Trophoblast-Derived Extracellular Vesicles Promote Preeclampsia by Regulating Macrophage Polarization

巨噬细胞极化 微泡 微泡 滋养层 子痫前期 川地163 巨噬细胞 M2巨噬细胞 流式细胞术 细胞生物学 生物 CD63 免疫学 免疫系统 炎症 胎盘 小RNA 体外 生物化学 怀孕 基因 遗传学 胎儿
作者
Xiu Liu,Haiyi Fei,Cuiyu Yang,Jianmin Wang,Xiaohong Zhu,Anran Yang,Zhan Shi,Xiaoying Jin,Fei Yang,Dan Wu,Lingling Jiang,Song-ying Zhang
出处
期刊:Hypertension [Ovid Technologies (Wolters Kluwer)]
卷期号:79 (10): 2274-2287 被引量:21
标识
DOI:10.1161/hypertensionaha.122.19244
摘要

BACKGROUND: Systemic inflammation caused by dysfunctional macrophages is a crucial pathogenetic event in preeclampsia (PE). Trophoblast-derived extracellular vesicles (T-EVs) are potent immune cell signaling modulators in pregnancy. Herein, we aimed to investigate T-EVs’ effect and mechanism on macrophage polarization and its role in PE pathogenesis, which remain unclear. METHODS: Flow cytometry and immunochemistry were used to determine placental macrophage phenotypes. T-EVs were immuno-isolated via placental alkaline phosphatase antibody and identified by transmission electron microscopy and nanoparticle tracking analysis. Quantitative real-time polymerase chain reaction and flow cytometry were used to examine the effects of T-EVs on macrophage polarization, and correlation analysis of T-EVs lipidomics and macrophages transcriptome were performed to explore how T-EVs modulate macrophages. Animal experiments were established to investigate the relationship among PE, T-EVs, and macrophages. RESULTS: Macrophages shift from the M2 to M1 phenotype in the preeclamptic placenta. Also, T-EVs from women with PE (PE-EVs) significantly upregulated M1 gene markers and significantly downregulated CD163 expression in macrophages compared with T-EVs in women with normal pregnancies (NP-EVs). Mechanistically, correlation analysis with T-EVs lipidome and the transcriptome of macrophages treated with PE-EVs or NP-EVs indicated that 37 lipids altered in PE-EVs considerably affected classical inflammatory biological pathways in macrophages. Finally, animal experiments revealed that PE-EVs triggered PE-like symptoms in pregnant mice, which were alleviated after macrophage depletion. CONCLUSIONS: T-EVs from women with PE could promote preeclampsia by inducing macrophage imbalance polarization, signifying a potential novel interventional target for the prevention and management of PE.
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