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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 2  |  Page : 63-71

Mifepristone (RU486) inducing abortion in a mouse model by regulating innate and adaptive immune responses


1 Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology; Department of Gynecology, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China
2 Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology; Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200032, China
3 Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200032, China
4 Laboratory for Reproductive Immunology, NHC Key Lab of Reproduction Regulation (Shanghai Institute of Planned Parenthood Research), Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 230032, China
5 Department of Gynecology, Jing'an District Central Hospital, Fudan University, Shanghai 200040, China

Date of Submission02-Feb-2020
Date of Decision09-Mar-2020
Date of Acceptance14-Mar-2020
Date of Web Publication26-Jun-2020

Correspondence Address:
Mei-Rong Du
Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital, Fudan University, Zhao Zhou Road 413, Shanghai 200032
China
Yan-Hong Li
Laboratory for Reproductive Immunology, Obstetrics and Gynecology Hospital, Fudan University, Zhao Zhou Road 413, Shanghai 200032
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2096-2924.288021

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  Abstract 


Objective: Mifepristone (RU486), one of the most common medications for artificial abortion, attenuates the immunoregulatory effects of progesterone. However, the specific immune regulatory mechanism of RU486 in abortion remains unknown. We intended to investigate the immunomodulatory effects of RU486 on abortion.
Methods: Sixty female mice were divided into the control group (0 mg RU486) and RU486 group (2 mg/kg RU486). The uterus, peripheral blood, and spleen were obtained for isolation of specific cell types. The population and phenotype of immune cells in the decidua, peripheral blood, and spleen were analyzed using flow cytometry. Statistical differences between groups were determined using two-tailed t- test. For all statistical tests, P < 0.05 was considered statistically significant.
Results: RU486 effectively induced abortion in pregnant mice, with a significantly higher number of decidual macrophages (dMφ) (control group = 25.55% ± 2.467%, RU486 group = 19.41% ± 1.423%; P < 0.05), especially the major histocompatibility complex IIhigh subset. No difference in Mφ number was observed in the spleen or peripheral blood. Moreover, the dMφ from mice with RU486-induced abortion displayed a remarkable activated phenotype, with increased expressions of inducible nitric oxide synthase, tumor necrosis factor-α, and interleukin (IL)-12 but decreased expressions of arginase-1 and IL-10. We also found elevated levels of decidual CD4+ T-cells in the RU486 group that exhibited a higher level of the proinflammatory cytokine interferon-γ and a lower level of the anti-inflammatory cytokines, IL-4 and IL-10.
Conclusions: We report a new mechanism of RU486-induced abortion via the regulation of innate cell Mφ activation and the adaptive response of CD4+ T-cells present in the decidua but not the periphery.

Keywords: Decidual CD4+ T-Cells; Decidual Macrophages; Induced Abortion; RU486


How to cite this article:
Li MD, Sang YF, Tang YH, Xu L, Xu CF, Li DJ, Li YH, Zhang JP, Du MR. Mifepristone (RU486) inducing abortion in a mouse model by regulating innate and adaptive immune responses. Reprod Dev Med 2020;4:63-71

How to cite this URL:
Li MD, Sang YF, Tang YH, Xu L, Xu CF, Li DJ, Li YH, Zhang JP, Du MR. Mifepristone (RU486) inducing abortion in a mouse model by regulating innate and adaptive immune responses. Reprod Dev Med [serial online] 2020 [cited 2020 Jul 8];4:63-71. Available from: http://www.repdevmed.org/text.asp?2020/4/2/63/288021




  Introduction Top


Mifepristone (RU486) treatment has been used as a medical abortion method to terminate unintended pregnancies since 1985, with an abortion rate of more than 90% when administered to women within 49 days of the last menstruation period.[1],[2] Compared with surgical abortion, i.e., vacuum aspiration, RU486 is less painful and more efficient.[3] RU486 can bind to the progesterone receptor (PR)[4] and inhibit the function of progesterone, resulting in degeneration and necrosis of the decidual tissues and separation of the decidua and chorionic lamina. RU486 can also increase the production of prostaglandins, which forcefully promote uterine contractions, and promote the sensitivity of the uterus to prostaglandins. The degradation of the extracellular matrix mediated by RU486 is also considered as one of the mechanisms of induced abortion.[5]

