Controversial role of neutrophilic granulocytes in the immunopathogenesis of COVID-19: correlation with imbalance of pro-inflammatory neutrophil-associated cytokines and interferon alpha deficiency

Neutrophilic granulocytes (NG) are the main drivers of pathological inflammation in COVID-19. Objective. To specify the mechanisms of immunopathogenesis of COVID-19 based on a comparative immunological study of the number and phenotype of CD16+СD62L+CD11b+CD63– and CD16+СD62L+CD11b+CD63+ subsets with an assessment of their effector functions against changing profile of NG-associated cytokines IL-8, IL-18, IL-17A, VEGF-A, IFNα, and IFNγ. Patients and methods. In patients with moderate-to-severe and severe COVID-19, we determined IL-1β, TNFα, IL-6, IL-8, IL-18, IL-17A, VEGF-A, IFNα, and IFNγ (ELISA), the phenotype of CD16+СD62L+CD11b+CD63– and CD16+СD62L+CD11b+CD63+ subsets, NF-κB-NG (CYTOMICS FC500), phagocytically active NG (%), neutrophil extracellular traps (NETs), NG in apoptosis, and the activity of NADPH oxidase. Results. In COVID-19 against the background of IFNα and IFNγ production blockade and high levels of NG-associated IL-8, IL-18, IL-17A, VEGF-A, a reduction in the number of mature and functionally active CD16brightСD62LbrightCD11bbrightCD63–NG subsets was revealed, as well as an increase in the number of CD16dimСD62LdimСD11bbrightCD63–NG subsets with an immunosuppressive phenotype and CD16brightСD62LbrightСD11bbrightCD63bright–NG subsets with high cytotoxic activity and ability to form NETs, a decrease in the percentage of phagocytically active NG and an increase in the activity of NADPH oxidase, NETs, and NG in apoptosis. Conclusion. IFNα deficiency provokes a hyperergic response of NG-associated cytokines, which leads to the formation of uncontrolled immune inflammation involving NG subsets with an immunosuppressive and cytotoxic phenotype, exacerbating the course of COVID-19. The use of recombinant IFNα-2b with antioxidants (Viferon®) in the early stages of the disease can help to restore immune homeostasis, normalize the level of NG-associated cytokines, reduce NERTs, and achieve good clinical efficacy. © 2022, Dynasty Publishing House. All rights reserved.