NLRP3 Inflammasome Activation Modulates Neutrophil Extracellular Trap Formation and Aggravates Airway Inflammation in Bronchiectasis

Neutrophilic inflammation and <i>Pseudomonas aeruginosa</i> infection have been implicated in the pathogenesis and progression of bronchiectasis. However, the mechanisms underlying the inflammasome activation and neutrophil extracellular traps (NETs) formation, which are triggered by lipopolysaccharide (LPS), thereby fostering relentless neutrophilic inflammation and airway destruction, remain poorly understood. Here, we investigated how nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome activation modulates NET formation, epithelial inflammation, and injury in bronchiectasis. Compared with those in the stable state, interleukin-1β levels in the exacerbation state were greater and were correlated with blood neutrophil counts. LPS triggered neutrophil NLRP3 inflammasome activation and induced NET formation. At exacerbation, caspase-1 p20, DNA-myeloperoxidase, and DNA-neutrophil elastase expression levels were increased compared with those in the stable state. LPS triggered the first signal, nuclear factor-κB, for NLRP3 inflammasome activation within the airway epithelium, leading to neutrophil chemotactic factor release. NETs served as the secondary signal for thorough NLRP3 inflammasome activation. Acting synergistically with LPS, NETs amplified epithelial inflammation, up-regulating mucin 5AC expression while suppressing zona occludens-1 and α-tubulin expression. Both MCC950 and Z-VAD-FMK inhibited NLRP3 inflammasome activation, whereas GSK484 and LDC7559 suppressed NET formation. Collectively, NLRP3 inflammasome activation facilitates NET formation in bronchiectasis, aggravating inflammation and eliciting injury to epithelial cells.