Recurrent spontaneous miscarriage (RSM) is a systemic disorder that has been defined as two or more pregnancies lost before the 20th week of gestation. Although the impaired function of macrophages at the maternal–fetal interface has been reported to be associated with RSM, the underlying mechanisms have not been fully elucidated. Here, we revealed that HDAC8 plays a critical role in RSM. Our results show that the mRNA and protein expression of HDAC8 was decreased in decidual macrophages from RSM patients. Moreover, the knockdown of HDAC8 resulted in a significant decrease in CD163 expression and an increase in apoptosis in dTHP-1 macrophages. Mechanistically, the ERK signaling pathway was activated in HDAC8-knockdown macrophages. When HDAC8-knockdown cells were pretreated with the ERK inhibitor U0126, expression levels of CD163, activated caspases 3, 7 and 9, and the apoptosis rate, were rescued. Taken together, our current results suggest that HDAC8 plays an important role in macrophage activation and apoptosis and may contribute to maintaining normal pregnancy by increasing the expression of M2 marker genes and inhibiting the apoptosis of macrophages at the maternal–fetal interface.

中文翻译：

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HDAC8 表达的下调通过激活复发性自然流产中的 ERK 信号通路来降低 CD163 水平并促进巨噬细胞凋亡。

复发性自然流产 (RSM) 是一种全身性疾病，其定义为在妊娠 20 周前两次或两次以上流产。尽管据报道母胎界面巨噬细胞功能受损与 RSM 相关，但其潜在机制尚未完全阐明。在这里，我们揭示了 HDAC8 在 RSM 中起着关键作用。我们的结果表明，来自 RSM 患者的蜕膜巨噬细胞中 HDAC8 的 mRNA 和蛋白质表达降低。此外，HDAC8的敲低导致 dTHP-1 巨噬细胞中 CD163 表达的显着降低和细胞凋亡的增加。从机制上讲，ERK 信号通路在HDAC8敲低巨噬细胞中被激活。当HDAC8用 ERK 抑制剂 U0126 预处理 -knockdown 细胞，CD163 的表达水平、活化的半胱天冬酶 3、7 和 9 以及细胞凋亡率得到拯救。综上所述，我们目前的结果表明，HDAC8 在巨噬细胞活化和凋亡中起重要作用，并且可能通过增加 M2 标记基因的表达和抑制母胎界面巨噬细胞的凋亡来维持正常妊娠。