т. Гематологический атлас. Настольное руководство врача-лаборанта. Litres; 2022. ISBN 978-5-04-256439-0.Murphy K.M., Weaver C. Janeway’s Immunobiology; Garland Science/Taylor & Francis Group, LLC; 2017. ISBN 978-0-8153-4505-3.Adamanskaya E.A., Yushkova E.B., Fedorova D.V., Sokolov A.V., Podoplelova N.A., Sveshnikova A.N. Methodology for Observing Neutrophil DNA Traps in Blood Samples of Pediatric Patients. Abstracts of the XXIV Congress of the Physiological Society named after I.P. Pavlov. St. Petersburg: VVM Publishing House LLC; 2023.Адаманская Е.А., Юшкова E.B., Федорова Д.В., Соколов А.В., Подоплелова Н.А., Свешникова А.Н. Методика наблюдения ДНК-ловушек нейтрофилов в образцах крови педиатрических пациентов. Сборник тезисов XXIV съезда физиологического общества им. И.П. Павлова. СПб.: ООО «Издательство ВВМ»; 2023.Nathan C. Neutrophils and Immunity: Challenges and Opportunities. Nat Rev Immunol 2006; 6: 173–82. DOI: 10.1038/nri1785Segal A.W. How Neutrophils Kill Microbes. Ann Rev Immunol 2005; 23: 197–223. DOI: 10.1146/annurev.immunol.23.021704.115653Mayadas T.N., Cullere X., Lowell C.A. The Multifaceted Functions of Neutrophils. Annu Rev Pathol 2014; 9: 181–218. DOI: 10.1146/annurev-pathol-020712-164023Witko-Sarsat V., Rieu P., Descamps-Latscha B., Lesavre P., Halbwachs-Mecarelli L. Neutrophils: Molecules, Functions and Pathophysiological Aspects. Lab Invest 2000; 80: 617–53. DOI: 10.1038/labinvest.3780067Smith C.K., Kaplan M.J. The Role of Neutrophils in the Pathogenesis of Systemic Lupus Erythematosus. Curr Opin Rheumatol 2015; 27: 448. DOI: 10.1097/BOR.0000000000000197Yu Y., Su K. Neutrophil Extracellular Traps and Systemic Lupus Erythematosus. J Clin Cell Immunol 2013; 4: 139. DOI: 10.4172/2155-9899.1000139Summers C., Rankin S.M., Condliffe A.M., Singh N., Peters A.M., Chilvers E.R. Neutrophil Kinetics in Health and Disease. Trends Immunol 2010; 31: 318–24. DOI: 10.1016/j.it.2010.05.006Petri B., Sanz M.-J. Neutrophil Chemotaxis. Cell Tissue Res 2018; 371: 425–36. DOI: 10.1007/s00441-017-2776-8Murphy P.M. Neutrophil Receptors for Interleukin-8 and Related CXC Chemokines. Semin Hematol 1997; 34: 311–8.Schoenwaelder S.M., Ruggeri Z.M., Westein E., Kaplan Z.S., Jackson S.P., Ashworth K.J., et al. The CXCR1/2 Ligand NAP-2 Promotes Directed Intravascular Leukocyte Migration through Platelet Thrombi. Blood 2013; 121: 4555–66. DOI: 10.1182/blood-2012-09-459636Damascena H.L., Silveira W.A.A., Castro M.S., Fontes W. Neutrophil Activated by the Famous and Potent PMA (Phorbol Myristate Acetate). Cells 2022; 11: 2889. DOI: 10.3390/cells11182889Karpurapu M., Lee, Y.G., Qian Z., Wen J., Ballinger M.N., Rusu L., et al. Inhibition of Nuclear Factor of Activated T Cells (NFAT) C3 Activation Attenuates Acute Lung Injury and Pulmonary Edema in Murine Models of Sepsis. Oncotarget 2018; 9: 10606–20. DOI: 10.18632/oncotarget.24320Zanoni I., Ostuni R., Capuano G., Collini M., Caccia M., Ronchi A.E., et al. CD14 Regulates the Dendritic Cell Life Cycle after LPS Exposure through NFAT Activation. Nature 2009; 460 (7252): 264–8. DOI: 10.1038/nature08118Businaro R., Scaccia E., Bordin A., Pagano F., Corsi M., Siciliano C., et al. Platelet Lysate-Derived Neuropeptide y Influences Migration and Angiogenesis of Human Adipose Tissue-Derived Stromal Cells. Sci Rep 2018; 8: 14365. DOI: 10.1038/s41598-018-32623-8Cassatella