PM2.5 exacerbates nasal epithelial barrier dysfunction in allergic rhinitis by inducing NLRP3-mediated pyroptosis via the AhR/CYP1A1/ROS axis

Abstract

Fine particulate matter (PM_2.5), a major air pollutant, plays a critical role in exacerbating respiratory diseases such as allergic rhinitis (AR) by inducing inflammation. While its association with AR is well established, the precise mechanisms by which PM_2.5 triggers pyroptosis and compromises nasal epithelial barrier integrity remain unclear. This study investigates the role of PM_2.5 in promoting pyroptosis in nasal epithelial cells and its contribution to AR pathogenesis. Clinical analysis revealed significantly elevated levels of NLRP3 inflammasomes and pyroptosis-related proteins in the nasal mucosa of patients with AR compared with the control group. In vitro and in vivo experiments further demonstrated that PM_2.5 exposure led to a dose-dependent increase in these markers in nasal epithelial cells and AR mouse models. Functional studies using NLRP3 agonists and inhibitors confirmed that PM_2.5 induces NLRP3-mediated pyroptosis, resulting in tight junction protein degradation and compromised epithelial barrier integrity. Mechanistic investigations showed that PM_2.5 activates the aryl hydrocarbon receptor (AhR) pathway, driving the transcription of cytochrome P450 1A1 (CYP1A1) and increasing reactive oxygen species (ROS) production. Notably, AhR downregulation alleviated PM_2.5-induced pyroptosis and epithelial barrier dysfunction, whereas CYP1A1 overexpression reversed these protective effects, highlighting the pivotal role of the AhR/CYP1A1/ROS axis in mediating PM_2.5-induced epithelial damage. In conclusion, this study uncovers a novel mechanism by which PM_2.5 promotes NLRP3-mediated pyroptosis through the AhR/CYP1A1/ROS signaling pathway, ultimately leading to epithelial barrier disruption and AR exacerbation. These findings highlight the urgent need for strategies to minimize PM_2.5 exposure and mitigate its detrimental effects on respiratory health.