Neutrophil activation and neutrophil extracellular traps (NETs) in COVID-19 ARDS and immunothrombosis

Abstract

Acute respiratory distress syndrome (ARDS) is an acute inflammatory condition with a dramatic increase in incidence since the beginning of the coronavirus disease 19 (COVID-19) pandemic. Neutrophils play a vital role in the immunopathology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by triggering the formation of neutrophil extracellular traps (NETs), producing cytokines including interleukin-8 (CXCL8), and mediating the recruitment of other immune cells to regulate processes such as acute and chronic inflammation, which can lead to ARDS. CXCL8 is involved in the recruitment, activation, and degranulation of neutrophils, and therefore contributes to inflammation amplification and severity of disease. Furthermore, activation of neutrophils also supports a prothrombotic phenotype, which may explain the development of immunothrombosis observed in COVID-19 ARDS. This review aims to describe hyperinflammatory ARDS due to SARS-CoV-2 infection. In addition, we address the critical role of polymorphonuclear neutrophils, inflammatory cytokines, and the potential targeting of CXCL8 in treating the hyperinflammatory ARDS population.

Keywords: ARDS; COVID-19; CXCL8; immunomodulators.

Figure 1

Infiltration of neutrophil in the lung contribute to ARDS. In ARDS, activated alveolar macrophages recruit neutrophils, and induce the secretion of IL‐8, into the lungs; this process leads to alveolar pathology associated with the development and severity of the condition. Excessive accumulation of neutrophils in the alveolar space may trigger release of reactive oxygen species, and neutrophil extracellular traps (NETs) which can result in epithelial injury. An excess of inflammatory cytokines further causes immune cell infiltration into inflamed lungs resulting in the pathologic hallmark of diffuse alveolar damage. ARDS, Acute respiratory distress syndrome; NETs, neutrophil extracellular traps; CXCL8, Interleukin 8; IL‐1b, interleukin 1 beta; IL‐2R, Interleukin 2 receptor; IL‐6, interleukin 6; TNF‐α, tumor necrosis factor alfa.

Figure 2

Neutrophil hyperactivation in ARDS COVID‐19. Neutrophil hyperactivation causes an enhancement of cellular processes including oxidation, degranulation, NETosis and increases in the production of various neutrophils effectors, ultimately leading to host tissue/organ damage. The most commonly reported effectors are ROS, MPO, NE, CatG, NETs and various pro‐inflammatory cytokines. IL‐1b, interleukin 1beta; IL‐2R, Interleukin 2 receptor; IL‐6, interleukin 6; CXCL8, Interleukin 8; TNF‐a, tumor necrosis factor alfa; ROS, reactive oxygen species; NE, neutrophil elastase; CatG, cathepsin G; MPO, myeloperoxidase; NETs, neutrophil extracellular traps; ARDS, Acute respiratory distress syndrome

Figure 3

Microvascular coagulopathy and immunothrombosis processes in patients with severe COVID‐19. A dysregulated inflammatory condition contributes to a prothrombotic phenotype characterized by activation of platelets, endothelial dysfunction and complement activation. This inflammatory induced coagulopathy can result in excessive formation of immunologically mediated thrombi primarily in the microvasculature, a process known as immunothrombosis. The microvascular coagulopathy and immunothrombosis observed in patients with severe COVID‐19 may be responsible for severe multiple organ dysfunction like ARDS. IL‐1b, interleukin 1β; IL‐2, Interleukin 2; IL‐6, interleukin 6; CXCL8, Interleukin 8; TNF‐a, tumor necrosis factor α; INF – γ, interferon gamma; NETs, neutrophil extracellular traps; ARDS, Acute respiratory distress syndrome.