S100A8/A9 decorated neutrophil extracellular traps contributes to endothelial cell dysfunction via impairing autophagic axis in sepsis lung injury.

Abstract

Endothelial dysfunction underpins the pathogenesis of sepsis-induced acute lung injury (SI-ALI), wherein neutrophil extracellular traps (NETs) serve as pivotal mediators driving excessive inflammatory responses and progressive tissue deterioration. This study aimed to elucidate the molecular mechanism by which NETs disrupt endothelial homeostasis and promote vascular dysfunction during sepsis. In vivo mice models and in vitro endothelial cell experiments consistently demonstrated that NETs markedly exacerbated endothelial barrier disruption and autophagic flux impairment. Mechanistically, NETs-derived S100A8/A9 activated the PI3K-AKT-mTOR signaling pathway via toll-like receptor 4 (TLR4), thereby triggering endothelial pro-inflammatory and pro-adhesive phenotypic transformation. S100A8/A9 also promoted reactive oxygen species (ROS) production and NET formation in neutrophils, forming a vicious cycle. Pharmacological inhibition of S100A8/A9 or TLR4 effectively restored autophagy and mitigated sepsis-associated lung injury. Collectively, these findings reveal that the S100A8/A9-TLR4-PI3K-AKT-mTOR-autophagy axis critically mediates NETs-induced endothelial dysfunction, providing promising therapeutic targets for the intervention of septic acute lung injury.