Department of Obstetrics, Gynecology and Reproductive Sciences, Division of Reproductive Sciences, Yale School of Medicine, New Haven, Connecticut, USA.
Institute of Reproductive Health, Center for Reproductive Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P. R. China.
J Leukoc Biol. 2020 Sep;108(3):983-998. doi: 10.1002/JLB.1A0420-012RR. Epub 2020 May 9.
Decidual macrophages are in close contact with trophoblast cells during placenta development, and an appropriate crosstalk between these cellular compartments is crucial for the establishment and maintenance of a healthy pregnancy. During different phases of gestation, macrophages undergo dynamic changes to adjust to the different stages of fetal development. Trophoblast-secreted factors are considered the main modulators responsible for macrophage differentiation and function. However, the phenotype of these macrophages induced by trophoblast-secreted factors and the factors responsible for their polarization has not been elucidated. In this study, we characterized the phenotype and function of human trophoblast-induced macrophages. Using in vitro models, we found that human trophoblast-educated macrophages were CD14 CD206 CD86 and presented an unusual transcriptional profile in response to TLR4/LPS activation characterized by the expression of type I IFN-β expression. IFN-β further enhances the constitutive production of soluble programmed cell death ligand 1 (PD-L1) from trophoblast cells. PD-1 blockage inhibited trophoblast-induced macrophage differentiation. Soluble PD-L1 (sPD-L1) was detected in the blood of pregnant women and increased throughout the gestation. Collectively, our data suggest the existence of a regulatory circuit at the maternal fetal interface wherein IFN-β promotes sPD-L1 expression/secretion by trophoblast cells, which can then initiate a PD-L1/PD-1-mediated macrophage polarization toward an M2 phenotype, consequently decreasing inflammation. Macrophages then maintain the expression of sPD-L1 by the trophoblasts through IFN-β production induced through TLR4 ligation.
蜕膜巨噬细胞在胎盘发育过程中与滋养层细胞密切接触，这些细胞区室之间的适当串扰对于建立和维持健康的妊娠至关重要。在妊娠的不同阶段，巨噬细胞发生动态变化以适应胎儿发育的不同阶段。滋养层细胞分泌的因子被认为是负责巨噬细胞分化和功能的主要调节剂。然而，滋养层细胞分泌的因子诱导的这些巨噬细胞的表型以及使其极化的因子尚未阐明。在这项研究中，我们描述了人滋养层诱导的巨噬细胞的表型和功能。使用体外模型，我们发现人滋养层教育的巨噬细胞呈 CD14+CD206+CD86+表型，并且对 TLR4/LPS 激活的反应具有异常的转录谱，其特征是表达 I 型 IFN-β。IFN-β 进一步增强了滋养层细胞中可溶性程序性细胞死亡配体 1（PD-L1）的组成性产生。PD-1 阻断抑制了滋养层诱导的巨噬细胞分化。可溶 PD-L1（sPD-L1）在孕妇的血液中被检测到，并在整个孕期增加。总之，我们的数据表明，在母体胎儿界面存在一个调节回路，其中 IFN-β 促进滋养层细胞中 sPD-L1 的表达/分泌，然后可以启动 PD-L1/PD-1 介导的巨噬细胞向 M2 表型极化，从而减少炎症。然后，巨噬细胞通过 TLR4 连接诱导的 IFN-β 产生来维持滋养层细胞中 sPD-L1 的表达。
