Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion.
Extracellular vesicles derived from M1 macrophages deliver miR-146a-5p and miR-146b-5p to suppress trophoblast migration and invasion by targeting TRAF6 in recurrent spontaneous abortion.
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M1巨噬细胞衍生的细胞外囊泡传递miR-146a-5p和miR-146b-5p，通过靶向TRAF6抑制复发性流产中的滋养层细胞迁移和侵袭
作者：
Ding J;Zhang Y;Cai X;Zhang Y;Yan S;Wang J;Zhang S;Yin T;Yang C;Yang J
基本原理：越来越多的证据表明，滋养细胞迁移和侵袭不足在复发性流产（RSA）的发病机制中起着关键作用。母胎界面的细胞间通讯对于维持滋养层细胞的侵袭和迁移至关重要。M1巨噬细胞是母胎界面的重要免疫细胞成分，据报道在RSA患者的蜕膜组织中升高。最近的研究表明，M1巨噬细胞调节滋养层细胞的生物学行为，然而，其潜在的机制仍然知之甚少。研究方法：通过超离心法从THP-1细胞诱导的M1巨噬细胞（M1-EVs）的上清液中分离胞外囊泡（EVs），通过透射电镜、纳米颗粒示踪分析和蛋白质印迹法鉴定，并通过miRNA测序对其进行表征。划痕伤口愈合和transwell试验用于研究M1-EV对滋养层细胞迁移和侵袭的影响。RT-PCR、蛋白质印迹和荧光素酶报告基因分析来揭示潜在的机制。最后，通过动物实验研究了M1-EV对小鼠胚胎吸收的影响。结果：M1巨噬细胞通过分泌EV抑制滋养细胞EMT，从而降低其迁移和侵袭能力。通过miRNA测序，miR-146 a-5 p和miR-146 b-5 p被鉴定为用M1-EV处理的滋养层中上调最多的miRNA。进一步的功能实验表明，M1-EVs通过转移miR-146 a-5 p和miR-146 b-5 p抑制滋养层细胞的迁移和侵袭。EV miR-146 a-5 p和miR-146 b-5 p通过在转录后水平直接抑制TNF受体相关因子6（TRAF 6）表达来抑制滋养层细胞的EMT。此外，M1-EV加重了小鼠的胚胎吸收。临床上，RSA患者胎盘绒毛组织中miR-146 a-5 p、miR-146 b-5 p和TRAF 6表达异常，且miR-146 a-5 p/miR-146 b-5 p与TRAF 6表达水平呈负相关。结论：我们的研究结果表明，来自EV的miR-146 a-5 p和miR-146 b-5 p在M1巨噬细胞和滋养细胞之间的细胞间通讯中起重要作用，阐明了M1巨噬细胞调节滋养细胞的新机制及其在RSA中的作用。
Rationale: Emerging evidence demonstrates that insufficient migration and invasion of trophoblasts play critical roles in the pathogenesis of recurrent spontaneous abortion (RSA). Cell-to-cell communication at the maternal-fetal interface is essential to maintain the invasion and migration of trophoblasts. M1 macrophages, important immune cellular components at the maternal-fetal interface, have been reported to be elevated in decidua tissues from patients with RSA. Recent studies indicate that M1 macrophages modulate trophoblast biological behaviors; however, the underlying mechanisms remain poorly understood. Methods: Extracellular vesicles (EVs) were isolated from the supernatant of M1 macrophages inducted from THP-1 cells (M1-EVs) by ultracentrifugation, identified by transmission electron microscopy, nanoparticle tracking analysis, and western blotting, and their miRNA profile was characterized by miRNA sequencing. Scratch wound healing and transwell assays were used to investigate the effect of M1-EVs on trophoblast migration and invasion. RT-PCR, western blotting, and luciferase reporter assays were conducted to uncover the underlying mechanism. Finally, animal experiments were employed to explore the effect of M1-EVs on embryo absorption in mice. Results: M1 macrophages suppressed trophoblast EMT to reduce their migration and invasion abilities in vitro by secreting EVs. Through miRNA sequencing, miR-146a-5p and miR-146b-5p were identified as the most upregulated miRNAs in trophoblasts treated with M1-EVs. Further functional experiments showed that M1-EVs inhibited trophoblast migration and invasion by transferring miR-146a-5p and miR-146b-5p. Mechanistically, EV miR-146a-5p and miR-146b-5p inhibited EMT of trophoblasts by directly suppressing TNF receptor-associated factor 6 (TRAF6) expression at the post-transcriptional level. Furthermore, M1-EVs aggravated embryo absorption in mice. Clinically, expression of miR-146a-5p, miR-146b-5p, and TRAF6 were aberrant in placental villous tissues from patients with RSA, and negative correlations were found between miR-146a-5p/miR-146b-5p and TRAF6 expression levels. Conclusions: Our findings indicate that miR-146a-5p and miR-146b-5p derived from EVs play important roles in intercellular communication between M1 macrophages and trophoblasts, illuminating a novel mechanism in M1 macrophage regulation of trophoblasts and their role in RSA.
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影响因子：
5.6
作者：
Guenther S;Vrekoussis T;Heublein S;Bayer B;Anz D;Knabl J;Navrozoglou I;Dian D;Friese K;Makrigiannakis A;Jeschke U
通讯作者：
Jeschke U
影响因子：
11.2
作者：
Bhagirath D;Yang TL;Bucay N;Sekhon K;Majid S;Shahryari V;Dahiya R;Tanaka Y;Saini S
通讯作者：
Saini S
影响因子：
3.7
作者：
Gustafsson C;Mjösberg J;Matussek A;Geffers R;Matthiesen L;Berg G;Sharma S;Buer J;Ernerudh J
通讯作者：
Ernerudh J
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影响因子：
3.6
作者：
Ding, Jin-Li;Diao, Liang-Hui;Yang, Jing
通讯作者：
Yang, Jing
影响因子：
4.2
作者：
He Z;Huang C;Lin G;Ye Y
通讯作者：
Ye Y