RANKL通过调节蜕膜巨噬细胞分化诱导母-胎免疫耐受的分子机制

人早孕期蜕膜巨噬细胞（dMφ）呈免疫耐受表型，参与胚胎植入和胎盘发育等妊娠过程。但其功能表型在蜕膜局部存在何种调控机制至今尚未明确。我们新近研究发现母-胎界面滋养细胞和蜕膜基质细胞(DSC)通过表达RANKL诱导dMφ向M2型分化（如IL-10分泌升高，IL-12和IL-23产生降低）。提示RANKL在维持dMφ呈M2型中发挥着重要的调节作用，但确切的分子机制尚不清楚。因此本课题以体外模拟母-胎界面微环境和体内动物实验为研究手段，分别研究1）人早孕期母-胎界面RANKL/RANK的表达调控机制；2）滋养细胞和DSC来源的RANKL调节dMφ分化的分子机制；3）RANKL异常低表达诱导dMφ功能异常进而诱发自然流产的病理机制。以期阐明RANKL信号通过加强母-胎交互对话参与维持dMφ耐受表型的分子机制，为母-胎免疫耐受机制研究提供新方向，为寻找防治自然流产的新策略提供科学依据。

Human dMφ was classified as resembling a tolerogenic phenotype, and was involved in several processes required for a successful pregnancy, including trophoblasts invasion as well as placental development. However, the regulatory mechanism of dMφ differentiation and polarization at the maternal-fetal interface remains largely unclear. Our recent studies show that receptor activator for nuclear factor-κ B ligand (RANKL) expressed on embryonic trophoblasts and maternal decidual stromal cells (DSCs), and polarizes dMφ towards a M2 phenotype (such as high level of IL-10 secretion, low level of IL-12 and IL-23). These results suggest that RANKL may be a pivotal regulator in maternal-fetal tolerance by licensing dMφ to ensure a successful pregnancy outcome. But the exact molecular mechanism is unclear. Therefore, taking advantage of in vitro trials for imitating the maternal-fetal microenvironment and in vivo animal experiments, our study intends to investigate 1) The regulation mechanism of RANKL/RANK expression at maternal fetal interface in human first-trimester; 2) The molecular mechanism of trophoblasts and DSC-derived RANKL on dMφ differentiation; 3) The pathological mechanism of abnormal low RANKL on spontaneous abortion through inducing the dysfunction of dMφ. This project will clarify the molecular mechanism of RANKL signaling on maintaining the tolerance phenotype of dMφ by strengthening maternal-fetal dialogue, provide a new direction for researching the mechanism of maternal-fetal immune tolerance, and the scientific basis for finding new strategies in the prevention and treatment of spontaneous abortion.