M.A. The Neutrophil: An Emerging Regulator of Inflammatory and Immune Response. Karger Medical and Scientific Publishers; 2003. ISBN 978-3-8055-7552-2.Lindbom L., Werr J. Integrin-Dependent Neutrophil Migration in Extravascular Tissue. Semin Immunol 2002; 14: 115–21. DOI: 10.1006/smim.2001.0348Pluskota E., Soloviev D.A., Szpak D., Weber C., Plow E.F. Neutrophil Apoptosis: Selective Regulation by Different Ligands of Integrin aMb2. J Immunol 2008; 181: 3609–19.Ugarova T.P., Yakubenko V.P. Recognition of Fibrinogen by Leukocyte Integrins. Ann N Y Acad Sci 2001; 936: 368–85. DOI: 10.1111/j.1749-6632.2001.tb03523.xZarbock A., Ley K. Platelet-Neutrophil-Interactions: Linking Hemostasis and Inflammation. Blood Rev 2007; 21 (2): 99–111. DOI: 10.1016/j.blre.2006.06.001Yago T., Shao B., Miner J.J., Yao L., Klopocki A.G., Maeda K., et al. E-Selectin Engages PSGL-1 and CD44 through a Common Signaling Pathway to Induce Integrin aLb2-Mediated Slow Leukocyte Rolling. Blood 2010; 116: 485–94. DOI: 10.1182/blood-2009-12-259556Zhou F., Zhang F., Zarnitsyna V.I., Doudy L., Yuan Z., Li K., et al. The Kinetics of E-Selectin- and P-Selectin-Induced Intermediate Activation of Integrin aLb2 on Neutrophils. J Cell Sci 2021; 134: jcs258046. DOI: 10.1242/jcs.258046Jenne C.N., Kubes P. Platelets in Inflammation and Infection. Platelets 2015; 26: 286–92. DOI: 10.3109/09537104.2015.1010441Koupenova M., Corkrey H.A., Vitseva O., Manni G., Pang C.J., Clancy L., et al. The Role of Platelets in Mediating a Response to Human Influenza Infection. Nat Commun 2019; 10: 1780. DOI: 10.1038/s41467-019-09607-xSveshnikova A., Stepanyan M., Panteleev M. Platelet Functional Responses and Signalling: The Molecular Relationship. Part 1: Responses. Systems Biol Physiol Rep 2021; 1: 20. DOI: 10.52455/sbpr.01.202101014Nicolai L., Schiefelbein K., Lipsky S., Leunig A., Hoffknecht M., Pekayvaz K., et al. Vascular Surveillance by Haptotactic Blood Platelets in Inflammation and Infection. Nat Commun 2020; 11: 5778. DOI: 10.1038/s41467-020-19515-0Gros A., Syvannarath V., Lamrani L., Ollivier V., Loyau S., Goerge T., et al. Single Platelets Seal Neutrophil-Induced Vascular Breaches via GPVI during Immune-Complex-Mediated Inflammation in Mice. Blood 2015; 126: 1017–26. DOI: 10.1182/blood-2014-12-617159Knorr D.A., Bachanova V., Verneris M.R., Miller J.S. Clinical Utility of Natural Killer Cells in Cancer Therapy and Transplantation. Semin Immunol 2014; 26: 161–72. DOI: 10.1016/j.smim.2014.02.002Shannon O. The Role of Platelets in Sepsis. Res Pract Thromb Haemost 2021; 5: 27–37. DOI: 10.1002/rth2.12465Schattner M., Jenne C.N., Negrotto S., Ho-Tin-Noe B. Editorial: Platelets and Immune Responses During Thromboinflammation. Front Immunol 2020; 11: 1079. DOI: 10.3389/fimmu.2020.01079Bonaventura A., Vecchié A., Dagna L., Martinod K., Dixon D.L., van Tassell B.W., et al. Endothelial Dysfunction and Immunothrombosis as Key Pathogenic Mechanisms in COVID-19. Nat Rev Immunol 2021; 21: 319–29. DOI: 10.1038/s41577-021-00536-9Zhu Y., Chen X., Liu X. NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond. Front Immunol 2022; 13: 838011. DOI: 10.3389/fimmu.2022.838011.de Bont C.M., Koopman W.J.H., Boelens W.C., Pruijn G.J.M. Stimulus-Dependent Chromatin Dynamics, Citrullination, Calcium Signalling and ROS Production during NET Formation. Biochim Biophys Acta Mol Cell Res 2018; 1865: 1621–9. DOI:10.1016/j.bbamcr.2018.08.014Khan M.A., Farahvash A., Douda D.N., Licht, J.