Notch-ILK-integrin信号轴介导嗜碱性粒细胞胞啃作用参与哮喘Th2过度分化的机制研究

Th1/2失衡是哮喘发病的重要免疫学机制。嗜碱性粒细胞（BA）经抗原刺激分泌初始IL-4，同时通过胞啃DC表面MHC-抗原肽复合物，高效诱导Th2分化。但目前有关BA胞啃DC的调控机制尚不清楚。我们既往首次报道敲除BA胞内Notch信号，可导致其表面抗原提呈分子表达下调，改善哮喘气道炎症。国外文献和我们的研究均证实Notch信号参与调控胞啃发生的关键步骤---免疫突触(IS)的形成。我们近期发现Notch信号缺失后BA-DC间IS形成减少，IS侧细胞骨架蛋白聚集减弱，强烈提示Notch可能参与BA-DC间胞啃的调控。本课题拟在此基础上，利用Notch敲除鼠构建BA嵌合哮喘小鼠模型，从体内外研究Notch信号对BA胞内ILK激酶的表达，细胞骨架蛋白的极化以及BA-DC突触的影响，并初步阐明Notch信号对BA胞啃DC的调控作用及相关分子调控机制，以期探索恢复哮喘Th1/2失衡的有效靶点。

Th1/2 bias is one of important immunological mechanisms of asthma. After stimulated by antigens, basophils (BA) induce Th2 differentiation efficiently by secreting the initial IL-4, and trogocytosis MHC peptide complex from DC surface. However, the regulatory mechanism of trogocytosis between DC-BAs is still uncertain. We have reported for the first time that knockout of the Notch in BAs could lead to the down-regulation of the expression of surface antigen presenting molecules and improve the airway inflammation of asthma. Foreign literature and our research have demonstrated that Notch signal is involved in the formation of immune synapse (IS), a key step in the regulation of trogocytosis. Recently, we found that the IS formation of BA-DC decreased and the cytoskeleton protein recruitment decreased after Notch signal knockout, which strongly suggested that Notch might be involved in the regulation of BA-DC trogocytosis. Based on this, this project intends to use Notch KO mice to construct a BA chimeric asthma mouse model, and research the effects of Notch signal on the expression of ILK enzyme in BAs, the polarization of cytoskeleton protein and the formation of IS with BA-DC in vitro and in vivo. It also preliminarily clarifies the regulatory effect of Notch signal on trogocytosis and the related molecular regulatory mechanism, in order to explore the effective target of restoring the Th1/2 bias in asthma.