Hippo通路核心激酶MST1正向调控DC促Th2功能参与变应性鼻炎发病的作用和机制

Dendritic cells (DCs) are key regulatory cells of Th2-skewed inflammation in airway mucosa. However, the molecular mechanisms by which DCs regulate Th2-type inflammation of allergic rhinitis (AR), especially their intracellular regulatory mechanisms, remain unclear. Our previous study unexpectedly found that the core protein kinase MST1 of hippo pathway was highly expressed in AR peripheral blood DCs, and the level of MST1 was significantly correlated with AR severity. In vitro experiments showed that DCs in AR patients had a significant decrease in Th2 function after silencing MST1. Therefore, we hypothesize that MST1 may be involved in the pathogenesis of AR by positively regulating the Th2 function of DCs. This study intends to further study the in vitro and in vivo effects of MST1 on the Th2 function of DCs and the corresponding intracellular signal transduction, and elucidate the upstream signals of MST1 by using a combination of in vivo animal and in vitro human studies. This study will provide new ideas for further understanding of the mechanisms of DCs in mediating the pathogenesis of AR and provide a new potential target for AR prevention and treatment.

树突状细胞（DC）是气道黏膜Th2炎症的关键调节细胞，但DC调控变应性鼻炎（AR）Th2型炎症的分子机制，特别是其胞内的调控机制仍不清楚。我们前期研究意外发现hippo通路的核心蛋白激酶MST1在AR外周血DC中高表达，并且MST1水平和AR严重程度显著相关。体外实验显示AR患者DC在沉默MST1后，其促Th2功能明显下降，据此我们提出科学假设：MST1可能通过正向调控DC的促Th2功能参与AR的发病。本课题拟在原有研究基础上进一步通过AR动物模型，采用DC体外培养、干预和体内过继转移的实验策略，深入研究MST1对DC促Th2功能的体内外效应，明确MST1通过调控DC功能介导AR发病的作用，探索MST1上游信号，并明晰MST1调控DC促Th2功能的胞内分子机制。本研究将为深入理解DC在介导AR发病的作用机制提供新思路，并为AR防治提供潜在的调控新靶点。

树突状细胞（DC）是气道黏膜Th2炎症的关键调节细胞，但DC调控变应性鼻炎（AR）Th2型炎症的分子机制，特别是其胞内的调控机制仍不清楚。本项目重点围绕“Hippo通路核心激酶MST1可能通过正向调控DC的促Th2功能参与AR的发病”这一科学假设，在成功构建单核细胞来源DC模型和AR动物模型的基础上，通过体外细胞试验和动物试验，主要完成了MST1在AR外周血及上下气道黏膜mDC的表达、TLR配体信号和尘螨变应原对mDC胞内MST1表达的影响、MST1对DC促Th2功能的影响等研究内容，明确了MST1在AR中正向调控DC促Th2功能的作用，明晰了诱导DC中MST1活化的信号，并对DC胞内MST1介导外界刺激信号调控DC促Th2炎症的分子机制以及DC受上皮源性细胞因子联合信号调控促Th2炎症的机制进行了探索，结果发现：AR外周血及上下气道黏膜mDC高表达MST1，尘螨变应原Der.p1信号可能是上调AR中mDC的MST1表达水平的关键信号，MST1具有正向调控AR来源DC促Th2功能的作用，IL-17RB、ST2和TSLPR三种信号联合可放大DC的促Th2功能，并与AR的疾病严重程度相关。本研究为深入理解DC在介导AR发病的作用机制提供了新思路，并为AR防治提供了潜在的调控新靶点。