SERPINB10 promotes neutrophilic airway inflammation in asthma

A subset of severe asthma is characterized by neutrophilic airway inflammation in which epithelial activation of the NLRP3 inflammasome pathway is implicated. Recent reports link SERPINB10 to neutrophil activation in inflammatory disease. We hypothesized that SERPINB10 contributes to neutrophilic inflammation in asthma. Since viral infection triggers airway neutrophilia in asthma, we sensitized mice with house dust mite (HDM) and challenged them with HDM and poly(I:C), a viral double-stranded RNA analog. Compared to wild-type mice, Serpinb10^-/- mice exhibited reduced neutrophil counts in bronchoalveolar lavage cells and alleviated inflammatory cell infiltration around airways. Expression of inflammatory cytokines such as Il-1β and Il-6 was also decreased in lung tissues from Serpinb10^-/- mice. In cultured HBE cells, SERPINB10 knockdown decreased IκBα phosphorylation and suppressed poly(I:C)-induced expression of IL-1β and IL-6. 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. Altogether, 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. SERPINB10 is a potential therapeutic target for airway neutrophilia in asthma.