Interferon Regulatory Factor 5 modulates CD11b+ cell composition and NLRP3-related factors in emphysema pathogenesis 2258665

Abstract

Abstract Introduction Although interferon regulatory factor 5 (IRF5) is known to play a central role in inflammation, its function in chronic obstructive pulmonary disease (COPD) remains unclear. Previous evidence revealed that IRF5 expression is elevated in the lungs of cigarette smoke (CS)—induced emphysema models. Methods 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 further define immune cell contributions, Ly6C ++ (Ly6Chigh) monocytes and Ly6Chigh T cells from Irf5-KO mice were introduced into emphysema mice. Results Irf5-KO mice showed decreased alveolar destruction after CS exposure. NLRP3 expression was suppressed, and gasdermin D cleavage was altered in Irf5-KO mice, indicating a protective effect against pyroptotic cell death. Among CD11b+Ly6G+ population, CD244.2, a PMN-MDSC-associated marker, was significantly elevated in Irf5-KO mice following CS exposure although Siglec-E, a neutrophil-associated marker, was most highly expressed in CS-exposed WT mice compared to all other groups. Moreover, Ly6Chigh monocytes and Ly6Chigh T cells were more abundant in the lungs of Irf5-KO mice after CS exposure, and their transfer attenuated NLRP3 expression and alveolar damage. Conclusion Our findings highlight IRF5 as a critical regulator of emphysema pathogenesis through NLRP3-mediated pyroptosis, altered composition in CD11b+Ly6G+ populations, and modulation of Ly6Chigh-expressing immune cells. Targeting IRF5 may be a potential therapeutic strategy for COPD. Funding Source n/a Topic Categories Immune Mechanisms of Human Disease (HUM)