Normal pregnancy is a complex physiological process. Because the fetus carries genetic material from the paternal line, it is essential that the maternal immune system accepts the semi-allogeneic fetus to maintain normal pregnancy.[6] In early pregnancy, numerous immune cell types, including decidual natural killer (dNK) cells, decidual macrophages (dMφ), dendritic cells (DCs), and various subsets of T-cells, localize to the maternal–fetal interface.[7],[8],[9] The dysregulation and/or dysfunction of immune cells can lead to early pregnancy failure.[10],[11] Our team found that Tim-3 signaling is indispensable for maintaining the functions of both peripheral and dNK cells.[12],[13] In recurrent miscarriage patients, Tim-3 abundance on the peripheral and dNK cells was reduced.[12],[13] dMφ are categorized into M1 and M2 phenotypes. The conventional M1/M2 classification is parallel to the Th1/Th2 paradigm.[14] In normal pregnancy, M2 Mφ are the predominant subtype. However, higher numbers of M1 Mφ are found in pathological pregnancy, which secrete harmful proinflammatory cytokines such as tumor necrosis factor (TNF)-α.[15] It has also been reported that the inhibition of Mφ can rescue the abortion outcome.[16] Moreover, overactivated production of proinflammatory cytokines and committed decidual CD4+ T-cells polarization toward inflammatory phenotype can trigger antigen-specific fetal loss.[17],[18] Because RU486 is a drug administered for abortion and immune disorders can cause abortion, it is reasonable to consider whether RU486 induces abortion by altering the functions and phenotypes of the maternal systemic and uterine immune cells. The immunoregulatory effects of progesterone on the Th1/Th2/Th17/Treg paradigm can be attenuated by RU486, which results in the upregulated secretion of Th1-type and Th17-type cytokines and induces abortion in both humans and mice.[19],[20],[21] In addition, overactive NK cells are observed in RU486-treated mice.[22],[23] Nevertheless, the specific peripheral and local decidual immunological changes induced by RU486 administration remain unclear.

In the present study, we first confirmed the efficacy of RU486 in causing abortion in mice and then investigated the changes in the innate immune cell population in the decidua, peripheral blood, and spleen in the RU486-treated mouse abortion model. Moreover, we observed the role of RU486 in the cytokine production and phenotype of dMφ. Finally, we measured the augmented infiltration of CD4+ T-cells and enhanced inflammatory response in the decidua. The findings of the present study provide evidence that RU486-induced abortion may through regulating Mφ activation and the adaptive response of CD4+ T-cells in the decidua.


  Methods Top


Animal model



A total of 60 female ICR mice aged 6–8 weeks were randomly divided into the control group (0 mg RU486) and RU486 group (2 mg/kg RU486). The two groups were paired with male mice (2 females:1 male) on experimental day 10. If a vaginal plug was detected the next day, it was considered day 0 of pregnancy (gestational day 0 [GD0]), and the days of pregnancy were calculated accordingly. On GD8, 30 pregnant mice were subcutaneously injected with 2 mg/kg RU486 (M8046, Sigma-Aldrich) freshly dissolved in 200 μL phosphate-buffered saline (PBS) before use. In the control group, 30 mice received a subcutaneous injection of 200 μL sterile PBS. All mice were sacrificed 6 h later. The peripheral blood and spleen were isolated for further analysis. Pregnancy rate and the number of embryos were recorded. All of the experimental procedures involving animals were conducted in accordance with the Guide for the Care and Use of Laboratory Animals (China), and permission was provided by the Medical Ethics Committee of Fudan University (2019-042).

Isolation of decidual immune cells

The murine fetal and placental tissues were carefully removed from the uteri at the time of sacrifice and washed in PBS. Dissected uteri were digested in RPMI 1640 medium supplemented with collagenase Type IV and DNase I (Sigma-Aldrich Corp., St. Louis, MO, USA) for 30 min at 37°C with gentle agitation. The total suspension was filtered and enriched by discontinuous Percoll gradient centrifugation (GE Healthcare Life Sciences, Little Chalfont, UK). After centrifugation, the cells between 60% and 40% Percoll were separated. The decidual immune cells (DICs) were collected from the suspension.

