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CD206+ M2-Like Macrophages Are Essential for Successful Implantation.

ABSTRACT: Macrophages (M?s) play important roles in implantation. Depletion of CD11b+ pan-M?s in CD11b-diphtheria-toxin-receptor (DTR) mice is reported to cause implantation failure due to decreased progesterone production in the corpus luteum. However, of the M1 and M2, the type of M?s that is important for implantation is unknown. In this study, we investigated the role of M2 M? in implantation using CD206-DTR mice. To deplete M2-M?, female CD206-DTR C57/BL6 mice were injected with DT before implantation. These M2-M? depleted mice (M2(-)) were naturally mated with Balb/C mice. As the control group, female C57/BL6 wild type (WT) mice injected with DT were mated with male Balb/C mice. The number of implantation sites and plasma progesterone levels at implantation were examined. Implantation-related molecule expression was determined using quantitative-PCR and immunohistochemistry of uterine tissues. The mRNA expression in the endometrial tissues of 38 patients with implantation failure was examined during the implantation window. In WT mice, CD206+M2-like M?s accumulated in the endometrium at the implantation period, on embryonic (E) 4.5. In M2(-), the implantation number was significantly lower than that in control (p < 0.001, 7.8 ± 0.8 vs. 0.2 ± 0.4), although the plasma progesterone levels were not changed. Leukemia inhibitory factor (LIF) and CD206 mRNA expression was significantly reduced (p < 0.01), whereas the levels of TNF? were increased on E4.5 (p < 0.05). In M2(-), the number of Ki-67+ epithelial cells was higher than that in control at the pre-implantation period. Accelerated epithelial cell proliferation was confirmed by significantly upregulated uterine fibroblast growth factor (FGF)18 mRNA (P < 0.05), and strong FGF18 protein expression in M2(-) endometrial epithelial cells. Further, M2(-) showed upregulated uterine Wnt/?-catenin signals at the mRNA and protein levels. In the non-pregnant group, the proportion of M2-like M? to pan M?, CD206/CD68, was significantly reduced (p < 0.05) and the TNF? mRNA expression was significantly increased (p < 0.05) in the endometrial tissues compared to those in the pregnant group. CD206+ M2-like M?s may be essential for embryo implantation through the regulation of endometrial proliferation via Wnt/?-catenin signaling.

SUBMITTER: Ono Y

PROVIDER: S-EPMC7644510 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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CD206+ M2-Like Macrophages Are Essential for Successful Implantation.

Ono Yosuke Y Yoshino Osamu O Hiraoka Takehiro T Sato Erina E Fukui Yamato Y Ushijima Akemi A Nawaz Allah A Hirota Yasushi Y Wada Shinichiro S Tobe Kazuyuki K Nakashima Akitoshi A Osuga Yutaka Y Saito Shigeru S

Frontiers in immunology 20201023

Macrophages (MΦs) play important roles in implantation. Depletion of CD11b+ pan-MΦs in CD11b-diphtheria-toxin-receptor (DTR) mice is reported to cause implantation failure due to decreased progesterone production in the corpus luteum. However, of the M1 and M2, the type of MΦs that is important for implantation is unknown. In this study, we investigated the role of M2 MΦ in implantation using CD206-DTR mice. To deplete M2-MΦ, female CD206-DTR C57/BL6 mice were injected with DT before implantatio ...[more]

PMID: 33193326

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Project description:Synchrony between embryo competency and uterine receptivity is essential for successful implantation. Mice with ablation of chicken ovalbumin upstream promoter-transcription factor II (COUP-TFII) in the uterus (PR(Cre/+);COUP-TFII(flox/flox)) exhibit implantation defects and increased estrogen receptor (ER)alpha activity in the luminal epithelium, suggesting high ERalpha activity may disrupt the window of uterine receptivity. To determine whether increased ERalpha activity in the PR(Cre/+);COUP-TFII(flox/flox) uterus is the cause of defective implantation, we assessed whether inhibition of ERalpha activity could rescue the PR(Cre/+);COUP-TFII(flox/flox) uterine implantation defect. ICI 182,780 (ICI), a pure ERalpha antagonist, was administered to PR(Cre/+);COUP-TFII(flox/flox) mutant and COUP-TFII(flox/flox) control mice during the receptive period, and the number of implantation sites was examined. COUP-TFII(flox/flox) control mice treated with oil or ICI showed the normal number of implantation sites. As expected, no implantation sites were observed in PR(Cre/+);COUP-TFII(flox/flox) mutant mice treated with oil, consistent with previous observations. In contrast, implantation sites were greatly increased in ICI-treated PR(Cre/+);COUP-TFII(flox/flox) mutant mice, albeit at a reduced number in comparison with the control mice. ICI treatment was also able to restore the expression of Wnt4 and bone morphogenetic protein 2, important for endometrial decidualization in the PR(Cre/+);COUP-TFII(flox/flox) mutant mice. To confirm that the rescue of embryo attachment and decidualization is a consequence of a reduced ERalpha activity upon ICI treatment, we showed a reduction of the expression of ERalpha target genes in PR(Cre/+);COUP-TFII(flox/flox) mutant mice. Because COUP-TFII was also shown in our laboratory to be important for placentation during pregnancy, we asked whether ICI treatment could also rescue the placentation defect to allow full-term pregnancy in these mice. We found that whereas mice were born in COUP-TFII(flox/flox) control mice given ICI, no pups were born in the PR(Cre/+);COUP-TFII(flox/flox) mutant mice, suggesting that the increased ERalpha activity is not the reason for placentation defects. These results demonstrate that during the periimplantation period, COUP-TFII regulates embryo attachment and decidualization through controlling ERalpha activity. However, COUP-TFII expression is still required in the postimplantation period to facilitate placentation.

Dataset Information

CD206+ M2-Like Macrophages Are Essential for Successful Implantation.

Publications

CD206+ M2-Like Macrophages Are Essential for Successful Implantation.

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