SERPINB10 promotes neutrophilic airway inflammation in asthma

RATIONALE: A subset of severe asthma is characterized by neutrophilic airway inflammation in which epithelial activation of the NLRP3 inflammasome pathway is implicated. SERPINB10 is linked to neutrophil activation in inflammatory diseases. OBJECTIVES: To investigate the role of SERPINB10 in airway neutrophilia in asthma. METHODS: We sensitized mice with house dust mite (HDM) and challenged them with HDM and poly(I: C), a viral double-stranded RNA analog. Airway inflammation and the expression of inflammatory cytokines in mouse lungs were analyzed. Mechanistic experiments were performed in HBE cells by RNA sequencing, western blotting, and immunofluorescence staining. The expression of SERPINB10, NLRP3, IL-1β, and IL-6 were determined in human bronchial brushings. MEASUREMENTS AND MAIN RESULTS: Serpinb10 -/- mice exhibited reduced neutrophil counts in bronchoalveolar lavage cells and alleviated inflammatory cell infiltration around airways. Il-1β and Il-6 expression was decreased in lung tissues from Serpinb10-/- mice. In cultured HBE cells, SERPINB10 knockdown decreased IκBα phosphorylation and suppressed poly(I: C)-induced IL-1β and IL-6 expression. Moreover, the expression of NLRP3 and pro-IL-1β in lung tissues of Serpinb10-/- mice was decreased. Conversely, SERPINB10 overexpression enhanced IL-1β and IL-6 expression in HBE cells, which was blocked by either an IκBα phosphorylation inhibitor or an NLRP3 inhibitor. Of note, SERPINB10 expression in bronchial brushings from non-eosinophilic asthma patients was enhanced and significantly correlated with the severity of airflow limitation, and the expression of NLRP3, IL-1β, and IL-6. CONCLUSIONS: SERPINB10 promotes IL-1β and IL-6 expression by upregulating NF-κB and NLRP3 signaling in airway epithelial cells, thereby driving neutrophilic airway inflammation in asthma.