Downregulation of EZH2 in Trophoblasts Induces Decidual M1 Macrophage Polarization: a Potential Cause of Recurrent Spontaneous Abortion.
Downregulation of EZH2 in Trophoblasts Induces Decidual M1 Macrophage Polarization: a Potential Cause of Recurrent Spontaneous Abortion.
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DOI：
10.1007/s43032-021-00790-1
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发表时间：
2022-10
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巨噬细胞在确保母胎界面免疫耐受微环境的建立中起着关键作用。尤其是滋养层细胞与蜕膜巨噬细胞(DM)保持着密切的联系，据报道，蜕膜巨噬细胞在DM的极化调节中起着积极的作用。因此，滋养细胞功能障碍可能与某些妊娠相关并发症有关，如反复自然流产(RSA)。ZAST同源增强子2(EZH2)是一个重要的表观遗传调控基因，已被证明与免疫调节有关。本研究评估了EZH2在健康对照组和RSA患者绒毛组织中的表达。收集滋养层细胞条件培养液，孵育THP-1细胞系分化出的巨噬细胞。用siRNA或GSK126抑制EZH2在滋养层细胞中的表达和功能。我们的结果显示，与健康对照组相比，RSA患者绒毛组织中EZH2的表达显著降低。此外，EZH2在滋养层细胞中表达或功能的抑制促进了M1巨噬细胞的极化，这可能参与了RSA的发病机制。此外，抑制EZH2还影响滋养层细胞免疫和炎症细胞因子的分泌。综上所述，这些结果表明EZH2在调节滋养层细胞的免疫功能中的重要性，从而突出了其作为预防和治疗妊娠丢失的治疗靶点的潜力。
Macrophages are known to be pivotal for ensuring the establishment of the immune tolerance microenvironment at the maternal–fetal interface. In particular, trophoblasts stay in close contact with decidual macrophages (DMs), which have been reported to play an active role in the modulation of the polarization of DMs. Thus, any dysfunction of trophoblasts might be associated with certain pregnancy‐related complications, such as recurrent spontaneous abortion (RSA). Enhancer of zeste homolog 2 (EZH2) is an important epigenetic regulatory gene that has been previously shown to be related to immune regulation. The present study assessed the expression of EZH2 in villi tissue obtained from healthy controls and RSA patients. Trophoblasts conditioned medium was collected to incubate macrophages differentiated from the THP‐1 cell line. The expression and function of EZH2 in trophoblasts were knocked down either by the use of siRNA or GSK126 as an inhibitor. Our results show a significant decrease in the expression of EZH2 in villi tissue from RSA patients as compared to healthy controls. Further, the inhibition of expression or function of EZH2 in trophoblasts promoted M1 macrophage polarization, which might be involved in the pathogenesis of RSA. Moreover, the suppression of EZH2 was found to affect the secretion of immune and inflammatory cytokines in trophoblasts. Altogether, these results indicated the importance of EZH2 in the regulation of immune functions of trophoblasts and thus highlighted its potential to be explored as a therapeutic target to prevent and treat pregnancy loss.
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