State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
University of Chinese Academy of Sciences, Beijing, China.
Front Immunol. 2021 Oct 12;12:763067. doi: 10.3389/fimmu.2021.763067. eCollection 2021.
Uterine M1/M2 macrophages activation states undergo dynamic changes throughout pregnancy, and inappropriate macrophages polarization can cause adverse pregnancy outcomes, especially during the peri-implantation period. Our previous studies have confirmed that Cytochrome P450 26A1 (CYP26A1) can affect embryo implantation by regulating uterine NK cells and DCs. The aim of this study was to investigate whether CYP26A1 regulates the polarization of uterine macrophages in early pregnancy. Here, we observed that was significantly upregulated in M1 as compared with M2 of uterine macrophages, Raw264.7 and iBMDM. Knockdown of CYP26A1 in mice uterine significantly decreased the number of embryo implantation sites and the proportion of CD45F4/80CD206 M1-like uterine macrophages. Primary uterine macrophages treated with anti-CYP26A1 antibody expressed significantly lower levels of M1 markers , , and . In CYP26A1 knockout Raw264.7 cells, the protein levels of M1 markers TNF-α, IL-6 and CD86 were significantly decreased as compared with the wild type cells. Moreover, CYP26A1 deficiency decreased the ability to produce nitric oxide and increased the phagocytosis capacity of Raw264.7 cells under M1 stimulation state. The re-introduction of CYP26A1 partially reversed the polarization levels of M1 in CYP26A1 knockout Raw264.7 cells. CYP26A1 may regulate the polarization of uterine macrophages to M1 through and . In summary, these results indicate that CYP26A1 plays a significant role in macrophage polarization, and knockdown of CYP26A1 can cause insufficient M1 polarization during the peri-implantation period, which has adverse effects on blastocyst implantation.
子宫 M1/M2 巨噬细胞激活状态在整个妊娠过程中发生动态变化，而巨噬细胞极化不当可导致不良妊娠结局，尤其是在着床期。我们之前的研究已经证实细胞色素 P450 26A1（CYP26A1）可以通过调节子宫 NK 细胞和 DC 来影响胚胎着床。本研究旨在探讨 CYP26A1 是否调节早孕时子宫巨噬细胞的极化。本研究观察到，与 M2 型子宫巨噬细胞相比，Raw264.7 和 iBMDM 中的 M1 型子宫巨噬细胞中明显上调。在小鼠子宫中敲低 CYP26A1 显著减少了胚胎着床部位的数量和 CD45F4/80CD206+M1 样子宫巨噬细胞的比例。用抗 CYP26A1 抗体处理的原代子宫巨噬细胞表达的 M1 标志物 、 、 和 水平明显降低。与野生型细胞相比，CYP26A1 敲除 Raw264.7 细胞中的 M1 标志物 TNF-α、IL-6 和 CD86 的蛋白水平显著降低。此外，CYP26A1 缺乏降低了 Raw264.7 细胞在 M1 刺激状态下产生一氧化氮的能力，并增加了其吞噬能力。在 CYP26A1 敲除 Raw264.7 细胞中重新引入 CYP26A1 部分逆转了 M1 的极化水平。CYP26A1 可能通过 和 调节子宫巨噬细胞向 M1 的极化。总之，这些结果表明 CYP26A1 在巨噬细胞极化中起重要作用，敲低 CYP26A1 可导致着床期 M1 极化不足，对囊胚着床产生不利影响。
