KCNJ2 is Required for NLRP3 Inflammasome Activation That Drives Allergic Airway Inflammation and Remodeling

Airway inflammation and remodeling are cardinal features of asthma pathogenesis. Genome-wide association studies have shown that several SNPs of KCNJ2, a member of the inwardly rectifying Potassium Channel family, are associated with asthma in patients. However, the role of KCNJ2 in airway inflammation and remodeling in asthma remains unknown. Here, we demonstrate that the Kcnj2 serves as a critical regulator of airway epithelial inflammation and remodeling. KCNJ2 expression is significantly reduced in the airway epithelium of asthmatic patients, which is associated with goblet cell metaplasia and mucus overproduction. Epithelial cell depletion of Kcnj2 attenuates airway inflammation, Th2 inflammatory response, goblet cell metaplasia, and mucus overproduction in the airways of asthmatic mice. In cultured primary airway epithelial cells of asthmatic patients, KCNJ2 inhibition also hampers goblet cell metaplasia, mucus production, and lung epithelial cell-derived alarmins expression. This process appears to be mediated, at least in part, through inhibition of NLRP3 by restricting CA²⁺ influx and K⁺ efflux, as pharmacological activation of NLRP3 diminishes the KCNJ2 inhibition-ameliorated airway phenotypes. These results provide insight into the role of Kcnj2 in airway inflammation and remodeling in asthmatic conditions.