溶血磷脂酸代谢-自噬失常诱发蜕膜巨噬细胞驻留障碍致复发流产的机制研究

人早孕期蜕膜存在大量巨噬细胞浸润、驻留且呈免疫耐受表型，参与胚胎植入和胎盘发育等妊娠过程，其数量和功能异常与复发流产密切相关。我们新近研究发现蜕膜巨噬细胞的溶血磷脂酸（LPA）代谢活跃且呈高自噬状态。LPA促进巨噬细胞自噬并增加其对蜕膜基质细胞的粘附。伴有LPA代谢失常的ENPP2+/-孕鼠子宫巨噬细胞减少、胚胎吸收率显著增加，自噬诱导剂雷帕霉素可改善自发流产小鼠胚胎丢失。因此我们假设LPA代谢活跃-高自噬促进巨噬细胞在早孕蜕膜驻留分化，参与正常妊娠建立和维持。故本项目以LPA代谢-自噬-免疫调节作为切入点，借助临床样本和疾病模型，通过高通量组学、生物信息学分析、荧光示踪或活细胞工作站、免疫耗竭和免疫重建等技术，研究LPA代谢-自噬失常致蜕膜巨噬细胞驻留分化异常致复发流产的分子机制。该项目有望为阐释母胎免疫代谢调节机制提供新方向，为从免疫代谢角度探索复发流产防治新策略提供科学依据。

A large number of infiltrated and resident human decidual macrophages (dMφ) with an immune tolerant phenotype in early pregnancy, are involved in several processes required for a successful pregnancy, including trophoblasts invasion as well as placental development. Abnormal number and dysfunction of dMφ are closely related to recurrent spontaneous abortion. Recently, we have found that decidual macrophages present active lysophosphatidic acid (LPA) metabolism and high autophagy. LPA promotes macrophage autophagy and increases its adhesion to decidual stromal cells. Along with decreased uterine macrophages, the absorption rate of Enpp2+/- pregnant mice with LPA metabolism disorder was significantly increased. Rapamycin, an autophagy inducer, could alleviate the embryo loss of spontaneous abortion mice. Therefore, we hypothesize that active LPA metabolism and high autophagy promotes macrophage residence and differentiation in the decidua of early pregnancy and participates in the establishment and maintenance of normal pregnancy. With the help of clinical samples and disease models, high-throughput omics technology, bioinformatics analysis, fluorescence tracing and live cell imaging system, immune depletion and immune reconstruction and other technologies, therefore, this project intends to take LPA metabolism, autophagy and immunoregulation as the starting point, and study the molecular mechanism of abnormal LPA metabolism and autophagy on recurrent spontaneous abortion by disturbing residence and differentiation of decidual macrophages. This project provides a new direction for explaining the mechanism of maternal-fetal immunometabolism regulation, and provides a scientific basis for exploring new strategies to prevent recurrent spontaneous abortion from the perspective of immunometabolism.