IL-33/ST2通路调控树突状细胞诱导Th17细胞分化参与ARDS时肺部炎症反应的机制研究

Regulation of the inflammatory response and immune response caused by primary disease is the direction that we have been eager to break through in ARDS treatment. Th17 cells not only secrete IL-17 to enhance the intensity of inflammatory response, but also promote the development of inflammatory response through neutrophils, and also interact with Treg cells to regulate the direction of inflammatory response. Therefore, Th17 cells are likely to be an important intervention target during the uncontrolled inflammatory reactions in ARDS. Important intervention targets. Dendritic cells are the central tache of prime naive CD4+ T cells differentiation, and IL-6 is a key costimulatory factor for dendritic cells to induce the differentiation of prime naive CD4+ T cells to Th17. Recent studies have found that IL-33/ST2 pathway matured dendritic cells and made them secrete IL-6. It was suggested that IL-33/ST2 pathway in dendritic cells maybe an important upstream pathway promoted Th17 cells differentiation. This study is to proof the effect of IL-33/ST2 pathway in dendritic cells on the differentiation of Th17 cells and inflammatory response in lung using genetically engineered mice ST2ΔDC, and establish the prime naive CD4+ T cell and dendritic cell culture system to further explore the possible mechanism at cell level. This is an improvement of our previous research and provides new theoretical basis for the immunotherapy of ARDS.

调控原发病导致的机体炎症反应及免疫应答是ARDS治疗一直渴望突破的方向。Th17细胞不仅能分泌IL-17增强炎症反应的强度，通过中性粒细胞促进炎症反应的发展，还能与Treg细胞相互作用调控炎症反应的方向，因此，Th17细胞极可能是ARDS时失控炎症反应的重要干预靶点。树突状细胞是CD4+T细胞分化的中心环节，IL-6是树突状细胞诱导初始CD4+T细胞向Th17分化的共刺激因子。新近研究发现，IL-33/ST2通路能刺激树突状细胞成熟并分泌IL-6，可能是调控Th17细胞分化的重要上游通路。本课题拟应用ST2ΔDC基因工程鼠明确树突状细胞上的IL-33/ST2通路对Th17细胞分化及肺组织炎症反应的影响，并建立初始CD4+T细胞和树突状细胞培养体系中，从细胞水平进一步阐明Th17细胞分化的调控机制。这是对我们前期研究的深入和完善，为ARDS的免疫治疗提供新的思路和理论依据。

调控原发病导致的机体炎症反应及免疫应答是ARDS治疗一直渴望突破的方向。Th17细胞不仅能分泌IL-17增强炎症反应的强度，通过中性粒细胞促进炎症反应的发展，还能与Treg细胞相互作用调控炎症反应的方向，我们前期研究发现，ARDS时Th17细胞分化增强，分泌IL-17增多，极可能是ARDS时失控炎症反应的重要干预靶点，但其调控机制仍未完全阐明。树突状细胞是CD4+T细胞分化的中心环节，而IL-33/ST2通路能刺激树突状细胞成熟并分泌IL-6，可能是调控Th17细胞分化的重要上游通路。本项目以ARDS动物模型及树突状细胞为研究对象，以IL-33/ST2通路是否调控Th17细胞介导的免疫反应为研究核心，采用基因敲除、外源性重组IL-33等干预手段，从体内外两个层面进行研究，探讨其在炎症反应调节中的作用，揭示IL-33/ST2通路调控Th17细胞免疫效应，影响ARDS时肺部炎症反应方向的的分子机制。研究结果将进一步完善树突状细胞在ARDS时炎症反应中作用机制，为ARDS的免疫治疗提供新的思路和理论依据。