滋养层来源细胞外囊泡通过调控巨噬细胞极化促进先兆子痫的机制研究

Abstract

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.