Platelets induce neutrophil extracellular traps in transfusion-related acute lung injury

TLDR

Platelets are key drivers of inflammation through interactions with innate immune cells, and neutrophil extracellular traps (NETs) are chromatin‑based structures released upon neutrophil activation. In a neutrophil‑ and platelet‑dependent mouse model of TRALI, activated platelets triggered NET formation in the lung microvasculature, and inhibition of platelet activation or direct neutralization of NET components with a histone‑blocking antibody or DNase1 reduced NETs and protected mice, indicating that NETs drive lung endothelial injury and represent a potential therapeutic target for acute lung injury.

Abstract

There is emerging evidence that platelets are major contributors to inflammatory processes through intimate associations with innate immune cells. Here, we report that activated platelets induce the formation of neutrophil extracellular traps (NETs) in transfusion-related acute lung injury (TRALI), which is the leading cause of death after transfusion therapy. NETs are composed of decondensed chromatin decorated with granular proteins that function to trap extracellular pathogens; their formation requires the activation of neutrophils and release of their DNA in a process that may or may not result in neutrophil death. In a mouse model of TRALI that is neutrophil and platelet dependent, NETs appeared in the lung microvasculature and NET components increased in the plasma. We detected NETs in the lungs and plasma of human TRALI and in the plasma of patients with acute lung injury. In the experimental TRALI model, targeting platelet activation with either aspirin or a glycoprotein IIb/IIIa inhibitor decreased NET formation and lung injury. We then directly targeted NET components with a histone blocking antibody and DNase1, both of which protected mice from TRALI. These data suggest that NETs contribute to lung endothelial injury and that targeting NET formation may be a promising new direction for the treatment of acute lung injury.