CD206+M2-Like Macrophages Are Essential for Successful Implantation

Macrophages (M Phi s) play important roles in implantation. Depletion of CD11b+ pan-M Phi 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 Phi s that is important for implantation is unknown. In this study, we investigated the role of M2 M Phi in implantation using CD206-DTR mice. To deplete M2-M Phi, female CD206-DTR C57/BL6 mice were injected with DT before implantation. These M2-M Phi 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 Phi 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 alpha 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/beta-catenin signals at the mRNA and protein levels. In the non-pregnant group, the proportion of M2-like M Phi to pan M Phi, CD206/CD68, was significantly reduced (p < 0.05) and the TNF alpha mRNA expression was significantly increased (p < 0.05) in the endometrial tissues compared to those in the pregnant group. CD206+ M2-like M Phi s may be essential for embryo implantation through the regulation of endometrial proliferation via Wnt/beta-catenin signaling.