Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway.
Trophoblast-derived miR-410-5p induces M2 macrophage polarization and mediates immunotolerance at the fetal-maternal interface by targeting the STAT1 signaling pathway.
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DOI：
10.1186/s12967-023-04831-y
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发表时间：
2024-01-04
影响因子：
7.4
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中科院分区：
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巨噬细胞表型偏差和免疫失衡在自然流产等妊娠相关疾病中起着至关重要的作用。滋养细胞调节巨噬细胞的表型变化，然而，其在妊娠期间的潜在机制尚不清楚。因此，本研究旨在阐明滋养细胞来源的miRNAs （miR-410-5p）在妊娠期巨噬细胞极化中的潜在功能。于2021年4月至12月在武汉大学人民医院生殖医学中心采集自然流产组和正常妊娠组（非医学原因人工流产）患者蜕膜巨噬细胞组织样本。并于2021年3月至2022年9月在深圳市中山妇产医院（原深圳市中山泌尿外科医院）采集自然流产患者和正常孕妇的胎盘绒毛和蜕膜组织样本进行验证和后续实验。作为动物模型，将36只雌性小鼠随机分为6组：单纯对照组、脂多糖模型组、agomir阴性对照预防组、agomir-410-5p预防组、agomir-410-5p阴性对照治疗组和agomir-410-5p治疗组。我们分析了miR-410-5p在流产组织和血浆样本中的表达；并补充miR-410-5p来评估体内胚胎吸收。分析了miR-410-5p在母胎界面的主要来源，并预测了miR-410-5p可能的靶基因——转录信号换能器和激活因子（STAT） 1。体外分析miR-410-5p和STAT1调控对巨噬细胞表型、氧化代谢和线粒体膜电位的影响。自然流产组MiR-410-5p水平低于正常妊娠组，血浆MiR-410-5p水平可预测妊娠和自然流产。在妊娠小鼠中预防性补充miR-410-5p可降低脂多糖介导的胚胎吸收并下调蜕膜巨噬细胞的促炎表型。MiR-410-5p主要分布在绒毛中，滋养细胞在母胎界面分泌外泌体- MiR-410-5p。巨噬细胞捕获外泌体后，细胞转向耐受表型。STAT1是miR-410-5p的潜在靶基因。MiR-410-5p结合STAT1 mRNA，抑制STAT1蛋白的表达。STAT1可以驱动巨噬细胞成熟为促炎表型。MiR-410-5p竞争性沉默STAT1可避免巨噬细胞免疫紊乱。MiR-410-5p通过抑制STAT1促进M2巨噬细胞极化，从而保证妊娠健康。这些发现对自然流产的诊断和预防具有重要意义，为该领域的进一步研究提供了新的视角。在线版本包含补充材料，可在10.1186/s12967-023-04831-y获得。
Macrophages phenotypic deviation and immune imbalance play vital roles in pregnancy-associated diseases such as spontaneous miscarriage. Trophoblasts regulate phenotypic changes in macrophages, however, their underlying mechanism during pregnancy remains unclear. Therefore, this study aimed to elucidate the potential function of trophoblast-derived miRNAs (miR-410-5p) in macrophage polarization during pregnancy. Patient decidual macrophage tissue samples in spontaneous abortion group and normal pregnancy group (those who had induced abortion for non-medical reasons) were collected at the Reproductive Medicine Center of Renmin Hospital of Wuhan University from April to December 2021. Furthermore, placental villi and decidua tissue samples were collected from patients who had experienced a spontaneous miscarriage and normal pregnant women for validation and subsequent experiments at the Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), from March 2021 to September 2022. As an animal model, 36 female mice were randomly divided into six groups as follows: naive-control, lipopolysaccharide-model, agomir-negative control prevention, agomir-410-5p prevention, agomir-negative control treatment, and agomir-410-5p treatment groups. We analyzed the miR-410-5p expression in abortion tissue and plasma samples; and supplemented miR-410-5p to evaluate embryonic absorption in vivo. The main source of miR-410-5p at the maternal–fetal interface was analyzed, and the possible target gene, signal transducer and activator of transcription (STAT) 1, of miR-410-5p was predicted. The effect of miR-410-5p and STAT1 regulation on macrophage phenotype, oxidative metabolism, and mitochondrial membrane potential was analyzed in vitro. MiR-410-5p levels were lower in the spontaneous abortion group compared with the normal pregnancy group, and plasma miR-410-5p levels could predict pregnancy and spontaneous abortion. Prophylactic supplementation of miR-410-5p in pregnant mice reduced lipopolysaccharide-mediated embryonic absorption and downregulated the decidual macrophage pro-inflammatory phenotype. MiR-410-5p were mainly distributed in villi, and trophoblasts secreted exosomes-miR-410-5p at the maternal–fetal interface. After macrophages captured exosomes, the cells shifted to the tolerance phenotype. STAT1 was a potential target gene of miR-410-5p. MiR-410-5p bound to STAT1 mRNA, and inhibited the expression of STAT1 protein. STAT1 can drive macrophages to mature to a pro-inflammatory phenotype. MiR-410-5p competitive silencing of STAT1 can avoid macrophage immune disorders. MiR-410-5p promotes M2 macrophage polarization by inhibiting STAT1, thus ensuring a healthy pregnancy. These findings are of great significance for diagnosing and preventing spontaneous miscarriage, providing a new perspective for further research in this field. The online version contains supplementary material available at 10.1186/s12967-023-04831-y.
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DOI：
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