Cathepsin C-driven enhancement of neutrophil extracellular trap formation contributes to acute lung injury

Acute lung injury (ALI) is a severe pulmonary inflammatory disease with high morbidity and mortality rates. The pulmonary inflammatory phenotype of ALI is driven by the excessive aggregation and activation of neutrophils, triggering a cytokine storm. Notably, the extensive formation of neutrophil extracellular traps (NETs) has been demonstrated to play a critical role in ALI. Our results revealed significant overexpression of Cathepsin C (CTSC) in macrophages after LPS stimulation, which subsequently promoted massive NET formation through a positive feedback mechanism. Specifically, LPS stimulation markedly elevated CTSC expression in macrophages, which subsequently promoted the autocrine secretion of CTSC from neutrophils, ultimately culminating in excessive NET formation through the activation of the PR3-IL-1β-p38 pathway. Consequently, the inhibition of CTSC or PR3 significantly reduced NET formation and attenuated lung injury in ALI mice. In summary, CTSC overexpression drives excessive NET formation in ALI mice through a neutrophil-mediated positive feedback loop regulated by the PR3-IL-1β-p38 pathway.