Changes to macrophage polarization affect the local microenvironment of the placenta, resulting in pathological pregnancy diseases such as recurrent spontaneous abortion (RSA). Macrophages are in close contact with trophoblasts during placental development, and trophoblast-derived cytokines are important regulators of macrophage polarization and function. Histone acetylation can affect the expression and secretion of cytokines, and ATP citrate lyase (ACLY) is an important factor that regulates histone acetylation. The aim of this study was to investigate the effect of ACLY expression differences in trophoblast on macrophage polarization and its mechanism. Our data demonstrate that ACLY level in placental villi of patients with RSA is decreased, which may lead to the inhibition of histone acetylation in trophoblasts, thereby reducing the secretion of IL-10. Reduced IL-10 secretion activates endoplasmic reticulum stress in macrophages, thus inhibiting their M2 polarization.
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.
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