Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts
Hypoxia-induced polarization of M2 macrophages and C-C motif chemokine ligand 5 secretion promotes the migration and invasion of trophoblasts
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DOI：
10.1093/biolre/ioac100
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发表时间：
2022-05
影响因子：
3.6
通讯作者：
Xin Chen;Qianlin Song;Rui Ji;Jia Yu Wang;Z. Li;Zhuoni Xiao;Duanying Guo;Jing Yang
中科院分区：
文献类型：
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作者：
Xin Chen;Qianlin Song;Rui Ji;Jia Yu Wang;Z. Li;Zhuoni Xiao;Duanying Guo;Jing Yang
摘要妊娠早期，胎盘缺氧对滋养细胞的迁移和侵袭具有重要意义。此外，巨噬细胞极性和活性的变化可通过影响细胞因子分泌来影响胚胎着床、滋养层迁移和侵袭以及血管重塑。然而，胎盘中缺氧条件对滋养层细胞的影响机制仍不清楚。我们对巨噬细胞进行基因敲除，对滋养层细胞进行药物处理，并在缺氧和常氧条件下培养它们。然后对细胞进行伤口愈合测定、Transwell细胞侵袭实验、定量实时逆转录聚合酶链反应（PCR）、蛋白质印迹和免疫荧光。检测各组巨噬细胞的极化、滋养细胞的迁移和侵袭能力以及磷脂酰肌醇-4，5-二磷酸3-激酶（PI 3 K）/蛋白激酶B（AKT）信号通路的变化。低氧条件诱导巨噬细胞的M2极化。缺氧条件下巨噬细胞的条件培养液可促进滋养细胞的迁移和侵袭，并提高滋养细胞中磷酸化（p）-PI 3 K和p-AKT的水平。在巨噬细胞中敲低C-C基序趋化因子配体5后，低氧条件下培养的巨噬细胞条件培养液促进滋养细胞迁移和侵袭的能力明显减弱。使用PI 3 K/AKT信号通路激动剂可以逆转C-C基序趋化因子配体5敲低引起的衰减效应。缺氧条件诱导M2巨噬细胞的极化及其C-C基序趋化因子配体5的分泌，从而激活滋养层中的PI 3 K/AKT信号通路，最终导致滋养层迁移和侵袭增强。图摘要妊娠早期胎盘的缺氧环境可能在巨噬细胞极化机制中发挥作用，缺氧条件可诱导巨噬细胞向M2型分化，刺激CCL 5的分泌。这将进一步促进滋养层细胞的迁移和侵袭。同时，来源于巨噬细胞的CCL 5参与了缺氧条件下滋养细胞中PI 3 K/AKT信号通路的激活。
Abstract In the early stage of pregnancy, hypoxia in the placenta is of great significance to the migration and invasion of trophoblasts. In addition, changes to the polarity and activity of macrophages can affect embryo implantation, trophoblast migration and invasion, and vascular remodeling by affecting cytokine secretion. However, the mechanism of the effects of hypoxic conditions in the placenta on trophoblasts remains unknown. We used gene knockdown on macrophages, and drug treatment on trophoblasts, and cultured them under hypoxic and normoxic conditions. The cells were then subjected to wound-healing assays, Transwell cell invasion experiments, quantitative real-time reverse transcription Polymerase Chain Reaction (PCR), western blotting, and immunofluorescence. The polarization of macrophages in each group, the migration and invasion ability of trophoblasts, and changes to the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway were detected. Hypoxic conditions induce M2 polarization of macrophages. The conditioned medium from macrophages under hypoxic conditions increased the migration and invasion of trophoblasts and enhanced the levels of phosphorylated (p)-PI3K and p-AKT in trophoblasts. After C-C motif chemokine ligand 5 knockdown in macrophages, the ability of conditioned medium from macrophages cultured under hypoxic conditions to promote the migration and invasion of trophoblasts was weakened significantly. The use of PI3K/AKT signaling pathway agonists could reverse the attenuation effect caused by C-C motif chemokine ligand 5 knockdown. Summary sentence Hypoxic conditions induced the polarization of M2 macrophages and their secretion of C-C motif chemokine ligand 5, thereby activating the PI3K/AKT signaling pathway in trophoblasts, ultimately leading to enhanced trophoblast migration and invasion. Graphical Abstract The hypoxic environment of the placenta in early pregnancy might play a role in the mechanism of macrophage polarization, in which hypoxic conditions can induce macrophages to polarize to the M2 type and stimulate the secretion of CCL5. This will further promote the migration and invasion of trophoblast cells. At the same time, CCL5 derived from macrophages is involved in the activation of the PI3K/AKT signaling pathway in trophoblasts under hypoxic conditions.