Preparation of peripheral blood mononuclear cells

Peripheral blood mononuclear cells (PBMCs) were isolated from peripheral blood samples from the control and RU486 groups using Ficoll density gradient centrifugation (Huajing, Shanghai) at 800 ×g for 20 min.

Isolation of murine spleen cells

The spleen was aseptically stored in RPMI 1640 medium. A single-cell suspension was produced using a 10 mL syringe plunger to pass splenic tissue through a 70-mm mesh strainer into the fresh medium. The spleen cells were cultured in RPMI 1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 mg/mL amphotericin B at 37°C in 5% CO2.

Flow cytometry assays

Cells were washed and incubated with the appropriate fluorochrome-conjugated antibodies for 30 min at 4°C for cell surface staining. Cells were fixed and permeabilized according to the manufacturer's protocol. Permeabilized cells were stained for intracellular cytokines. Flow cytometric (FCM) analysis was performed on a CyAn ADP analyzer (Beckman Coulter, Inc., Kraemer Boulevard Brea, CA, USA), and the data were analyzed with FlowJo version 6.1 software (Tree Star, Asland, OR, USA). The following mouse monoclonal antibodies were used: antigen-presenting cells (APC)-cy7-conjugated anti-mouse CD45, FITC-conjugated anti-mouse CD45, BV421-conjugated anti-mouse CD4, FITC-conjugated anti-mouse CD3, PE-conjugated anti-mouse CD49b, BV421-conjugated anti-mouse F4/80, AF647-conjugated anti-mouse major histocompatibility complex II (MHC-II), PE-conjugated anti-mouse CD11c, and PE-cy7-conjugated anti-mouse interleukin (IL)-4, BV510-conjugated anti-mouse IL-10, PE-conjugated anti-mouse IL-12, APC-conjugated anti-mouse interferon (IFN)-γ, and PE-cy7-conjugated anti-mouse TNF-α. All of these antibodies were purchased from BD Bioscience. PE-conjugated anti-mouse arginase-1 (Arg1) was purchased form R&D Systems, and PE-conjugated anti-mouse inducible nitric oxide synthase (iNOS) was from eBioscience.

Statistical analysis

All data are presented as means ± standard error of the mean. Significant differences between groups were determined using two-tailed t- tests. For all statistical tests, P < 0.05 was considered statistically significant.


  Results Top


Mifepristone effectively induced abortion in pregnant mice

Previous clinical studies have identified the effect of RU486 in causing abortion in humans.[24],[25],[26] To confirm the efficacy of RU486 in inducing murine abortion, female ICR mice received subcutaneous administration of RU486 on GD8 and were sacrificed 6 h later [Figure 1]a. We verified abortion induction by RU486 by calculating the embryo resorption rate. As expected, the mice treated with 2 mg/kg RU486 (n = 30) displayed significantly higher embryo resorption rates compared with control pregnant mice (n = 30) [resorption = 4.06% in the control group, 77.78% in the RU486 group, P < 0.01; [Figure 1]b and [Figure 1]c. Our results demonstrate that RU486 can induce abortion effectively in pregnant mice.
Figure 1: Administration of RU486 induced abortion in mice. (a) Schema of RU486 treatment in a model of abortion in mice. (b) Representative images of embryos in the uterus from normal mice and RU486-treated mice. (c) The embryo resorption rate in pregnant mice treated as indicated. Data are presented as mean ± SEM, n = 30 mice per group. *P < 0.01. RU486: Mifepristone; s.c.: Subcutaneous injection; SEM: Standard error of the mean.

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Elevated decidual macrophages levels were observed with mifepristone-induced abortion

