AhR在变应性鼻炎组织重构中的作用机制

Allergic rhinitis (AR) is a commonly disease with a significant impact on the quality of life, whose pathpgenesis is related to environmental exprosure and methylation of related gene, resulting in tissue remodelling in AR. However, the mechanism remains to be declared. Aryl hydrocarbon receptor (AhR) plays a key role in mediating environmental factors,which induced the body disease. Transforming growth factor (TGF)-β1 which was the most powerful factor promoting the deposition of extracellular matrix. Previous studies showed that the increased expression of AhR in AR patients; Furthermore, the ITE (AhR agonist) up-regulated the expression of pSmad2 (signal transduction factor of TGF-β1). Base on those findings, one intriguing and plausible hypothesis is proposed that the expression of AhR and TGF-β1 in nasal mucosa is up-regulated via gene promoter methylation, and their crosstalk in tissue remodelling. In this study, AhR and TGF-β1 pathway were designed as the entry point. This study aimed to evaluate the mechanism of methylation in the crosstalk between AhR and TGF-β1 in AR tissue remodeling. Firstly, we will explore the expression of AhR and TGF-β1 pathway molecules in nasal fibroblast cells and nasal mucosa from AR mice, and the correlation with tissue remodeling. Secondly, we will investigate the crosstalk in primary cells and tissue level in vitro and its effect on nasal mucosa remoeling. Thirdly, we will evaluate the status of methylation of key gene promoter in the crosstalk. Collectively, the project will advance our understanding of molecular mechaism of tissue remodeling in AR, and contribute to provided a new strategy in clinic prevention and treatment of AR.

变应性鼻炎(AR)严重影响患者生活质量，其发病与环境及基因甲基化有关，导致鼻黏膜组织重构改变，但具体机制不详。芳香烃受体(AhR)是环境因素诱导机体疾病的关键机制，TGF-β1则是目前已知最强大的细胞外基质沉积剂。我们前期研究证实AR的发病与AhR高表达相关，经AhR激动剂ITE干预后的TGF-β1信号传导因子pSmad2表达增高。在此基础上我们提出科学假说：AhR与受甲基化调控的TGF-β1在AR中高表达并发生crosstalk作用，导致组织重构。本项目以AhR与TGF-β1信号途径为切入点，通过评价AhR与TGF-β1通路在AR小鼠中表达水平及与组织重构的相关性，探讨小鼠体外原代细胞和组织水平是否存在AhR与TGF-β1的crosstalk作用及其对组织重构的影响，探寻AhR与TGF-β1基因启动子甲基化状态及意义。研究结果将丰富AR组织重构的分子机制，为临床防治AR提供前期理论基础。

缺氧是变应性鼻炎(AR)的一个重要特征，然而，缺氧在AR中的作用仍有待更进一步的研究。本研究目的是探讨缺氧对AR患者AhR-Th17反应轴的影响。研究选取23例AR患者和15例正常人作为研究对象，检测常氧和缺氧条件，检测CD4 + T细胞中HIF-1α、AhR、CYP1A1和 CYP1B1的表达及Th17细胞的百分比数量。此外，常氧和缺氧条件下分别用ITE处理CD4 + T细胞后，检测ARNT与HIF-1α或AhR结合的亲和力。研究发现HIF-1α和AhR在AR患者CD4 + T细胞表达更高。在低氧环境中,HIF-1α 在AR患者和健康对照组CD4 + T细胞的表达均增高。同时，在缺氧条件下，AhR无毒配体(ITE)对AR患者和健康对照组细胞Th17反应的抑制作用及其对IL-10产生的促进作用均被抑制。这主要是由于HIF-1α与AhR竞争性地与ARNT结合从而抑制了AhR信号通路的活性。我们目前的研究结果表明缺氧环境通过增加HIF-1α活性，降低AhR活性进而促进Th17反应；因此，缺氧可能与AR的发病机制密切相关。