-C., Grasemann H., Sweezey N., Palaniyar N. JNK Activation Turns on LPS- and Gram-Negative Bacteria-Induced NADPH Oxidase-Dependent Suicidal NETosis. Sci Rep 2017; 7: 3409. DOI: 10.1038/s41598-017-03257-zAgarwal S., Loder S., Cholok D., Li J., Bian G., Yalavarthi S., et al. Disruption of Neutrophil Extracellular Traps (NETs) Links Mechanical Strain to Post-Traumatic Inflammation. Front Immunol 2019; 10: 2148. DOI: 10.3389/fimmu.2019.02148Pai D., Gruber M., Pfaehler S.-M., Bredthauer A., Lehle K., Trabold B. Polymorphonuclear Cell Chemotaxis and Suicidal NETosis: Simultaneous Observation Using fMLP, PMA, H7, and Live Cell Imaging. J Immunol Res 2020; 2020: e1415947. DOI: 10.1155/2020/1415947Arroyo R., Khan M.A., Echaide M., Pérez-Gil J., Palaniyar N. SP-D Attenuates LPS-Induced Formation of Human Neutrophil Extracellular Traps (NETs), Protecting Pulmonary Surfactant Inactivation by NETs. Commun Biol 2019; 2: 1–13. DOI: 10.1038/s42003-019-0662-5Papayannopoulos V. Neutrophil Extracellular Traps in Immunity and Disease. Nat Rev Immunol 2018; 18: 134–47. DOI: 10.1038/nri.2017.105孝泰野村 NETosis. 日本小児アレル ギー学会誌 2019; 33: 348–9. DOI: 10.3388/jspaci.33.348Remijsen Q., Kuijpers T.W., Wirawan E., Lippens S., Vandenabeele P., Vanden Berghe T. Dying for a Cause: NETosis, Mechanisms behind an Antimicrobial Cell Death Modality. Cell Death Differ 2011; 18: 581–8. DOI: 10.1038/cdd.2011.1Thiam H.R., Wong S.L., Wagner D.D., Waterman C.M. Cellular Mechanisms of NETosis. Annu Rev Cell Dev Biol 2020; 36: 191–218. doi: 10.1146/annurev-cellbio-020520-111016Stoimenou M., Tzoros G., Skendros P., Chrysanthopoulou A. Methods for the Assessment of NET Formation: From Neutrophil Biology to Translational Research. Int J Mol Sci 2022; 23: 15823. DOI: 10.3390/ijms232415823Andrews R.K., Arthur J.F., Gardiner E.E. Neutrophil Extracellular Traps (NETs) and the Role of Platelets in Infection. Thromb Haemost 2014; 112: 659–65. DOI: 10.1160/TH14-05-0455Balázs A., Mall M.A. Mucus Obstruction and Inflammation in Early Cystic Fibrosis Lung Disease: Emerging Role of the IL-1 Signaling Pathway. Pediatr Pulmonol 2019; 54: S5–12. DOI: 10.1002/ppul.24462Martinod K., Witsch T., Farley K., Gallant M., Remold-O’Donnell E., Wagner D.D. Neutrophil Elastase-Deficient Mice Form Neutrophil Extracellular Traps in an Experimental Model of Deep Vein Thrombosis. J Thromb Haemost 2016; 14 (3): 551–8. DOI: 10.1111/jth.13239Martyanov A.A., Boldova A.E., Stepanyan M.G., An O.I., Gur’ev A.S., Kassina D.V., et al. Longitudinal Multiparametric Characterization of Platelet Dysfunction in COVID-19: Effects of Disease Severity, Anticoagulation Therapy and Inflammatory Status. Thromb Res 2022; 211: 27–37. DOI: 10.1016/j.thromres.2022.01.013Ramacciotti E., Myers D.D., Wrobleski S.K., Deatrick K.B., Londy F.J., Rectenwald J.E., et al. P-Selectin/PSGL-1 Inhibitors versus Enoxaparin in the Resolution of Venous Thrombosis: A Meta-Analysis. Thromb Res 2010; 125: e138–42. DOI: 10.1016/j.thromres.2009.10.022Lee K.H., Kronbichler A., Park D.D.