芳香烃受体在葡萄膜炎中的作用及机制研究

The role of aryl hydrocarbon receptor in uveitis and the mechanism

目的拟探究Ah R的配体2,3,7,8-四氯二苯-对-二恶英(TCDD)在实验性自身免疫性葡萄膜炎(EAU)中的作用及其机制。方法选择C57BL/6雌性小鼠,随机分为Na?ve组、EAU+vehicle组和EAU+TCDD组。采用视网膜光感受器间维生素A类结合蛋白_(651-670)(IRBP_(651-670))建立小鼠EAU模型。EAU+TCDD组小鼠自免疫前1天腹腔注射TCDD,EAU+vehicle组同法给予等体积空白溶剂(橄榄油)。通过分别对小鼠眼前段和眼后段进行临床评分和病理评分,检测巨噬细胞/小胶质细胞数量和炎症因子表达水平,探讨Ah R相关通路在葡萄膜炎发生中的作用机制。结果与EAU+vehicle组相比,TCDD处理后的EAU小鼠临床评分和病理评分明显降低,F4/80标记的巨噬细胞/小胶质细胞数量明显减少,促炎因子表达水平明显降低,Notch-1表达明显减少。结论 TCDD激活Ah R后,通过减少巨噬细胞/小胶质细胞数量和促炎因子表达,从而起到控制EAU炎症反应的作用,可能的机制是抑制Notch通路来实现其抑炎作用。

Uveitis is characterized as a common cause of blindness. Aryl hydrocarbon receptor（Ah R） has been implicated in immunomodulatory processe in human uveitis, although the exact mechanisms remain poorly understood. This study aimed to explore the role of a Ah R ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin（TCDD） in experimental autoimmune uveitis（EAU） and related mechanism. Female C57 BL/6 mice were randomly divided into three groups： naive group, EAU ＋ vehicle group, and EAU ＋ TCDD group. Mice were immunized with interphotoreceptor retinoid-binding protein 651-670（IRBP651-670） to induce experimental autoimmune uveitis.TCDD was administered intraperitoneally one day before immunization in EAU ＋ TCDD group,while the equal volume of vehicle（olive oil） was administered in the same way to the EAU＋vehicle group. The severity of EAU was evaluated with clinical and histological scores. We also tested the number of macrophage/microglia and the production pro-inflammatory cytokines. Data showed that clinical and histopathological manifestations were significantly ameliorated in the EAU＋TCDD group as compared with the EAU＋vehicle group. In addition, TCDD decreased the number of F4/80 positive macrophage/microglia, inhibited the expressions of pro-inflammatory cytokines, and reduced the activation of Notch-1. In conclusion, Ah R activation with TCDD exhibits an anti-inflammatory effect by reducing the number of macrophages/microglia, decreasing pro-inflammatory cytokines,and inhibiting the Notch pathway during EAU.