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.
Highlights
Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection [1]
Targeted pharmacological inhibition of viral replication reduces neutrophil extracellular traps (NETs) formation [13]. Another mechanism behind SARS-COV-2-induced NETosis and NETs lies in the fact that SARS-CoV-2 infection causes neutrophils to increase the production of pro-NETosis mediators
The characteristic COVID-19 NET-induced thrombus contributes to microvascular obstruction and organ damage
Summary
Coronavirus disease 2019 (COVID-19) is a global pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection [1]. Targeted pharmacological inhibition of viral replication reduces NET formation [13] Another mechanism behind SARS-COV-2-induced NETosis and NETs lies in the fact that SARS-CoV-2 infection causes neutrophils to increase the production of pro-NETosis mediators. SARS-CoV-2 may stimulate the production of proinflammatory mediators or induce the release of DAMPs when contacting epithelial cells and other neighboring cells (e.g., macrophages) in the airway, resulting in a massive amplification of inflammatory and chemotactic responses Proinflammatory mediators such as IL-8 and IL-1b are important NET-inducing mediators, and they are produced abundantly by SARS-CoV-2-infected epithelial cells and macrophages, increasing NETosis in tissues and intravascular neutrophils [40, 41]. Other studies showed that autoantibodies against phospholipids and phospholipid-binding proteins (aPL antibodies) or PF4 are raised by SARS-CoV-2 infection [47] or vaccination [48] These autoantibodies trigger NET release in neutrophils isolated from healthy individuals. NETosis and NETs may have a role in the development of post COVID-19 syndromes, including lung fibrosis, neurological disorders, tumor growth, and worsening of concomitant diseases
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