RANKL-mediated harmonious dialogue between fetus and mother guarantees smooth gestation by inducing decidual M2 macrophage polarization

Kai-Kai Chang,Hui Li,Jie Mei,Wen-Jie Zhou,Da-Jin Li,Li-Ping Jin,Yu-Han Meng,Jian Wang,Ming-Qing Li,Li-Bing Liu

doi:10.1038/cddis.2017.505

Abstract

Decidual macrophages (dMϕ) contribute to maternal–fetal tolerance. However, the mechanism of dMϕ differentiation during pregnancy is still largely unknown. Here, we report that receptor activator for nuclear factor-κ B ligand (RANKL), secreted by human embryonic trophoblasts and maternal decidual stromal cells (DSCs), polarizes dMϕ toward a M2 phenotype. This polarization is mediated through activation of Akt/signal transducer and activator of transcription 6 (STAT6) signaling, which is associated with the upregulation of histone H3 lysine-27 demethylase Jmjd3 and IRF4 in dMϕ. Such differentiated dMϕ can induce a Th2 bias that promotes maternal–fetal tolerance. Impaired expression of RANKL leads to dysfunction of dMϕ in vivo and increased rates of fetal loss in mice. Transfer of RANK+Mϕ reverses mouse fetal loss induced by Mϕ depletion. Compared with normal pregnancy, there are abnormally low levels of RANKL/RANK in villi and decidua from miscarriage patients. These results suggest that RANKL is a pivotal regulator of maternal–fetal tolerance by licensing dMϕ to ensure a successful pregnancy outcome. This observation provides a scientific basis on which a potential therapeutic strategy can be targeted to prevent pregnancy loss.

Highlights

To investigate the role of RANKL/RANK signaling at the maternal–fetal interface, we first analyzed the expression of RANKL and found that both embryonic trophoblasts from villi and maternal decidual stromal cells (DSCs) from decidua are positive for RANKL in human first-trimester pregnancy (Figures 1a and b)
Similar results for RANKL expression levels were obtained by Enzyme-linked immunosorbent assay (ELISA) and flow cytometry (FCM) of the isolated trophoblasts and DSCs
We have demonstrated that RANKL derived from embryonic trophoblasts and maternal DSCs drives dMφ polarization toward an M2 phenotype by activating Akt/signal transducer and activator of transcription 6 (STAT6) signaling and enhancing the transcription of IRF4 and Jmjd[3]; it contributes to the formation and maintenance of maternal–fetal tolerance by further inducing Th2 bias (Figure 7)

Summary

Introduction

Decidual macrophages (dMφ) contribute to maternal–fetal tolerance. the mechanism of dMφ differentiation during pregnancy is still largely unknown. We report that receptor activator for nuclear factor-κ B ligand (RANKL), secreted by human embryonic trophoblasts and maternal decidual stromal cells (DSCs), polarizes dMφ toward a M2 phenotype. This polarization is mediated through activation of Akt/signal transducer and activator of transcription 6 (STAT6) signaling, which is associated with the upregulation of histone H3 lysine-27 demethylase Jmjd[3] and IRF4 in dMφ. There are abnormally low levels of RANKL/RANK in villi and decidua from miscarriage patients These results suggest that RANKL is a pivotal regulator of maternal–fetal tolerance by licensing dMφ to ensure a successful pregnancy outcome. Receptor activator of NF-κB ligand (TNFSF11, known as RANKL) and its tumor necrosis factor (TNF)-family receptor

Methods

Results

Conclusion