IL-17A activates the PI3K/AKT/mTOR pathway to regulate bronchial fibroblast autophagy-mediated airway remodeling: evidence from conditional IL-17RA-deficient mice.

Background: Airway remodeling (AR) is a key pathological feature of chronic lung diseases and is closely associated with disease progression. IL-17A has been implicated in airway inflammation and fibrosis, but its role in AR and the underlying mechanisms remain incompletely understood. This study investigated whether IL-17A regulates bronchial fibroblast autophagy and airway remodeling through the PI3K/AKT/mTOR pathway. Methods: An AR mouse model was established by intratracheal administration of an adenovirus expressing IL-1β. Lung histopathology and pulmonary function were evaluated in wild-type mice and conditional IL-17RA-deficient mice. Primary mouse bronchial fibroblasts were used to assess the effects of IL-17A on autophagy-related proteins, inflammatory and profibrotic mediator secretion, collagen production, and PI3K/AKT/mTOR pathway activation. The autophagy inhibitor 3-methyladenine (3MA) was used to further examine the relationship between autophagy and pathway activation. Results: Conditional IL-17RA deficiency attenuated airway inflammation, collagen deposition, and pulmonary function impairment in AR mice. In primary bronchial fibroblasts, IL-17A decreased LC3II/I expression, increased p62 expression, promoted collagen I/III production, altered inflammatory and profibrotic mediator secretion, and activated the PI3K/AKT/mTOR pathway. These effects were reduced in fibroblasts with lower IL-17RA expression. Moreover, IL-17A partially reversed the inhibitory effect of 3MA on PI3K/AKT/mTOR phosphorylation. Conclusion: IL-17A/IL-17RA signaling contributes to airway remodeling by suppressing bronchial fibroblast autophagy and promoting inflammatory and fibrotic responses, at least partly through PI3K/AKT/mTOR pathway activation. These findings suggest that IL-17A may represent a potential therapeutic target for AR.