Social defeat stress aggravates asthma airway inflammation through neutrophils.

Abstract

BACKGROUNDS: Psychological stress is a recognized contributor to asthma progression and is associated with increased neutrophils. OBJECTIVE: To investigate the role of neutrophils and NETosis in psychosocial stress aggravates asthma airway inflammation. METHODS: We constructed murine asthma models under social defeat stress (SDS) intervention. Wild-type,Csf3-deficient (Csf3, neutropenic), andPadi4-deficient (Padi4, impaired NETosis) mice were used to explore neutrophil-driven mechanisms. RESULTS: In murine asthma models, SDS exacerbated airway hyperresponsiveness, inflammation, and remodeling. The amplified effects of SDS were attenuated in Csf3mice with neutropenia but exacerbated in neutrophilic mice. Transcriptomic analysis revealed SDS enhanced neutrophil extracellular traps (NETs) formation. Genetic inhibition of NETosis (Padi4) mitigated the SDS-induced asthma hyperresponsiveness and inflammation. CONCLUSIONS: Neutrophils and NETosis are critical mediators of SDS-induced asthma airway hyperresponsiveness, inflammation and mucus hypersecretion, highlighting potential therapeutic targets.