Russian Journal of Infection and ImmunityRussian Journal of Infection and ImmunityИнфекция и иммунитет2220-76192313-7398SPb RAACI205810.15789/2220-7619-TRO-2058REVIEWSОБЗОРЫReview ArticleThe role of neutrophil extracellular traps (NETs) in the immunopathogenesis of severe COVID-19: potential immunotherapeutic strategies regulating NET formation and activityРоль нейтрофильных экстрацеллюлярных сетей (NETs) в иммунопатогенезе тяжелого COVID-19: потенциальные иммунотерапевтические стратегии, регулирующие процесс формирования и активность NETsNesterovaIrina V.НестероваИрина Вадимовна
Russian Federation

DSc (Medicine), Professor, Head Researcher, Department of Clinical and Experimental Immunology and Molecular Biology, Central Scientific Research Laboratory; Department of Allergology and Immunology, Faculty of Continuing Medical Education

д.м.н., профессор, главный научный сотрудник отдела клинико-экспериментальной иммунологии и молекулярной биологии Центральной научно-исследовательской лаборатории; профессор кафедры аллергологии и иммунологии

inesterova1@yandex.ruAtazhakhovaMargarita G.АтажаховаМаргарита Галимовна
Russian Federation

PhD Candidate, Department of Clinical Immunology, Allergology and Laboratory Diagnostics of FAT and PRS

аспирант кафедры клинической иммунологии, аллергологии и лабораторной диагностики факультета повышения квалификации и профессиональной переподготовки специалистов

inesterova1@yandex.ruTeterinYuri V.ТетеринЮрий Валерьевич
Russian Federation

PhD Candidate, Department of Clinical Immunology, Allergology and Laboratory Diagnostics of FAT and PRS

аспирант кафедры клинической иммунологии, аллергологии и лабораторной диагностики факультета повышения квалификации и профессиональной переподготовки специалистов

inesterova1@yandex.ruMatushkinaValeriya A.МатушкинаВалерия Александровна
Russian Federation

PhD Candidate, Department of Infectious Diseases and Epidemiology of FAT and PRS

соискатель кафедры инфекционных болезней и эпидемиологии факультета повышения квалификации и профессиональной переподготовки специалистов

inesterova1@yandex.ruChudilovaGalina A.ЧудиловаГалина Анатольевна
Russian Federation

DSc (Biology), Associate Professor, Head of the Department of Clinical and Experimental Immunology and Molecular Biology of the Central Scientific Research Laboratory, Professor, Department of Clinical Immunology, Allergology and Laboratory Diagnostics of FAT and PRS

д.б.н., доцент, зав. отделом клинико-экспериментальной иммунологии и молекулярной биологии ЦНИЛ, профессор кафедры клинической иммунологии, аллергологии и лабораторной диагностики факультета повышения квалификации и профессиональной переподготовки специалистов

inesterova1@yandex.ruMitropanovaMarina N.МитропановаМарина Николаевна
Russian Federation

DSc (Medicine), Associate Professor, Head of the Department of Pediatric Dentistry, Orthodontics and Dentofacial Surgery

д.м.н., доцент, зав. кафедрой детской стоматологии, ортодонтии и челюстно-лицевой хирургии

inesterova1@yandex.ruKuban State Medical University of the Ministry of Healthcare of the Russian FederationФГБОУ ВО Кубанский государственный медицинский университет Министерства здравоохранения Российской ФедерацииPeoples’ Friendship University of RussiaФГАОУ ВО Российский университет дружбы народов14022023010420231319283110202212022023Copyright ©; 2023, Nesterova I.V., Atazhakhova M.G., Teterin Y.V., Matushkina V.A., Chudilova G.A., Mitropanova M.N.Copyright ©; 2023, Нестерова И.В., Атажахова М.Г., Тетерин Ю.В., Матушкина В.А., Чудилова Г.А., Митропанова М.Н.2023Nesterova I.V., Atazhakhova M.G., Teterin Y.V., Matushkina V.A., Chudilova G.A., Mitropanova M.N.Нестерова И.В., Атажахова М.Г., Тетерин Ю.В., Матушкина В.А., Чудилова Г.А., Митропанова М.Н.https://creativecommons.org/licenses/by/4.0https://iimmun.ru/iimm/article/view/2058

