IL-17RA Promotes Cigarette Smoke-Induced Alveolar Epithelial Cell Pyroptosis in COPD via Dual Activation of the NLRP3/Caspase1/GSDMD and NF-κB/GSDME Pathways

Xuan An, Yanhui Gu, Jian Zhou, Yuting Liu, Shengyi Yu, Lanying Zhang, Yao Ouyang Department of Respiratory and Critical Care Medicine, Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563003, People’s Republic of ChinaCorrespondence: Yao Ouyang, Email [email protected]: Chronic obstructive pulmonary disease (COPD) leads to persistent and irreversible airflow limitation due to lung tissue inflammation. Pyroptosis is closely involved in the pathogenesis of COPD and participates in the release of inflammatory factors. IL-17RA is a key receptor for IL-17A; however, the impact of IL-17RA on pyroptosis requires further investigation.Methods: This study elucidates the promoting effect of IL-17RA on the progression of COPD by constructing IL-17RA alveolar type II (AT2) epithelial cell-specific knockout animal models and knockdown models of IL-17RA in AT2 epithelial cells. The process of cellular pyroptosis was observed through transmission electron microscopy. Molecular biology techniques and functional experiments were conducted both in vivo and in vitro to validate the activation of canonical and non-canonical pyroptosis pathways by IL-17RA.Results: Our research findings indicate that the specific knockout of IL-17RA significantly alleviates damage to alveolar epithelial cells in a mouse model exposed to cigarette smoke, thereby delaying the progression of COPD in these mice. In this model, the absence of IL-17RA inhibits pyroptosis in cells and reduces the expression of proteins associated with pyroptosis. In the AT2 cell lines line, the knockdown of IL-17RA significantly suppresses the CSE-induced NLRP3/Caspase1/GSDMD and NFκB/GSDME pathways, thereby mitigating the occurrence of pyroptosis. In the AT2 cell lines line, IL-17A binds to IL-17RA, triggering the NLRP3/Caspase1/GSDMD pathway without activating the NFκB/GSDME pathway.Conclusion: Our research emphasizes that IL-17RA promotes pyroptosis by activating the NLRP3/Caspase1/GSDMD and NFκB/GSDME pathways, and is involved in the progression of COPD, providing a promising target for the prevention and intervention of COPD in clinical settings.Keywords: IL-17A, IL-17RA, GSDMD, GSDME, pyroptosis, COPD