IRF8 and FOXM1 Regulation in COPD Progression: Impacts on Inflammation and Senescence

This study aims to investigate the role of Interferon Regulatory Factor-8 (IRF8) in chronic obstructive pulmonary disease (COPD) and its underlying mechanisms. A COPD mouse model was established by cigarette smoke exposure, which revealed the aberrant upregulation of IRF8 in lung tissues, with IRF8 expression being associated with genes related to inflammation and cellular senescence. In a COPD mouse model, knockdown of IRF8 significantly alleviated lung injury. This was demonstrated by a reduced lung index, improved emphysema, decreased inflammatory cell infiltration, and lower levels of inflammatory factors. Furthermore, IRF8 knockdown inhibited cell senescence in lung tissue, as characterized by downregulated expression of markers (p16, p53, p21), reduced SA-β-gal activity, and modulation of the Akt/mTOR signaling pathway. In vitro experiments demonstrated that the expression of IRF8 was increased in human bronchial epithelial cells (BEAS-2B) treated with cigarette smoke extract, while knockdown of IRF8 could suppress cigarette smoke extract-induced inflammatory responses and cellular senescence, and the protective effects of IRF8 knockdown could be reversed by Akt activation. Further studies showed that IRF8 was transcriptionally regulated by FOXM1, which could bind to the IRF8 promoter, and FOXM1 overexpression increased IRF8 expression, while FOXM1 knockdown decreased it, and FOXM1 regulated cigarette smoke extract-induced inflammation and senescence by modulating IRF8. In summary, IRF8 promotes the progression of COPD through the transcriptional regulation by FOXM1, which subsequently affects inflammatory responses and cellular senescence, providing a potential therapeutic target for COPD.