鼻黏膜上皮细胞表达的miR-146a对变应性鼻炎的调节作用研究

Allergic rhinitis (AR) as an extremely common disease affects 500 million people around the world,which is associated with the increased risk of lower respiratory diseases such as asthma. As the first-line cell exposed to inhaled environmental factors such as pathogens, allergens and pollutants, epithelial cells may play a crucial role in the regulation of mucosal inflammation in AR progression. In our previous study, over-expression of miR-146a in epithelial cells has been found in AR patients and mice model. Based on this observation, we hypothesized that miR-146a might play a role in regulating the epithelial cell function and influencing the initiation and maintainance of AR. Our study herein plans to establish the correlationship between miR-146a expression and inflammatory status in nasal mucosa, as well as the activation and cytokine production profile of epithelial cells, and then investigate the regulatory effect of miR-146a on epithelial cell function by using agomir/antagomir in vivo and in vitro. We speculate that our findings would be beneficial to the better understanding of the pathogenesis of AR, and would provide a novel strategy on the management of AR.

变应性鼻炎(AR)直接影响到了世界上5亿人口，并且是诱发下呼吸道疾病尤其是哮喘的危险因素。AR的发生和发展与免疫细胞网络失衡有关，鼻黏膜上皮细胞作为鼻腔局部黏膜免疫的第一道细胞屏障，可通过对变应原进行识别以及对其他免疫细胞进行调控从而在AR发病中发挥关键作用。我们前期研究中发现，AR患者及小鼠鼻粘膜上皮细胞中miR-146a的表达与对照组相比明显增高，因此推测miR-146a在鼻黏膜上皮细胞的高表达可能对变应性鼻炎的发生起重要促进作用。本研究拟研究miR-146a表达、上皮细胞的活化和炎性因子分泌模式以及鼻黏膜局部变应性炎症状态三者之间的关系，通过在体内和体外应用agomir/antagomir对鼻黏膜上皮细胞中miR-146a的表达进行调控，炎症miR-146a在AR发病中的关键作用及机制。这项研究的完成，有可能为进一步理解变应性鼻炎的发病机制，探索可能的免疫学干预手段提供一个新的思路。

黏膜上皮细胞作为鼻腔局部黏膜免疫的第一道细胞屏障，可能变应性鼻炎（AR）发病的关键。miRNAs作为新型的免疫调控分子在黏膜慢性炎症中的作用有待阐明。本项目通过分析AR鼻黏膜miRNA表达谱，选定miR-146a为进一步研究对象，研究了miR-146a表达、上皮细胞的活化和炎性因子分泌模式以及鼻黏膜局部变应性炎症状态三者之间的关系。我们发现：（1）miR-146a在AR鼻黏膜上皮细胞（NECs）中过表达；（2）利用鼻黏膜上皮细胞的分离培养及基因干扰技术，证实miR-146a靶向IRAK1、CARD10，通过抑制NF-κB信号通路下调NECs共刺激因子CD86、CD40的表达，并减少Th2炎性因子的表达和分泌；（3）在动物体内实验中，应用滴鼻的方法成功干预miR-146a在鼻黏膜上皮细胞的表达，初步证明miR-146a能有效减轻小鼠鼻黏膜变应性炎症状态。这项研究的完成，有望开发一个具有潜在临床价值的干预靶点，具有重要的科学价值和临床意义；并为进一步理解黏膜变应性炎症的发病机制，探索可能的免疫学干预手段提供一个新的思路。