FOXP2在Th9/IL-9介导的支气管哮喘炎症反应中的调控作用及其分子机制

Asthma is a chronic inflammatory disease of the conducting airways characterized by reversible airway obstruction and airway hyperresponsiveness, resulting in repeated periods of shortness of breath and wheezing. Th9 cells secrete IL-9 to mediate mast cell maturation and secretion. The release of several bronchoconstrictors by mast cells plays a key role in asthma attacks. In the previous study of this research group, we established a mouse model of asthma and found the expression of IL-9 in the lung tissue and BALF of the experimental group was significantly up-regulated, and the down-regulation of FOXP2 mRNA expression was negatively correlated with IL-9 mRNA expression. Overexpression of FOXP2 in Th9 cells significantly inhibited the mRNA expression levels of IL-9 and Th9-related transcription factors. It is suggested that FOXP2 may be involved in the regulation of IL-9 expression in Th9 cells, but the mechanism is still unclear. Therefore, this project intends to analyze: (1) the role of FOXP2 in regulating Th9 cell differentiation and IL-9 gene expression and the possible molecular mechanisms through in vitro and in vivo experiments; (2) The biological effects of FOXP2 in Th9 cell-mediated allergic bronchial asthma inflammation; (3) Clinical significance of FOXP2 expression levels in T cells of children with asthma. In conclusion, this project aims to investigate the role and mechanism of FOXP2 in Th9/IL-9-mediated asthmatic inflammatory response to bronchial asthma.

哮喘是以气道高反应性为特征的可逆性气道阻塞，导致反复发作的喘息、气促等症状的呼吸道慢性炎症性疾病，Th9细胞分泌IL-9介导肥大细胞成熟后分泌多种促进支气管收缩的物质是哮喘发作的重要因素。本课题组前期通过建立哮喘小鼠模型发现：实验组肺组织及BALF中IL-9表达明显上调，FOXP2的mRNA表达水平明显下调与IL-9呈负相关。Th9细胞中过表达FOXP2可明显抑制IL-9及相关转录因子的mRNA表达水平。提示我们FOXP2可能参与调控Th9细胞IL-9的表达，但机制尚不清楚。因此本项目拟通过体内外实验，分析（1）FOXP2在调控Th9细胞分化以及IL-9基因表达中的作用及可能的分子机制；（2）FOXP2在Th9细胞介导的过敏性支气管哮喘炎症中的生物学作用；（3）哮喘患儿T细胞中FOXP2表达水平的临床意义。总之，本项目旨在探讨FOXP2在Th9/IL-9介导的哮喘炎症反应中的作用及其机制。

哮喘是以气道高反应性为特征的可逆性气道阻塞，导致反复发作的喘息、气促等症状的呼吸道慢性炎症性疾病，Th9细胞分泌IL-9介导肥大细胞成熟后分泌多种促进支气管收缩的物质是哮喘发作的重要因素。本研究探索IL-9以及其上游调控因子Foxp2在儿童哮喘中的作用，以期发现儿童哮喘新型诊疗靶点。.本项目通过收集并检测儿童哮喘外周样本，设计体外试验并构建小鼠哮喘动物模型，明确了Foxp2及IL-9在儿童哮喘中的作用及相关机制。结果显示在哮喘患者外周血PBMC中Foxp2表达下调，而IRF4及BATF表达上调，血浆IL-9表达显著上调。体外试验发现诱导成功的Th9细胞内Foxp2表达降低，而IL-9的表达及分泌升高。并通过建立小鼠哮喘模型，证实Foxp2能通过抑制Th9细胞内转录因子IRF4及BATF的表达，降低IL-9的表达及分泌，改善哮喘的病理改变。使用抗IL-9单克隆抗体进行干预治疗能减少哮喘小鼠体内Th9细胞的分化，上调Foxp2的表达，抑制BATF及IRF4的表达水平，减少IL-9的表达与分泌，从而减轻哮喘小鼠的临床症状。.相关成果发表国内或国际论文6篇，其中SCI3篇，中文核心期刊3篇。获全国妇幼科学技术奖三等奖1项。