Contrasting immunomodulatory effects of benzo[a]pyrene in allergic airway inflammation and DSS-induced colitis
學生姓名:
李芳頡
指導教授:
黃崇雄
學期:
115上
摘 要:
Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon ubiquitous in vehicle exhaust, tobacco smoke, and high-temperature foods, possesses a dual biological profile as an aryl hydrocarbon receptor (AHR) agonist and a pro-mutagenic toxicant. However, its route-dependent and organ-specific immunomodulatory variations remain not to be fully elucidated. This study aimed to cross-compare the contrasting immunomodulatory mechanisms of intranasal BaP exposure in house dust mite (HDM)-induced allergic airway inflammation versus low-dose oral BaP administration in dextran sulfate sodium (DSS)-induced ulcerative colitis. Respiratory experiments utilized female C57BL/6J wild-type and Nlrp3⁻/⁻ mice subjected to intranasal HDM (25 µg) ± BaP (10 µg) challenges, evaluating airway hyperresponsiveness (AHR), Bronchoalveolar lavage fluid（BALF） cell counts, inflammatory cytokines, dendritic cell (DC) adoptive transfer, and T-cell polarization. Gastrointestinal experiments employed C57BL/6J mice receiving dietary oral BaP (~12.5 mg/kg/day) alongside 3% DSS in drinking water, assessing body weight, disease activity index（DAI） scores, colon length, histopathology, RT-qPCR gene expression, and ³²P-postlabeled BaP-DNA adducts. The results showed that intranasal BaP synergized with HDM to activate the DC-intrinsic NLRP3 inflammasome, accelerating Caspase-1 cleavage and mature IL31 1β/IL-18 release, upregulating CD80/CD86, and driving naive CD4⁺ T cells toward pathogenic Th2 (IL-4/5/13) and Th17 (IL-17A) polarization, which markedly exacerbated airway resistance, eosinophilic/neutrophilic infiltration, and goblet cell metaplasia. Conversely, low-dose oral BaP successfully activated the intestinal AHR pathway (strongly inducing Cyp1a1 expression) and broadly downregulated colonic pro-inflammatory genes (Il6, Il17a, Il1b, Cxcl1, Cxcl2) and plasma IL-6 protein, significantly attenuating weight loss, colon shortening, DAI scores, and mucosal crypt damage without increasing colonic BaP-DNA adducts. In conclusion, BaP exhibits route-dependent and organ-specific dual immunomodulatory effects, exacerbating airway allergy via the DC-intrinsic NLRP3 axis upon inhalation, while conferring anti inflammatory protection via the intestinal AHR pathway upon ingestion. These results offer distinct therapeutic targets for pollution-exacerbated severe asthma and inflammatory bowel disease.
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