Benzo[a]pyrene Exacerbates Allergen-Induced Airway Inflammation through NLRP3-Dependent Dendritic Cell Activation and Pathogenic T Helper Cell Polarization

Pingchang Yang^*Huamei ZouJiaqi DuanYongmin XieRuien ChenYanyu YeAizhi ZhangGui YangXiaoyu Liu

• Shenzhen University, Shenzhen, China

Background: Environmental pollutants are known to aggravate allergic diseases, but the molecular mechanisms by which polycyclic aromatic hydrocarbons such as benzo[a]pyrene (BaP) potentiate allergic airway inflammation remain poorly understood. Objective: We investigated how BaP co-exposure modifies house dust mite (HDM)–driven allergic airway responses, focusing on the role of the NLRP3 inflammasome in dendritic cells (DCs). Methods: Mice were sensitized and challenged intranasally with HDM with or without BaP. Airway hyperresponsiveness (AHR), bronchoalveolar lavage (BAL) cell counts, lung histopathology, and serum HDM-specific IgE were assessed. Cytokine production and epithelial alarmins were measured by ELISA. The role of NLRP3 was evaluated using Nlrp3⁻/⁻ mice, in vitro bone marrow–derived DC (BMDC) cultures, and adoptive transfer of lung DCs. T helper cell polarization was analyzed in OT-II co-culture assays. Results: Co-exposure to BaP and HDM markedly exacerbated airway inflammation, with enhanced AHR, increased eosinophil and neutrophil infiltration, severe goblet cell hyperplasia, and elevated HDM-specific IgE. Cytokine analysis revealed synergistic induction of Th2 (IL-4, IL-5, IL-13) and Th17 (IL-17A) responses, alongside increased epithelial alarmins (TSLP, IL-33). This exacerbated phenotype was abolished in Nlrp3⁻/⁻ mice, which failed to produce IL-1β/IL-18 and exhibited attenuated inflammation. In vitro, BaP synergized with HDM to activate NLRP3 in BMDCs, leading to caspase-1 cleavage, IL-1β release, and enhanced CD80/CD86 expression. Adoptive transfer of BaP/HDM-exposed WT lung DCs, but not Nlrp3⁻/⁻ DCs, was sufficient to drive allergic airway inflammation in naïve recipients. Finally, BaP– conditioned WT DCs skewed naïve CD4⁺ T cells toward Th2 and Th17 lineages, an effect absent in Nlrp3⁻/⁻ DCs. Conclusion: BaP amplifies allergic airway disease by activating the NLRP3 inflammasome in DCs, thereby enhancing DC maturation, cytokine release, and pathogenic Th2/Th17 polarization. These findings identify a critical mechanism linking environmental pollutants to exacerbated allergic asthma and highlight the NLRP3 inflammasome as a potential therapeutic target.