Interferon regulatory factor 5 involves the pathogenesis of emphysema through NLRP3 and Ly6C expressing cells.

Abstract

Interferon regulatory factor 5 (IRF5) is a key regulator of inflammatory responses; however, its role in chronic obstructive pulmonary disease remains unknown. A previous study showed increased IRF5 expression in the lungs of cigarette smoke (CS)-induced emphysema. Here we investigated the function of IRF5 in emphysema using Irf5-knockout (KO) mice. Alveolar destruction, inflammatory cell infiltration, cytokine levels and pyroptosis-related gene expression were assessed in CS-induced emphysema. To investigate the role of immune cells, Ly6C(Ly6C) monocytes and Ly6CT cells from Irf5-KO mice were introduced into emphysema mice. The correlation between IRF5 levels and emphysema in humans was also evaluated. Irf5-KO mice showed decreased alveolar destruction after CS exposure. NLRP3 expression was suppressed, and gasdermin D cleavage was altered in Irf5-KO mice, suggesting a protective effect against pyroptotic cell death. Moreover, Ly6Cmonocytes and Ly6CT cells were more abundant in the lungs of Irf5-KO mice after CS exposure, and their transfer attenuated NLRP3 expression and alveolar damage. Furthermore, IRF5 expression was significantly elevated in lung tissues from patients. Our findings highlight IRF5 as a critical regulator of emphysema pathogenesis via NLRP3-mediated pyroptosis and Ly6C-expressing immune cells. Targeting IRF5 may be a potential therapeutic strategy for chronic obstructive pulmonary disease.