Neutrophil Extracellular Traps (NETs) in Severe SARS-CoV-2 Lung Disease

Abstract

Neutrophil extracellular traps (NETs), built from mitochondrial or nuclear DNA, proteinases, and histones, entrap and eliminate pathogens in the course of bacterial or viral infections. Neutrophils’ activation and the formation of NETs have been described as major risk factors for acute lung injury, multi-organ damage, and mortality in COVID-19 disease. NETs-related lung injury involves both epithelial and endothelial cells, as well as the alveolar-capillary barrier. The markers for NETs formation, such as circulating DNA, neutrophil elastase (NE) activity, or myeloperoxidase-DNA complexes, were found in lung specimens of COVID-19 victims, as well as in sera and tracheal aspirates obtained from COVID-19 patients. DNA threads form large conglomerates causing local obstruction of the small bronchi and together with NE are responsible for overproduction of mucin by epithelial cells. Various components of NETs are involved in the pathogenesis of cytokine storm in SARS-CoV-2 pulmonary disease. NETs are responsible for the interplay between inflammation and thrombosis in the affected lungs. The immunothrombosis, stimulated by NETs, has a poor prognostic significance. Better understanding of the role of NETs in the course of COVID-19 can help to develop novel approaches to the therapeutic interventions in this condition.

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

“…In addition, the cytotoxic action of the enzymes and histones that are released from NETs can promote endothelial cell death and endothelial dysfunction ( 65 , 66 ), which is considered a critical pathogenic mechanism of organ injury in COVID-19 patients ( 67 , 68 ). Moreover, NET production promotes lung epithelial cell death and intravascular thrombus formation, thereby crucial for inducing acute lung injury in COVID-19 ( 69 , 70 ). Indeed, due to the presence of abundant pulmonary vascular neutrophils and dynamically released platelets, NET-induced immunothrombosis is more likely to occur, resulting in occlusion of the microvasculature and ischemic injury ( 16 , 71 ).…”

Hyperinflammatory Immune Response and COVID-19: A Double Edged Sword

“…In addition, viral proteins and inflammatory cytokines induce neutrophil activation, leading to ROS secretion and the formation of neutrophil extracellular traps (NETs) ( 24 , 25 ). HMGB1, which is triggered by ROS, may also play a role in NET activation ( 26 ).…”

Endothelial Dysfunction Induced by Extracellular Neutrophil Traps Plays Important Role in the Occurrence and Treatment of Extracellular Neutrophil Traps-Related Disease

“…At the same time, neutrophils are known to synthesize and store MMP-9 and MMP-25 [ 56 ], which are externalized during NETosis; thus, MMP-25 is supposed to produce a similar effect with MMP-9, enhancing endothelial MMP-2 activation and exacerbating ED and inflammation. Moreover, it has also been reported that both NE and MPO, as the components of NETs, can impair ECs [ 57 , 58 ]. NE can mediate the neutrophil-induced tissue damage and effectively degrade extracellular matrix components [ 2 ], while MPO is a heme protein in neutrophils and monocyte particles known to generate ROS [ 59 ].…”