Abortion incidence is closely related to disorders of the maternal immune system. During early pregnancy, a huge number of immune cells localize to the maternal–fetal interface. To understand the effect of RU486 on immune cells, we first measured the number of typical innate immune cells in the decidua by FCM. Interestingly, we found that the amount of F4/80+ Mφ was significantly upregulated in the decidua after RU486 treatment [P < 0.05; [Figure 2]a. The increased number of Mφ in the uterus may indicate the enrichment of this immune subset in the decidua. The percentage of dNK cells (CD3 CD49b+) as well as NKT cells (CD3+ CD49b+) [ns; [Figure 2]b was comparable between the mice treated with RU486 and the control group. In addition, a slight increase in the number of decidual DC cells (CD45+ F4/80 CD11c+) was observed with RU486 treatment in pregnant mice, although this was not significant [ns; [Figure 2]c.
Figure 2: Treatment with RU486 altered the innate immune milieu within the decidua. (a) Representative and quantitative FCM results for Mφ in DICs. Data depict the percentages of F4/80+ Mφ among DICs. (b and c) Representative and quantitative FCM results for (b) NK cells, NKT cells, and (c) DCs in DICs in the control and RU486 groups. (d and f) Representative and quantitative FCM results for NK cells and NKT cells in (d) PBMCs and (f) the spleen. (e and g) Representative and quantitative FCM results for DCs in (e) PBMCs and (g) spleen. Data are presented as means ± SEM, n = 30 mice per group. *P < 0.05. RU486: Mifepristone; FCM: Flow cytometry; Mφ: Macrophage; DICs: Decidual immune cells; NK cells: Natural killer cells; NKT cells: Natural killer T-cells; DCs: Dendritic cells; PBMCs: Peripheral blood mononuclear cells; SEM: Standard error of the mean.

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Besides decidua, the maternal immune system in the periphery also contributes to the establishment and the maintenance of normal pregnancy. Disorder or dysfunction of the systemic immune system closely relates to adverse pregnancy outcomes such as abortion.[13] Therefore, we also detected the immune cell populations in peripheral blood and spleen to explore whether RU486 had an influence on the peripheral immune milieu. As shown in [Figure 2]d and [Figure 2]e, no remarkable differences were found when we analyzed the amount of NK cells, NKT cells, and monocytes in the PBMCs between the control and RU486 groups [ns; [Figure 2]d and [Figure 2]e. Similar results were obtained in the spleen [ns; [Figure 2]f and [Figure 2]g. These data indicate that RU486 may cause abortion by increasing the number of dMφ, which might further affect the immune microenvironment in the decidua.

Activated and proinflammatory decidual macrophages were present in mice with mifepristone-induced abortion

Since the function of dMφ is critical to the maintenance of pregnancy by promoting angiogenesis by trophoblasts and sustaining maternal immune tolerance,[27] we explored the activation and functions of these elastic cells to systemically characterize the phenotype of dMφ in the control and RU486 groups. As shown in [Figure 3]a and [Figure 3]b, administration of RU486 significantly upregulated the expression of MHC-II on dMφ (P < 0.05), suggesting that local dMφ had transformed into an activated phenotype. M1/M2 bias in the immune milieu at the maternal–fetal interface has long been considered one of the main mechanisms of maternal–fetal tolerance.[27] We next directly analyzed the related cytokine production of dMφ. As expected, dMφ from mice treated with RU486 had conspicuously higher levels of proinflammatory cytokines such as iNOS (P < 0.05), TNF-α (P < 0.001), and IL-12 (P < 0.05) [Figure 3]c. The production of inhibitory molecules Arg1 (P < 0.05) and IL-10 (P < 0.05) was significantly downregulated by RU486, although there was no effect of RU486 on the expression of IL-4 in the dMφ [ns; [Figure 3]c. These findings show that RU486 can transform dMφ into an activated and proinflammatory phenotype, which might be a critical trigger for induced abortion.
Figure 3: dMφ displayed an activated and proinflammatory phenotype in RU486-induced abortion in mice. (a) Representative and quantitative FCM results for MHC-II molecule expression in dMφ. (b) The percentages of MHC-IIlow and MHC-IIhigh dMφ in the control and RU486 groups. (c) FCM analysis of iNOS (an M1 marker), Arg1 (an M2 marker), proinflammatory cytokines (IL-12 and TNF-α), and anti-inflammatory cytokines (IL-10 and IL-4) in dMφ in the control and RU486 groups. Data are presented as means ± SEM, n = 30 mice per group. *P < 0.05,-P < 0.001. RU486: Mifepristone; dMφ: Decidual macrophage; FCM: Flow cytometry; MHC-II: Major histocompatibility complex II; iNOS: Inducible nitric oxide synthase; Arg1: Arginase-1; IL-12: Interleukin-12; TNF-α: Tumor necrosis factor-α; IL-10: Interleukin-10; IL-4: Interleukin-4; SEM: Standard error of the mean.

