Targeting NLRP3 with GDC-2394 ameliorates airway inflammation and smooth muscle hyperplasia in experimental asthma by...

Uncontrolled childhood asthma contributes to chronic airway inflammation and remodeling, primarily characterized by bronchial smooth muscle hyperplasia. Although the NLR family pyrin domain-containing 3 (NLRP3) inflammasome regulates airway inflammation, its role in abnormal airway smooth muscle cell (ASMC) proliferation remains poorly understood. Here, we evaluated the selective NLRP3 inhibitor GDC-2394 in a house dust mite (HDM)-induced murine model of asthma with a vehicle control group, focusing on the NLRP3-IL-6/JAK2/STAT3 signaling axis. HDM-challenged mice displayed increased airway hyperresponsiveness, elevated levels of eosinophils, IgE, IL-1β, IL-18, type 2 cytokines, and IL-6, as well as marked airway inflammation, smooth muscle thickening, goblet cell hyperplasia, and mucus hypersecretion. Vehicle alone showed no significant effects. GDC-2394 treatment attenuated these pathological changes, supporting the specificity of the drug. Mechanistically, pharmacological NLRP3 inhibition reduced ASMC hyperplasia in association with decreased IL-6-induced phosphorylation of JAK2 and STAT3, without affecting their mRNA expression levels. These findings suggest that NLRP3 may contribute to ASMC hyperproliferation, at least in part through the IL-6/JAK2/STAT3 pathway, in experimental asthma. While these results support a role for ASMCs, immune cell populations may also contribute. These data warrant further investigation of NLRP3 inhibition as a potential strategy against airway remodeling in asthma.