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

ABSTRACT: Decidual macrophages (dM?) contribute to maternal-fetal tolerance. However, the mechanism of dM? differentiation during pregnancy is still largely unknown. Here, we report that receptor activator for nuclear factor-? B ligand (RANKL), secreted by human embryonic trophoblasts and maternal decidual stromal cells (DSCs), polarizes dM? 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 dM?. Such differentiated dM? can induce a Th2 bias that promotes maternal-fetal tolerance. Impaired expression of RANKL leads to dysfunction of dM? in vivo and increased rates of fetal loss in mice. Transfer of RANK⁺M? reverses mouse fetal loss induced by M? 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 dM? 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.

SUBMITTER: Meng YH

PROVIDER: S-EPMC5682671 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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

Meng Yu-Han YH Zhou Wen-Jie WJ Jin Li-Ping LP Liu Li-Bing LB Chang Kai-Kai KK Mei Jie J Li Hui H Wang Jian J Li Da-Jin DJ Li Ming-Qing MQ

Cell death & disease 20171012 10

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 associat ...[more]

PMID: 29022922

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Project description:Dysfunction of decidual macrophages (DMs) is considered a critical event in the pathogenesis of pre-eclampsia (PE). T cell immunoglobulin mucin 3 (Tim-3) is an important negative regulatory molecule that induces immune tolerance by interacting with its ligand Galectin-9 (Gal-9) and thus modulating function of various immune cells, including macrophages. However, the regulatory effects of Tim-3/Gal-9 signaling on DMs polarization and its role in PE remain unclear. In this study, we established a PE-like rat model by administering 1.0 μg/kg lipopolysaccharide (LPS) to normal pregnant Sprague-Dawley rats via the tail vein at embryonic day 5 (E5). Apart from the pre-eclamptic manifestations, increased M1 subtype and decreased M2 subtype were observed at the maternal-fetal interface, as well as increased pro-inflammatory cytokines (TNF-α and IL-1β) and reduced anti-inflammatory cytokines (TGF-β and IL-10). Moreover, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were reduced. After administration of recombinant Galectin-9 (rGal-9) protein, we found that liver and renal injuries and maternofetal placental functional deficiency, including inadequate trophoblast cells invasion, impaired spiral artery remodeling and fetal capillary development, were reversed. In addition, the polarization of DMs was inclined to M2 subtype, which was similar to the polarization of DMs in the control rats but contrary to the PE-like rats. Interestingly, at E9, the expression of Tim-3 in DMs and that of Gal-9 at the maternal-fetal interface were significantly increased in the rGal-9 protein intervention group. Taken together, our findings show that administration of rGal-9 protein can alleviate the PE-like rat manifestations induced by LPS. This finding may be related to the activation of the Tim-3/Gal-9 signaling pathway, which promotes DMs polarization dominantly shifting to M2 subtype. Moreover, upregulation of Tim-3 in DMs and Gal-9 at the maternal-fetal interface at E9 suggests that Tim-3/Gal-9 pathway may play some important roles in early pregnancy and even embryo development.

Dataset Information

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

Publications

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

Similar Datasets

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