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Increased infiltration of CD4

+T-cells with enhanced inflammatory responses occurred in the decidua of mice with mifepristone-induced abortion

As described above, we explored the effects of RU486 on innate immune cells. We also questioned whether RU486 plays a role in adaptive immunity. T-cells account for nearly 10% of DICs and CD4+ T-cells are the most abundant type. Previous studies[19],[21] revealed that RU486 could interfere with the Th1/Th2/Th17/Treg paradigm at the maternal–fetal interface and impacted T-cell cytokine production. Thus, we examined the number and function of CD4+ T-cells by FCM. Compared with the control group, the amount of CD4+ T-cells was enhanced in RU486-treated mice, exclusively in the decidua [P < 0.001; [Figure 4]a, while there was no distinct difference in CD4+ T-cell number in PBMCs or the spleen [ns; [Figure 4]c and [Figure 4]d. Moreover, this particular T-cell subset in the decidua of RU486-treated mice had decreased expression of anti-inflammatory cytokines IL-4 (P < 0.05) and IL-10 (P < 0.01) and increased production of proinflammatory cytokine IFN-γ (P < 0.05), although the expression of IL-12 and TNF-α was similar in both groups [Figure 4]b. These data indicate that the elevated proinflammatory phenotype and the lack of anti-inflammatory functions of CD4+ T-cells caused by RU486 may cause dysregulation of the immune microenvironment at the maternal–fetal interface and eventually bring about abortion.
Figure 4: RU486 induces infiltration of proinflammatory decidual CD4+ T-cells. (a) Representative and quantitative FCM results for CD4+ T-cells in DICs. Data depict the percentages of CD4+ T-cells among DICs. (b) FCM analysis of proinflammatory (IFN-γ, IL-12, and TNF-α,) and anti-inflammatory (IL-4 and IL-10) cytokines in decidual CD4+ T-cells. (c and d) Representative and quantitative FCM results for CD4+ T-cells in (c) PBMCs and (d) the spleen. Data are presented as means ± SEM, n = 30 mice per group. *P < 0.05, -P < 0.01,P < 0.001. RU486: Mifepristone; DICs: Decidual immune cells; IFN-γ: Interferon-γ; IL-12: Interleukin-12; TNF-α: Tumor necrosis factor-α; IL-4: Interleukin-4; IL-10: Interleukin-10; PBMCs: Peripheral blood mononuclear cells; SEM: Standard error of the mean.

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  Discussion Top


RU486 is administered in combination with prostaglandins for the purpose of medical abortion, which is widely used in human.[28] To investigate its potential mechanisms, RU486-induced mice model was gradually established.[19],[20],[21] Its effect of induced abortion had also been previously studied in guinea pigs and dogs.[29],[30],[31] The main biological mechanism of RU486 is blocking the PR. In recent years, progesterone has been widely identified as an immune system regulator. High levels of progesterone can both suppress the innate immune function of the endometrium and modulate CD8+ T-cell-mediated antigen-nonspecific IFN-γ production during pregnancy.[32],[33] Therefore, we investigated changes in the mother's immune system pattern induced by RU486 and the potential mechanisms involved.

Fetal-derived trophoblast cells have poor antigenic properties so that they avoid attack by the maternal immune system.[34] However, these cells can still induce maternal immune activation and produce antipaternal HLA antibodies during pregnancy. It was reported that maternal APCs produced antipaternal HLA antibodies in response to the presentation of fetal antigens.[35] Mφ are known to be one of the APCs. Activated Mφ can express MHC-II molecules.[36] Through MHC-II molecules, Mφ can present embryonic antigens to CD4+ T-cells for recognition, thus generating immunological rejection.[37] In this study, we found that the proportion of both MHC-IIhigh dMφ and CD4+ T-cells were significantly upregulated when RU486 was administered. Our data have demonstrated that RU486 may promote embryo rejection by enhancing the functions of APCs and upregulating the numbers of T-cells at the maternal–fetal interface.

