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。