IL-17A regulates airway remodelling in COPD through the PI3K/AKT/mTOR pathway.

The airway and lung tissue inflammation and structural changes caused by COPD lead to persistent and irreversible airflow limitation in patients. Several studies have associated IL-17A with COPD airway inflammation and collagen deposition, while autophagy is essential for maintaining normal cell function. Based on these findings, we propose a hypothesis that IL-17 affecting the autophagy of macrophages through the PI3K/AKT/mTOR pathway may contribute to the regulation of the airway remodeling process in COPD. The COPD airway remodelling model was confirmed by pulmonary function tests and HE and Masson staining. IL-17A, IL-6 and CCL20 were detected by ELISA, autophagosomes (APs) were observed by transmission electron microscopy, and western blotting was used to detect PI3K/AKT/mTOR-related proteins, autophagy-related proteins and collagen. Immunofluorescence revealed colocalization of LC3 in mouse bronchial fibroblasts (MBFs). MBFs were isolated and cultured via lentiviral transfection, IL-17RA overexpression or silencing, and quantitative analysis of PI3K/AKT/mTOR pathway-related proteins and autophagy-related proteins via western blotting. The results validated the establishment of the COPD model. Increased IL-17A in the COPD airway and increased IL-6 and CCL20 expression were observed in the COPD mice supplemented with the autophagy inhibitor 3MA. Using TEM, we observed a significant reduction in the number of APs in the airways in both the COPD and 3MA groups. Moreover, the PI3K/AKT/mTOR pathway phospho-p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios were also increased in the COPD group. Moreover, as P62 increased, Beclin-1 and LC3II/I expression decreased correspondingly, while Collagen I and Collagen III also increased. In our study of cultured mouse MBFs, the results showed that overexpression (OE) virus-mediated transfection of MBFs overexpressing IL-17RA increased the p-PI3K/PI3K, p-AKT/AKT, and p-mTOR/mTOR ratios, increased the P62 content and reduced the expression of Beclin-1 and LC3II/I. However, compared with the OE group, the silencing (sh)-mediated transfection of MBFs with IL-17RA had almost opposite effects. Increased collagen production and the expression of IL-17A, IL-6 and CCL20 in the airways of COPD mice. Autophagy decreased, and the PI3K/AKT/mTOR pathway was activated in COPD airway tissue. In primary cultured MBFs from COPD mice, IL-17A combined with IL-17RA activates the PI3K/AKT/mTOR pathway, thereby inhibiting autophagy.