Neutrophils during SARS‐CoV‐2 infection: Friend or foe?

Abstract

Summary Coronavirus disease 2019 (COVID‐19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) and has resulted in more than 6 million deaths worldwide. COVID‐19 is a respiratory disease characterized by pulmonary dysfunction leading to acute respiratory distress syndrome (ARDs), as well as disseminated coagulation, and multi‐organ dysfunction. Neutrophils and neutrophil extracellular traps (NETs) have been implicated in the pathogenesis of COVID‐19. In this review, we highlight key gaps in knowledge, discuss the heterogeneity of neutrophils during the evolution of the disease, how they can contribute to COVID‐19 pathogenesis, and potential therapeutic strategies that target neutrophil‐mediated inflammatory responses.

Neutrophils and their friends

“…These interactions contribute to the morbidity and mortality seen in infections with SARS‐CoV‐2. Castanheira and Kubes 23 discuss how NET formation figures in the pathogenesis of COVID‐19 and of the thrombosis, disseminated intravascular coagulation, and respiratory failure that frequently complicate severe disease. Their discussion focuses attention on neutrophil heterogeneity both in general and in the specific context of COVID‐19.…”

COVID‐19‐associated liver injury: Adding fuel to the flame

“…Too large or numerous pathogen, which is difficult for neutrophils to phagocytize may account for the formation of NETs. 125 Moreover, it is probably that prolonged innate immune response after SARS-CoV-2 infection resulted in inefficient adaptive immune response and accumulated activated neutrophils that generate intracellular oxidative stress, which triggered NETosis and NETs release mediated by peptidyl arginine deiminase 4 (PAD4). 126,127 PAD4 is significantly increased in neutrophils from patients with severe COVID-19, and it regulates chromatin unfolding in neutrophils.…”

“…126,127 PAD4 is significantly increased in neutrophils from patients with severe COVID-19, and it regulates chromatin unfolding in neutrophils. 125 Fluid penetrates the alveolar cells after its and vascular endothelial cells damage, meanwhile, platelets are attracted to damage position and initiates the coagulation cascade, which driving fibrin deposition in the extracellular matrix. High levels of D-dimer, fibrinogen, and low antithrombin means a forewarning to thrombosis.…”

“…Generally, severe cytokine storm is closely related to neutrophils, while NETs, whose exact molecular mechanism of activation remains to be elucidated, lead to pulmonary microthrombosis. Too large or numerous pathogen, which is difficult for neutrophils to phagocytize may account for the formation of NETs 125 . Moreover, it is probably that prolonged innate immune response after SARS‐CoV‐2 infection resulted in inefficient adaptive immune response and accumulated activated neutrophils that generate intracellular oxidative stress, which triggered NETosis and NETs release mediated by peptidyl arginine deiminase 4 (PAD4) 126,127 .…”

“…Moreover, it is probably that prolonged innate immune response after SARS‐CoV‐2 infection resulted in inefficient adaptive immune response and accumulated activated neutrophils that generate intracellular oxidative stress, which triggered NETosis and NETs release mediated by peptidyl arginine deiminase 4 (PAD4) 126,127 . PAD4 is significantly increased in neutrophils from patients with severe COVID‐19, and it regulates chromatin unfolding in neutrophils 125 . Fluid penetrates the alveolar cells after its and vascular endothelial cells damage, meanwhile, platelets are attracted to damage position and initiates the coagulation cascade, which driving fibrin deposition in the extracellular matrix.…”