PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.
PlGF/FLT-1 deficiency leads to reduced STAT3-C/EBPβ signaling and aberrant polarization in decidual macrophages during early spontaneous abortion.
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PlGF/FLT-1缺陷导致早期自然流产过程中蜕膜巨噬细胞中STAT 3-C/EBPβ信号转导减少和异常极化
DOI：
10.3389/fimmu.2023.1061949
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发表时间：
2023
影响因子：
7.3
通讯作者：
Hu, Lina
中科院分区：
文献类型：
--
作者：
Chang, Ruiqi;Dai, Jingcong;Wang, Li;Liu, Hao;Jiang, Huanhuan;Liu, Xiaoyu;Jiang, Linying;He, Fan;Hu, Lina
关键词：
早期蜕膜中巨噬细胞极化失调（过量的M1样或有限的M2样巨噬细胞）导致同种异体胎儿排斥，从而导致早期自然流产。然而，M1/M2平衡的调制器在早期母胎界面仍然是未知的。采集正常妊娠行选择性终止妊娠妇女和自然流产患者孕早期蜕膜组织。我们检测了胎盘生长因子（PlGF）和Fms样酪氨酸激酶受体1（FLT-1）的表达，并表征了蜕膜中巨噬细胞的特征。值得注意的是，我们研究了重组人PlGF（rhPlGF）对正常妊娠蜕膜巨噬细胞（dM φ s）的作用，并揭示了体外和体内的潜在机制。PlGF/FLT-1表达下调可能通过诱导人早期蜕膜巨噬细胞M1样偏移而导致自然流产。CBA/J × DBA/2流产小鼠子宫巨噬细胞中FLT-1的表达低于CBA/J × BALB/c对照妊娠小鼠。在体外模型中，发现rhPlGF处理通过STAT3/CEBPB信号传导途径驱动dM φ s的M2样极化。除了子宫巨噬细胞中STAT3转录和C/EBP β表达降低外，Pgf敲除小鼠中更高的胚胎吸收率和子宫巨噬细胞功能障碍进一步支持了这些发现。PlGF通过经由FLT-1-STAT3-C/EBP β信号传导途径使dM φ s偏向M2样表型而在早期妊娠维持中起关键作用。令人兴奋的是，我们的研究结果强调了PlGF是预防早期自然流产的一个有希望的靶点。
Dysregulated macrophage polarization (excessive M1-like or limited M2-like macrophages) in the early decidua contributes to allogeneic fetal rejection and thus early spontaneous abortion. However, the modulators of M1/M2 balance at the early maternal-fetal interface remain mostly unknown. First-trimester decidual tissues were collected from normal pregnant women undergoing elective pregnancy terminations and patients with spontaneous abortion. We measured the expression of placental growth factor (PlGF) and Fms-like-tyrosine-kinase receptor 1 (FLT-1), and characterized the profiles of macrophages in decidua. Notably, we investigated the effect of recombinant human PlGF (rhPlGF) on decidual macrophages (dMφs) from normal pregnancy and revealed the underlying mechanisms both in vitro and in vivo. The downregulated expression of PlGF/ FLT-1 may result in spontaneous abortion by inducing the M1-like deviation of macrophages in human early decidua. Moreover, the CBA/J×DBA/2 abortion-prone mice displayed a lower FLT-1 expression in uterine macrophages than did CBA/J×BALB/c control pregnant mice. In in vitro models, rhPlGF treatment was found to drive the M2-like polarization of dMφs via the STAT3/CEBPB signaling pathway. These findings were further supported by a higher embryo resorption rate and uterine macrophage dysfunction in Pgf knockout mice, in addition to the reduced STAT3 transcription and C/EBPβ expression in uterine macrophages. PlGF plays a key role in early pregnancy maintenance by skewing dMφs toward an M2-like phenotype via the FLT-1-STAT3-C/EBPβ signaling pathway. Excitingly, our results highlight a rationale that PlGF is a promising target to prevent early spontaneous abortion.
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