环境中塑化剂通过芳香烃受体调控DC及诱导过敏反应的机制研究

Results from our past and ongoing studies have suggested that common environmental chemicals and pollutants may target regulatory cell types and influence mucosal immune function via, in part, their abilities to modify signaling, stress response and metabolic programming. Notably, our recent evidence suggests an important role of the aryl hydrocarbon receptor (AhR; a unique cellular chemical sensor)-ligand axis in controlling cellular homeostasis, maturation and optimal activation of several regulatory cell types, including dendritic cells (DCs). Further, our initial discovery work has identified a novel regulatory pathway involving a transcription factor, the intestinal-specific homeobox gene (ISX), as a target of the AhR-ligand axis, which may control cellular differentiation and function. Importantly, our recent pilot study also suggests a potential 3-generational impact of exposure to a common phthalate, DEHP, in a mouse model of antigen-induced asthma. To capitalize on these exciting findings, we intend to delineate the molecular mechanisms by which common environmental chemicals target and program DCs, considering their strategic location at the site of mucosa where exposure to environmental pollutants occurs. We plan to investigate, mechanistically, the functional impact of the AhR-ligand axis and ISX gene on the differentiation and function of DCs, as well as to continue to monitor the trans-generational and epigenetic effect of DEHP on DC differentiation and function. The accomplishment of our proposed studies is expected to provide a rational basis for the development of effective treatment and prevention strategies that will have direct and significant impact on the well-being of our general population.

目前所知常见的环境污染物，比如塑化剂（邻苯二甲酸酯，DEHP），可通过细胞内化学传感器（芳香烃受体，AhR）调控树突状细胞（DCs）的成熟与活化，进而影响黏膜免疫功能及过敏反应。我们的前期结果显示，孕期DEHP暴露导致子代DCs分化及肺部过敏反应受到影响，而且子代脾脏DCs亚群的比例与数目都明显减少。我们最近新发现AhR下游的肠道特异性转录因子（ISX）参与调控DCs的分化与功能。因此，本课题假设母代小鼠暴露于塑化剂后，会引起DCs表观基因的变化，导致子代后天免疫系统失调，进而诱导了过敏性哮喘。因此，本课题拟建立哮喘动物模型，采用分子生物学、表观遗传学等方法，探讨塑化剂通过AhR作用于转录因子ISX调控DCs功能从而诱导哮喘发生的机制。同时结合临床实验数据，为过敏性疾病致病机制的研究提供一个新的思路与方向，并为建立有效的预防和治疗策略提供理论依据。

流行病学调查显示，环境污染物中的多环芳香烃（PAH）、塑化剂（DEHP）等，可能是造成哮喘及其他过敏性疾病高发、病情恶化的原因。但是，环境污染物与哮喘发病的因果关系尚未建立，其作用机制不甚清楚。本课题围绕着“环境污染与健康”这一重大科学问题，拟通过AhRd转基因小鼠，模拟人类长期低剂量暴露于DEHP中的情况，同时结合临床实验数据，首次探讨环境污染物塑化剂（DEHP）通过AhR信号通路、改变表观遗传基因调控机制影响DCs的分化与功能，从而诱导哮喘发生的机制。已证实塑化剂 DEHP与芳香烃受体(AhR)或过氧化物酶体增殖物激活受体(PPARs)直接或间接的相互作用调控免疫调节细胞及过敏反应。DEHP可通过表观基因调控机制AhR-ISX信号通路抑制DCs表达干扰素的能力，促进过敏性疾病的发生。DEHP与HDM共同作用可加重HDM诱导产生的炎症因子和炎症反应；DEHP可通过其次级代谢产物MEHP影响转录 PPARγ进而促使肺巨噬细胞向M2转变，M2型巨噬细胞增多会加重 HDM诱发的Th2反应加重过敏性哮喘。此外本项目研究还发现在肺部炎症条件下，AhR通过靶向Notch1信号传导和抗炎介质的产生，在控制肺棒细胞稳态中至关重要。其次，我们通过小鼠和细胞实验发现环境污染物BaP 与尘螨过敏原Der f 1共同暴露在人支气管上皮细胞 (HBEC) 和哮喘小鼠模型的气道后，可增强了 Der f 1 诱导的 TSLP、IL-33和TGFβ1 分泌和信号激活，进一步加重哮喘气道炎症。项目研究结果将可能为哮喘不同表型的临床诊治和靶向治疗药物的研制提供新途径和依据，具有显著的社会及经济效益。