Neutrophils and Neutrophil Extracellular Traps Drive Necroinflammation in COVID-19

Abstract

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.

Keywords: MERS-CoV; NETs; SARS-CoV-2; complement; coronavirus; necroinflammation; neutrophils; thrombosis.

Figure 1

Neutrophils and neutrophil extracellular traps drive necroinflammation in COVID-19. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) binds to ACE2 and enter epithelial as well as endothelial cells along with it leading to reduced ACE2 expression that stimulates neutrophil recruitment. Subsequently, neutrophils undergo degranulation and NET formation releasing intracellular danger-associated molecular patterns, e.g., DNA, histones, neutrophil elastase that activate the pattern recognition receptors on surrounding immune and non-immune cells to induce cytokine secretion. The extracellular DNA released by NETs activates platelets and aggregated NETs provide a scaffold for binding of erythrocytes and activated platelets that promote thrombus formation. The extracellular histones present on NETs induce necrosis in epithelial or endothelial cells leading to the release of associated molecular patterns. This sets up an auto-amplification loop of necroinflammation that aggravate the disease severity during COVID-19. SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2, ACE2 = angiotensin-converting enzyme 2, NET = neutrophil extracellular traps, DAMPs = danger-associated molecular patterns.