The role of neutrophil granulocytes (NG) in the pathogenesis of COVID-19 is associated with the NG recruitment into inflammatory foci, activation of their functions and enhanced formation of neutrophil extracellular networks (NETs). In this review, we analyzed a large body of scientific literature devoted to the features of developing NETs, their role in the COVID-19 pathogenesis, a role in emerging immunothrombosis, vasculitis, acute respiratory distress syndrome, cytokine storm syndrome, and multi-organ lesions. Convincing data are presented clearly indicating about a profound role of NETs in the COVID-19 immunopathogenesis and associated severe complications resulting from intensified inflammation process, which is a key for the course of SARS-CoV-2 virus infection. The presented role of NGs and NETs, along with that of other immune system cells and pro-inflammatory cytokines, is extremely important in understanding development of overactive immune response in severe COVID-19. The scientific results obtained available now allow to identify an opportunity of regulatory effects on hyperactivated NGs, NETosis at various stages and on limiting a negative impact of pre-formed NETs on various tissues and organs. All the aforementioned data should help in creating new, specialized immunotherapy strategies designed to increase the odds of survival, reduce severity of clinical manifestations in COVID-19 patients as well as markedly reduce mortality rates. Currently, it is possible to use existing drugs, while a number of new drugs are being developed, the action of which can regulate NG quantity, positively affect NG functions and limit intensity of NETosis. Continuing research on the role of hyperactive NG and NETosis as well as understanding the mechanisms of regulating NET formation and restriction in severe COVID-19, apparently, are of high priority, because in the future the new data obtained could pave the basis for development of targeted approaches not only for immunotherapy aimed at limiting education and blocking negative effects already formed NETs in severe COVID-19, but also for immunotherapy, which could be used in combination treatment of other netopathies, primarily autoimmune diseases, auto-inflammatory syndromes, severe purulent-inflammatory processes, including bacterial sepsis and hematogenous osteomyelitis.

Роль нейтрофильных гранулоцитов (НГ) в патогенезе COVID-19 связана с рекрутированием НГ в очаги воспаления, активацией их функций и усиленным образованием нейтрофильных экстрацеллюлярных сетей (NETs). В данном обзоре нами проанализирован достаточно большой объем научной литературы, посвященной особенностям формирования NETs, их роли в патогенезе COVID-19, участию в возникновении иммунотромбозов, васкулита, острого респираторного дистресс-синдрома, синдрома цитокинового шторма, мультиорганных поражений. Приведены убедительные данные, четко указывающие на значительное участие NETs в иммунопатогенезе COVID-19 и связанными с ними тяжелыми осложнениями, возникающими в результате усиления процесса воспаления, который является ключевым для течения инфекции, вызванной вирусом SARS-CoV-2. Представленная роль НГ и NETs, наряду с ролью других клеток иммунной системы и провоспалительных цитокинов, чрезвычайно важна в понимании развития гиперактивного иммунного ответа при тяжелой форме COVID-19. Полученные научные результаты, доступные на сегодняшний день, позволяют идентифицировать возможности регуляторных воздействий на гиперактивированные НГ, на процессы формирования NETs на различных этапах и на ограничение негативного воздействия уже сформированных NETs на различные ткани и органы. Все вышеперечисленное должно помочь в создании новых, специализированных иммунотерапевтических стратегий, предназначенных для увеличения шансов на выживание, уменьшения тяжести клинических проявлений у пациентов с COVID-19, а также в значительном снижении показателей смертности. В настоящее время возможно применение уже существующих лекарственных препаратов, и разрабатывается целый ряд новых лекарственных средств, действие которых может регулировать количество НГ, позитивно влиять на функции НГ и ограничивать интенсивность формирования NETs. Продолжение исследований роли гиперактивированных НГ и нетоза, а также понимание механизмов регуляции феномена образования и ограничения активности NETs при тяжелом COVID-19, по-видимому, являются приоритетными, поскольку в дальнейшем полученные новые данные могли бы стать основой в разработке таргетных подходов не только к иммунотерапии, направленной на ограничение образования и блокирование негативных воздействий уже сформировавшихся NETs при тяжелом COVID-19, но и к иммунотерапии, которую можно было бы использовать в комплексном лечении других нетопатий, в первую очередь, аутоиммунных болезней, аутовоспалительных синдромов, тяжелых гнойно-воспалительных процессов, в том числе бактериального сепсиса и гематогенного остеомиелита.

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