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.
Wang et al. (2026) studied this question.