NCX1 reverse mode promotes calcium-dependent Neutrophil Extracellular Trap formation and lung damage in chronic obstructive pulmonary disease

Abstract Neutrophil-driven inflammation is central to the pathogenesis of chronic obstructive pulmonary disease (COPD). Emerging evidence suggests that Ca²⁺ signaling is critical in regulating neutrophil activation, recruitment and tissue residency. In this study, we investigated the function of Na⁺/Ca²⁺ exchanger 1 (NCX1), a Ca²⁺/cation membrane transporter, in neutrophils during COPD pathogenesis. Analysis of human specimens show that NCX1 is primarily upregulated in neutrophils from patients with mixed chronic bronchitis and emphysema. Cigarette smoke exposure induces NCX1 upregulation and promotes its reverse-mode transport activity, leading to elevated intracellular Ca²⁺ levels and enhanced NETs formation. Neutrophil-specific genetic deletion of Slc8a1 or pharmacological inhibition of NCX1 reverse transport effectively suppresses Ca²⁺ influx, NETs release, and neutrophil accumulation and retention, thereby ameliorating chronic bronchitis and emphysematous changes. Collectively, our findings identify NCX1 as a regulator of Ca²⁺-dependent NETs release in neutrophils. Targeting NCX1-mediated Ca²⁺ influx or NETs formation represents a potential therapeutic strategy for neutrophilic inflammation in COPD.