子宫蜕膜巨噬细胞极化（M1/M2）在母胎耐受和妊娠维持中发挥重要作用，其中M1的显著增加与不明原因性复发性流产（uRM）关系密切，研究M1/M2的调控因素对探讨复发性流产机制至关重要。我们发现uRM患者蜕膜巨噬细胞中PGE2核受体PPARr表达降低，而uRM患者绒毛外滋养层细胞（EVT）中PGE2膜受体EP3表达增加，且EP3与PPARγ均与调控巨噬细胞极化的NF-κB信号转导通路相关。我们推测EP3和PPARγ可能诱导蜕膜巨噬细胞向M1转化，促炎症因子合成增加，母胎界面微环境向局部免疫炎症发展，导致EVT生物功能受损致使复发性流产。为验证此推测，本项目将使用EP3和PPARγ激动剂、抑制剂、过表达、敲除技术，利用人体组织、体外细胞和动物模型，通过观察EP3和PPARγ对蜕膜巨噬细胞极化的影响，阐述二者在uRM发生中的作用，探索M1对EVT生物功能的影响，为防治uRM探索新的治疗靶点。

Macrophage polarization (M1/M2) plays a vital role in immune tolerance and pregnancy maintenance. Decidual macrophages activation towards M1 phenotype is associated with the pathology of unexplained recurrent miscarriages (uRM). Therefore, it is necessary and critical to investigate modulators of balancing macrophages polarization in order to uncover the pathological mechanism of uRM. Our previous study found that the decreased expression of PGE2 nuclear receptor peroxisome proliferators-activated receptor γ (PPARγ) in the macrophages and increased expression of PGE2 membrane receptor EP3 in the extra villous trophoblasts (EVT) of uRM patients. Additionally, EP3 and PPARγ are involved in the nuclear factor-κB (NF-κB) signalling pathway, which is closely associated with macrophages polarization. We hypothesized that EP3 and PPARγ might induce M1 polarization and promote pro-inflammatory cytokines, thereby affecting EVT functions, creating a pro-inflammatory microenvironment in the feto-maternal interference and finally contributing to miscarriages. To prove it, we will utilize the agonists and antagonists of EP3 and PPARγ, as well as overexpression or knockdown to explore their effects on macrophage polarization with human tissues, in vitro cells and animal model. The final aim of our project is to elucidate the roles of EP3 and PPARγ in macrophage polarization and to search for new biomarkers for potential uRM treatments.