The role of neutrophil extracellular traps (NETs) in the immunopathogenesis of severe COVID-19: potential immunotherapeutic strategies regulating NET formation and activity

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Abstract

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.

About the authors

Irina V. Nesterova

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation; Peoples’ Friendship University of Russia

Author for correspondence.
Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar; Moscow

Margarita G. Atazhakhova

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation

Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar

Yuri V. Teterin

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation

Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar

Valeriya A. Matushkina

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation

Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar

Galina A. Chudilova

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation

Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar

Marina N. Mitropanova

Kuban State Medical University of the Ministry of Healthcare of the Russian Federation

Email: inesterova1@yandex.ru

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

Russian Federation, Krasnodar

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