CD40 对烟草烟雾暴露下小鼠树突状细胞诱导Th17分化的调控作用研究

Cigarette smoking is the most important risk factor for chronic obstructive pulmonary disease(COPD). Th17 engages on the chronic inflammation of COPD,while dendritic cells play an vital role in the differentiation of T cells.In our previous studies, we found that the expression of CD40 on dendritic cells was upregulated after challenged by cigarette smoke extract(CSE) .CD40 is a costimulatory molecule on the surface of dendritic cell and there are studies reported that dendritic cells can promote CD4+T cells differentiate into Th17 cell by CD40/CD40L pathway under infection status.Thus, we speculated that CD40 may be an essential regulatory molecule of dendritic cell in the promotion of CD4+T cell differentiated into Th17 under the circumstance of cigarette smoke exposure.In present study, We first observe the function changes of dendritic cell and Th17 cell in CD40 knockout mice aftercigarette smoke exposure.Subsequently, we investigate the effect of blocking the CD40/CD40L pathway on the differentiation of Th17 induced by dendritic cell and aim to provide a noval target for the prevention and treatment of COPD.

烟草烟雾暴露是COPD (chronic obstructive pulmonary diseases)炎症最重要的危险因素，Th17是COPD慢性炎症的主要效应细胞，而树突状细胞在抗原递呈诱导T细胞的分化中起关键作用。我们的前期研究提示香烟提取物刺激可以促进树突状细胞上调CD40表达。CD40是树突状细胞表面的共刺激分子，研究显示在感染状态下树突状细胞可通过CD40/CD40L途径促进CD4+T细胞向Th17分化。据此，我们推测在烟草烟雾暴露下，CD40可能是树突细胞促进CD4+T细胞向Th17分化的重要的调控因子。故本项目以CD40为靶点，首先观察烟草烟雾暴露下CD40敲除小鼠树突状细胞的功能状态和Th17变化，进而研究在阻断CD40/CD40L路径条件下树突细胞对CD4+T细胞向Th17的分化的影响，为COPD的防治提供新的思路及靶点。

烟草烟雾暴露是COPD (chronic obstructive pulmonary diseases)炎症最重要的危险因素，Th17是COPD慢性炎症的主要效应细胞，而树突状细胞在抗原递呈诱导T细胞的分化中起关键作用。本课题研究围绕烟草烟雾暴露-树突状细胞上的CD40分子-Th17细胞活化三者关系变化展开，通过CD40拮抗剂与CD40敲基因小鼠模型，探讨了树突状细胞上CD40分子及其通路CD40/CD40L在烟草暴露下对T细胞向Th17分化的影响。结果显示：1.烟草烟雾暴露可促进小鼠肺或骨髓来源树突状细胞表面的CD40表达上调，并通过CD40/CD40L通路诱导初始CD4+T细胞向Th17分化，炎症因子IL-17增多；阻断CD40/CD40L通路，树突诱导初始CD4+T细胞向Th17分化受抑制，IL-17产生减少。2.烟草暴露可以促使小鼠肺树突状细胞共刺激因子CD40、CD86、MHCII升高，Th17细胞比例升高。相同烟草烟雾暴露环境下CD40敲除小鼠与野生型小鼠相比，Th17细胞比例下降。此外，我们还发现香烟烟雾提取物可诱导小鼠中性粒细胞产生中性粒细胞外诱捕网（NETs），在体外实验中活化浆细胞样树突状细胞（pDCs），上调共刺激分子CD40等，经过NETs活化的pDCs与初始CD4+T淋巴细胞共培养诱导Th1和Th17细胞。为后续更深入的研究COPD发病机制提供理论基础，为COPD的防治提供新的思路及靶点。