Department of Obstetrics, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China.
Front Immunol. 2021 Apr 28;12:642071. doi: 10.3389/fimmu.2021.642071. eCollection 2021.
Changes in decidual macrophage polarization affect local inflammatory microenvironment and lead to adverse pregnancy outcomes. However, the regulatory mechanism of macrophage polarization in preeclampsia (PE) remains unclear. In this study, we found that α7nAChR expression was significantly down-regulated in decidual macrophages in PE patients compared to normal pregnant women, accompanied by a reduced proportion of M2 phenotype and an increased proportion of M1 phenotype; these results suggested that the reduced α7nAChR activity might contribute to changes in the polarization of decidual macrophages. Then, we further investigated the regulatory role of α7nAChR activation by nicotine on decidual macrophage polarization and placental remodeling in the PE-like mouse model. The PE mice were obtained by i.p. injection of 10 µg/kg lipopolysaccharide (LPS) gestational day (GD) 13, and 40 µg/kg LPS daily until GD16. Subcutaneous injection of 1.0 mg/kg nicotine was administrated from GD14 to GD18. Nicotine treatment increased the decreased M2 phenotype and inhibited the increased M1 phenotype in decidua of pregnant mice induced by LPS. The levels of pro-inflammatory cytokines in decidua were higher but the levels of anti-inflammatory cytokines were lower in PE mice compared to the controls, nicotine reversed these changes. The level of choline acetyltransferase (CHAT) was reduced in the LPS-treated group, it was increased following nicotine treatment. Damage of spiral artery remodeling and down-regulation of markers related to trophoblast invasion in placentas were found in PE mice; nicotine improved these pathological structures of placentas. α-bungarotoxin (α-BGT) which is specific antagonist for α7nAChR could abolish the effects of nicotine on decidual macrophage polarization, trophoblast arrangement and vascular structure in placental tissue in PE mice. These results suggest that α7nAChR plays an important regulatory role in maternal-fetal inflammation and placental remodeling in preeclampsia and may provide a theoretical basis for the discovery of new strategies for preeclampsia.
蜕膜巨噬细胞极化的改变影响局部炎症微环境，导致不良妊娠结局。然而，子痫前期（PE）中巨噬细胞极化的调节机制尚不清楚。在这项研究中，我们发现与正常孕妇相比，PE 患者的蜕膜巨噬细胞中α7nAChR 的表达明显下调，同时 M2 表型的比例降低，M1 表型的比例增加；这些结果表明，α7nAChR 活性的降低可能导致蜕膜巨噬细胞极化的改变。然后，我们进一步研究了尼古丁激活α7nAChR 对 PE 样小鼠模型中蜕膜巨噬细胞极化和胎盘重塑的调节作用。PE 小鼠通过腹腔注射 10μg/kg 脂多糖（LPS）于妊娠第 13 天（GD）获得，并于 GD16 每天给予 40μg/kg LPS。从 GD14 至 GD18 给予 1.0mg/kg 尼古丁皮下注射。尼古丁处理增加了 LPS 诱导的妊娠小鼠蜕膜中减少的 M2 表型，并抑制了增加的 M1 表型。与对照组相比，PE 小鼠蜕膜中促炎细胞因子水平升高，抗炎细胞因子水平降低，而尼古丁则逆转了这些变化。LPS 处理组的胆碱乙酰转移酶（CHAT）水平降低，而尼古丁处理后则升高。PE 小鼠胎盘螺旋动脉重塑受损，滋养细胞侵袭相关标志物表达下调，而尼古丁改善了这些胎盘的病理结构。α-银环蛇毒素（α-BGT）是一种特异性的α7nAChR 拮抗剂，它可以消除尼古丁对 PE 小鼠蜕膜巨噬细胞极化、滋养细胞排列和胎盘组织血管结构的影响。这些结果表明，α7nAChR 在子痫前期的母胎炎症和胎盘重塑中发挥重要调节作用，为子痫前期的新策略发现提供了理论依据。
