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

Fine particulate matter (PM2.5), 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 PM2.5 triggers pyroptosis and compromises nasal epithelial barrier integrity remain unclear. This study investigates the role of PM2.5 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 PM2.5 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 PM2.5 induces NLRP3-mediated pyroptosis, resulting in tight junction protein degradation and compromised epithelial barrier integrity. Mechanistic investigations showed that PM2.5 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 PM2.5-induced pyroptosis and epithelial barrier dysfunction, whereas CYP1A1 overexpression reversed these protective effects, high-lighting the pivotal role of the AhR/CYP1A1/ROS axis in mediating PM2.5-induced epithelial damage. In conclusion, this study uncovers a novel mechanism by which PM2.5 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 PM2.5 exposure and mitigate its detrimental effects on respiratory health.