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

Abstract

The role of neutrophil granulocytes (NG) in the pathogenesis of COVID-19 is associated with the recruitment of NG into inflammatory foci, activation of their functions and enhanced formation of neutrophil extracellular networks (NETs). In this review, we analyzed a fairly large volume of scientific literature devoted to the peculiarities of the formation of NETs, their role in the pathogenesis of COVID-19, participation in the occurrence of immunothrombosis, vasculitis, acute respiratory distress syndrome, cytokine storm syndrome, multi-organ lesions. Convincing data are presented that clearly indicate the significant involvement of NETs in the immunopathogenesis of COVID-19 and the associated severe complications resulting from the intensification of the inflammation process, which is key for the course of infection caused by the SARS-CoV-2 virus. The presented role of NG and NETs, along with the role of other immune system cells and pro-inflammatory cytokines, is extremely important in understanding the development of an overactive immune response in severe COVID-19. The obtained scientific results, available today, allow identifying the possibilities of regulatory effects on hyperactivated NG, on the formation of NETs at various stages and on limiting the negative impact of already formed NETs on various tissues and organs. All of the above should help in the creation of new, specialized immunotherapy strategies designed to increase the chances of survival, reduce the severity of clinical manifestations in patients with COVID-19, as well as significantly reduce mortality rates. Currently, it is possible to use existing drugs and a number of new drugs are being developed, the action of which can regulate the amount of NG, positively affect the functions of NG and limit the intensity of NETs formation. Continuing research on the role of hyperactive NG and netosis, as well as understanding the mechanisms of regulation of the phenomenon of formation and restriction of NETs activity in severe COVID-19, apparently, are a priority, since in the future the new data obtained could become the basis for the development of targeted approaches not only to immunotherapy aimed at limiting education and blocking negative effects already formed NETs in severe COVID-19, but also to immunotherapy, which could be used in the complex treatment of other netopathies, first of all, autoimmune diseases, auto-inflammatory syndromes, severe purulent-inflammatory processes, including bacterial sepsis and hematogenous osteomyelitis.