IL-33's role in NET formation and neutrophil-mediated inflammation in smoke-exposed asthma through autophagy

Cigarette smoke (CS) exposure is a significant risk factor for asthma development. IL-33 has emerged as a key regulator in asthma pathogenesis. This study aimed to investigate the impact of IL-33 on neutrophil-mediated inflammation in CS-exposed asthma. We investigated CS-induced airway inflammation and explored the underlying mechanisms using RNA sequencing. We also examined the role of IL-33 in the pathogenesis of asthma and the regulation of neutrophil extracellular traps (NETs) and autophagy in a CS-exposed asthma model and asthmatics. Our results demonstrated that CS exposure exacerbated lung function impairment, increased inflammation, and elevated neutrophils in asthma. Moreover, increased IL-33 release was observed in response to CS exposure, contributing to the neutrophil-mediated inflammation. The administration of sST2 resulted in reduced inflammation in CS-exposed asthmatic mice. Transcriptomic analysis revealed that IL-33 promoted NET formation, which not only impaired lung function but also induced dendritic cell-Th2/Th17 polarization. Furthermore, a positive feedback loop between NETs and autophagy was discovered. IL-33 knockout inhibited autophagy and NET formation, while autophagy induction reversed the suppression of NETs in a mTOR-dependent manner. These findings highlight the role of IL-33-autophagy-NET axis in CS-exposed asthma and its association with neutrophilic inflammation. <fig><object-id>erj;64/suppl_68/OA4672/F1</object-id><object-id>F1</object-id><object-id>F1</object-id><graphic></graphic></fig>