粘蛋白1在哮喘气道上皮细胞与树突状细胞交互对话中的作用及机制研究

The role of Mucin1 in lung dendritic cell-epithelial cell crosstalk in asthma. Asthma is a Th2 lymphocyte-controlled disease of airway caused by inflammation, overproduction of mucus and airway remodeling which lead to airway hyperreactivity and airflow obstruction. Dendritic cells (DC) have been shown to be responsible for the initiation and maintenance of Th2 responses in asthma. It is increasingly clear that DC functions are strongly directed by the crosstalk with neighboring cells such as airway epithelial cells, which release the cytokines to promote Th2 responses in asthma. Mucin 1(Muc1) is a membrane-tethered mucin-like glycoprotein that is widely expressed in mucosal epithelial cells as well as hematopoietic cells such as lymphocytes and dendritic cells. Recently researches showed that Muc1 plays the protective role in lung infection and the inflammatory diseases. However, it is unknown whether Muc1 plays a protective role in asthma. In the initial study, we found that Muc1 might suppress the airway inflammation in the asthma model. In this study, the regulation function of Muc1 will be determined in the interaction of dendritic cell and airway epithelial cell in vitro and in vivo. This study might report for the first time that Muc1 deficiency increases the severity of asthma. Improved understanding of the effect of Muc1 on lung dendritic cell-epithelial cell crosstalk might provide important mechanistic insight for asthma. Based on this study, the new therapeutic strategies of asthma might be developed in the near future, which can prevent the exacerbations and alter the natural course of asthma.

哮喘是一种慢性气道炎症性疾病，近年来， Lambrecht BN等提出一种新的"交互对话"理论，认为肺树突状细胞(DCs)与邻近气道上皮细胞之间密切的"交互对话"，是启动和维持哮喘Th2免疫反应的重要发病机制。 粘蛋白1(Muc1)是粘蛋白家族一员，广泛表达于气道上皮细胞、DCs及T细胞，近期发现Muc1是一种重要的抗感染性炎症分子和免疫调节剂而受到广泛关注。但其对哮喘Th2免疫炎症是否有作用及机制如何，目前国内外未见报道。 本项目拟在长期从事哮喘研究和前期预实验初步发现Muc1可抑制哮喘气道炎症的基础上，进一步以气道上皮细胞及肺DCs为干预靶点，通过体内外实验检测Muc1基因敲除对哮喘气道上皮细胞和DCs之间"交互对话"及DCs诱导Th2免疫反应的影响，探讨Muc1对哮喘气道炎症反应的调节作用及机制。结果将对哮喘发病机制研究提供一定参考，并可能发现一种抑制哮喘气道炎症的新型候选药物。

哮喘是一种慢性气道炎症性疾病，肺树突状细胞(DCs)与邻近气道上皮细胞之间的交互对话是启动和维持哮喘免疫反应的重要发病机制。粘蛋白1(Muc1)是粘蛋白家族一员，广泛表达于气道上皮细胞、DCs及T细胞，Muc1是一种重要的抗感染性炎症分子和免疫调节剂而受到广泛关注。. 本项目以气道上皮细胞及DCs为干预靶点，通过体内外实验检测Muc1基因敲除对哮喘气道上皮细胞、DCs及DCs诱导Th2免疫反应的影响，探讨Muc1对哮喘气道炎症反应的调节作用及机制。结果发现：Muc1缺乏加重哮喘气道炎症及BALF中炎症因子分泌增加；MUC1高表达抑制IL-13诱导的气道上皮细胞细胞因子的分泌，并通过结和RIPK1抑制TNF-α诱导的气道上皮细胞的坏死性凋亡；Muc1缺乏的BM-DCs诱导CD4+T细胞分化为Th17细胞。结果提示Muc1缺乏增加气道上皮细胞分泌过多的细胞因子，促进DCs诱导CD4+T细胞分化为Th17细胞，从而加重哮喘气道炎症，为进一步阐明哮喘的发病机制提供了理论依据，为哮喘抗炎治疗Muc1相关的新型候选药物研发奠定基础。