We also showed that mice treated with RU486 present an M1 phenotype. Determination of the molecular mechanisms underlying Mφ polarization is a very active research area that will provide novel opportunities for manipulating immune and inflammatory responses. In both humans and mice, dMφ display an M2 phenotype and may be involved in endometrium remodeling, trophoblast invasion, and the development of the tolerant milieu required for successful progression of pregnancy.[7],[38] An intolerant immune milieu can lead to miscarriage and adverse pregnancy outcomes.[11],[39] We found that RU486 could upregulate the expression of iNOS, TNF-α, and IL-12 (M1 markers) and downregulate the expression of Arg1 and IL-10 (M2 markers) on dMφ. Therefore, RU486 may also induce abortion by strengthening the transformation of Mφ into a proinflammatory phenotype, thereby enhancing the maternal local immune inflammatory response.

A maternal–fetal HLA-C mismatch can lead to an increased proportion of CD4+-activated T-cells in the decidua.[40] Although T-cells only account for about 10% of DICs, their stability and function are key to maternal–fetal immune tolerance.[41] The anti-inflammatory phenotype of T-cells at the maternal–fetal interface is dominant in normal pregnancy. Studies have found that RU486 can regulate the Th1/Th2/Th17/Treg paradigm, increase the proportion of CD4+ IFN-γ+ T-cells, and downregulate the proportion of CD4+ IL-4+ T-cells.[19],[21],[42] As expected, our results suggest that RU486 may account for the proinflammatory status at the maternal–fetal interface. It induced the production of a high amount of proinflammatory cytokines such as IFN-γ and very low amounts of anti-inflammatory cytokines IL-4 and IL-10 in the CD4+ T-cells. These data may help to explain the potential mechanism that RU486 causes abortion via maternal rejection of the allogeneic fetus.

Collectively, our study demonstrates that RU486 can induce medical abortion by modulating an increased or overactivated immune response in the decidual tissue but not in the periphery. RU486 not only increases the number of dMφ, enhances their expression of activation markers, and promotes their antigen-presenting cellular function, but also activates the adaptive immune response. This may connect innate immunity with the adaptive immune response and ultimately lead to abortion occurrence [Figure 5]. The dysregulation of immune balance may be one of the mechanisms of RU486 during medical abortion. This research elucidates a deeper understanding of immune regulation as a mechanism of RU486 in abortion and provides novel insights into the immunological paradox of the complicated maternal–fetal relationship.
Figure 5: Schema of how RU486 alters the immune milieu within the decidua to induce abortion. RU486 altered the immune microenvironment by increasing the number of local macrophages and CD4+ T-cells in the uterus. Administration of RU486 increased the expression of activated MHC-II on decidual macrophages and enhanced the function of macrophages as antigen-presenting cells, which promoted the presentation of embryonic antigen to CD4+ T-cells, leading to the abortion. Moreover, RU486 promoted transformation of M2 macrophages to an M1 phenotype and increased the expression of proinflammatory cytokines produced by CD4+ T-cells, resulting in a local inflammatory microenvironment in the decidua. Therefore, the mechanism by which RU486 promotes embryo antigen presentation requires further exploration. RU486: Mifepristone; MHC-II: Major histocompatibility complex II.

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Acknowledgment

This work was supported by the National Key R&D Program of China (Grant Nos. 2017YFC1001403 to MRD and 2017YFC1001404 to DJL), the Nature Science Foundation from National Nature Science Foundation of China (Grant Nos. 31970859, 81630036 to MRD, and 31900663 to YHL), the Program of Shanghai Academic/Technology Research Leader (Grant No. 17XD1400900 to MRD), and the Innovation-oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (Grant No. CX2017-2 to MRD).

Financial support and sponsorship

This work was supported by the National Key R&D Program of China (Grant nos. 2017YFC1001403 to MRD and 2017YFC1001404 to DJL), the Nature Science Foundation from National Nature Science Foundation of China (Grant Nos. 31970859, 81630036 to MRD, and 31900663 to YHL), the Program of Shanghai Academic/Technology Research Leader (Grant No. 17XD1400900 to MRD), and the Innovation oriented Science and Technology Grant from NPFPC Key Laboratory of Reproduction Regulation (Grant No. CX2017 2 to MRD).

Conflicts of interest

There are no conflicts of interest.



 
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