NETosis and Neutrophil Extracellular Traps in COVID-19: Immunothrombosis and Beyond

Abstract

Infection with SARS-CoV-2, the causative agent of the Coronavirus disease 2019 (COVID-19) pandemic, causes respiratory problems and multifaceted organ dysfunction. A crucial mechanism of COVID-19 immunopathy is the recruitment and activation of neutrophils at the infection site, which also predicts disease severity and poor outcomes. The release of neutrophil extracellular traps (NETs), occurring during a regulated form of neutrophil cell death known as NETosis, is a key effector function that mediates harmful effects caused by neutrophils. Abundant NETosis and NET generation have been observed in the neutrophils of many COVID-19 patients, leading to unfavorable coagulopathy and immunothrombosis. Moreover, excessive NETosis and NET generation are now more widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection. In this minireview, we introduce subtypes of NET-producing neutrophils (e.g., low-density granulocytes) and explain the biological importance of NETs and the protein cargos of NETs in COVID-19. In addition, we discuss the mechanisms by which SARS-CoV-2 causes NETosis by upregulating viral processes (e.g., viral entry and replication) as well as host pro-NET mechanisms (e.g., proinflammatory mediator release, platelet activation, and autoantibody production). Furthermore, we provide an update of the main findings of NETosis and NETs in immunothrombosis and other COVID-19-related disorders, such as aberrant immunity, neurological disorders, and post COVID-19 syndromes including lung fibrosis, neurological disorder, tumor progression, and deteriorated chronic illness. Finally, we address potential prospective COVID-19 treatment strategies that target dysregulated NETosis and NET formation via inhibition of NETosis and promotion of NET degradation, respectively.

Neutrophils and Neutrophil Extracellular Traps in Cardiovascular Disease: An Overview and Potential Therapeutic Approaches

“…Neutrophil-induced inflammation and NET-induced immunological thromboembolism may contribute to the pathophysiology of COVID-19–related CVD. Indeed, NET formation by circulating and infiltrating neutrophils is increased in patients with COVID-19 [ 111 ] and correlates with the clinical severity and prognosis in these patients [ 112 ]. The oxidative burst that is associated with SARS-CoV-2 infection stimulates NET formation [ 113 ], and the spike proteins and viral RNA of SARS-CoV-2, together with the proinflammatory cytokines TNFα and IL-8, can activate neutrophils.…”

The Role of Exposomes in the Pathophysiology of Autoimmune Diseases II: Pathogens

“…With regards to COVID-19, a crucial mechanism of the disease is the recruitment and activation of neutrophils at the infection site. Abundant NETosis and NET generation has been observed in many COVID-19 patients, resulting in unfavorable coagulopathy and immunothrombosis [270]. Additionally, excessive NETosis and NET generation are now widely recognized as mediators of additional pathophysiological abnormalities following SARS-CoV-2 infection [270].…”

Prophylactic treatment of Glycyrrhiza glabra mitigates COVID-19 pathology through inhibition of pro-inflammatory cytokines in the hamster model and NETosis

“…Moreover, a high neutrophil to lymphocyte ratio (NLR) and elevated serum levels of IL-8, the neutrophil chemoattractant cytokine, have been associated with mortality in the COVID-19 patients (9). Sera and postmortem lung biopsies from COVID-19 patients have a high concentration of neutrophil extracellular traps (NETs) components especially in the inflammatory interstitial lesions and airways (10)(11)(12). Moreover, activated neutrophils and NETs are known to promote clotting without any other coagulation triggers (11,13).…”

“…Sera and postmortem lung biopsies from COVID-19 patients have a high concentration of neutrophil extracellular traps (NETs) components especially in the inflammatory interstitial lesions and airways (10)(11)(12). Moreover, activated neutrophils and NETs are known to promote clotting without any other coagulation triggers (11,13). NETosis is a redox-sensitive phenomenon involving both cytosolic and mitochondrial free radicals.…”

“…NETosis is a redox-sensitive phenomenon involving both cytosolic and mitochondrial free radicals. NETs formation is a defensive microbicidal phenomenon to exterminate the invading foreign pathogens but a loss of its control and persistence during inflammation results in the host tissue damage as seen in rheumatic arthritis, diabetes, sepsis, and COVID-19 (10)(11)(12).…”