-Y., Park Y., Moon H., Kim H., et al. Neutrophil Extracellular Traps (NETs) in Autoimmune Diseases: A Comprehensive Review. Autoimmun Rev 2017; 16: 1160–73. DOI: 10.1016/j.autrev.2017.09.012Mesa M.A., Vasquez G. NETosis. Autoimmune Diseases 2013; 2013: e651497. DOI: 10.1155/2013/651497Philip F., Kadamur G., Silos R.G., Woodson J., Ross E.M. Synergistic Activation of Phospholipase C-B3 by Gaq and Gbg Describes a Simple Two-State Coincidence Detector. Curr Biol 2010; 20: 1327–35. DOI: 10.1016/J.CUB.2010.06.013Vorobjeva N., Galkin I., Pletjushkina O., Golyshev S., Zinovkin R., Prikhodko A. et al. Mitochondrial Permeability Transition Pore Is Involved in Oxidative Burst and NETosis of Human Neutrophils. Biochim Biophys Acta Mol Basis Dis 2020; 1866: 165664. DOI: 10.1016/j.bbadis.2020.165664Yang C., Wang Z., Li L., Zhang Z., Jin X., Wu P., et al. Aged Neutrophils Form Mitochondria-Dependent Vital NETs to Promote Breast Cancer Lung Metastasis. J Immunother Cancer 2021; 9: e002875. DOI: 10.1136/jitc-2021-002875Luo H.R., Loison F. Constitutive Neutrophil Apoptosis: Mechanisms and Regulation. Am J Hematol 2008; 83: 288–95. DOI: 10.1002/ajh.21078Fuchs T.A., Abed U., Goosmann C., Hurwitz R., Schulze I., Wahn V., et al. Novel Cell Death Program Leads to Neutrophil Extracellular Traps. J Cell Biol 2007; 176: 231–41. DOI: 10.1083/jcb.200606027Bianchi M., Hakkim A., Brinkmann V., Siler U., Seger R.A., Zychlinsky A., et al. Restoration of NET Formation by Gene Therapy in CGD Controls Aspergillosis. Blood 2009; 114: 2619–22. DOI: 10.1182/blood-2009-05-221606Saffarzadeh M., Juenemann C., Queisser M.A., Lochnit G., Barreto G., Galuska S.P., et al. Neutrophil Extracellular Traps Directly Induce Epithelial and Endothelial Cell Death: A Predominant Role of Histones. PLoS One 2012; 7: e32366. DOI: 10.1371/journal.pone.0032366Thiam H.R., Wong S.L., Qiu R., Kittisopikul M., Vahabikashi A., Goldman A.E., et al. NETosis Proceeds by Cytoskeleton and Endomembrane Disassembly and PAD4-Mediated Chromatin Decondensation and Nuclear Envelope Rupture. Proc Natl Acad Sci U S A 2020; 117: 7326–37. DOI: 10.1073/pnas.1909546117Metzler 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 2014; 8: 883–96. DOI: 10.1016/j.celrep.2014.06.044Chen T., Li Y., Sun R., Hu H., Liu Y., Herrmann M., et al. Receptor-Mediated NETosis on Neutrophils. Front Immunol 2021; 12: 775267.Vorobjeva N.V., Chernyak B.V. NETosis: Molecular Mechanisms, Role in Physiology and Pathology. Biochemistry (Mosc) 2020; 85: 1178–90. DOI: 10.1134/S0006297920100065Klopf J., Brostjan C., Eilenberg W., Neumayer C. Neutrophil Extracellular Traps and Their Implications in Cardiovascular and Inflammatory Disease. Int J Mol Sci 2021; 22: 559. DOI: 10.3390/ijms22020559von Köckritz-Blickwede M., Winstel V. Molecular Prerequisites for Neutrophil Extracellular Trap Formation and Evasion Mechanisms of Staphylococcus Aureus. Front Immunol 2022; 13: 836278.Yipp B.G., Kubes P. NETosis: How Vital Is It? Blood 2013; 122: 2784–94. DOI: 10.1182/blood-2013-04-457671Pilsczek F.H., Salina D., Poon K.K.H., Fahey C., Yipp B.G., Sibley C.D., et al. A Novel Mechanism of Rapid Nuclear Neutrophil Extracellular Trap Formation in Response to Staphylococcus Aureus. J Immunol 2010; 185: 7413–25. DOI: 10.4049/jimmunol.1000675Martinod K., Demers M., Fuchs T.A., Wong S.L., Brill A., Gallant M., et al. Neutrophil Histone Modification by Peptidylarginine Deiminase 4 Is Critical for Deep Vein Thrombosis in Mice. Proc Natl Acad Sci U S A 2013; 110: 8674–9. DOI: 10.1073/pnas.1301059110