circGDI2 promotes epithelial IL-33 release and allergic airway inflammation in asthma

Dysregulated epithelial alarmin release is a key driver of chronic airway inflammation in asthma. Interleukin-33 (IL-33), released from activated airway epithelial cells, amplifies type 2 immune responses, yet the upstream mechanisms that link epithelial stress to IL-33 secretion remain incompletely defined. We investigated whether circGDI2 contributed to epithelial IL-33 release and allergic airway inflammation.

circGDI2 expression was examined in IL-13-stimulated BEAS-2B cells. Its functional role was evaluated in a house dust mite (HDM)-induced murine asthma model using adeno-associated virus-mediated circGDI2 knockdown, miR-103a-3p agomir, and NLRP3 siRNA. Molecular interactions were assessed by dual-luciferase reporter assays, RNA pull-down, and fluorescence in situ hybridization. NLRP3 inflammasome activation was monitored by cleaved caspase-1 p20, mature IL-1β, and IL-18 secretion, along with LDH release.

circGDI2 was upregulated in IL-13-stimulated BEAS-2B cells. circGDI2 silencing alleviated airway inflammation, mucus hypersecretion, and remodeling, and reduced type 2 immune responses in HDM-exposed mice. Mechanistically, circGDI2 sponged miR-103a-3p to derepress NLRP3 and promoted epithelial IL-33 release, accompanied by increased cleaved caspase-1 p20 and mature IL-1β and IL-18 secretion together with only a limited and NLRP3-dependent increase in LDH release. Consistent with this, miR-103a-3p restoration, NLRP3 knockdown, or MCC950 treatment each attenuated airway inflammation and IL-33 release, confirming the circGDI2/miR-103a-3p/NLRP3 axis.

circGDI2 promotes allergic airway inflammation by enhancing epithelial IL-33 release through the miR-103a-3p/NLRP3 pathway. These findings support circGDI2 as an upstream regulator of inflammatory responses in experimental asthma.