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

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.