The Role of Macrophages in Implantation and Early Pregnancy Success.

Attenuation in the cellular structure and function of the endometrial tissue confers transient maternal receptivity to embryo implantation and trophoblast invasion during early pregnancy. The changes in endometrial tissue composition and surface biochemistry that allow implantation are largely directed by ovarian steroid hormones, but the means by which hormonal effects are exerted at the cellular level are not well defined. We have hypothesised that macrophages have roles in the endometrial tissue remodeling and acquisition of epithelial cell adhesiveness which underpin the receptive state. In mice, exposure to male seminal fluid at mating is essential for recruiting the macrophages that populate the endometrium during the period prior to and during embryo implantation. Our previous studies have shown that disruption in the seminal fluid-induced inflammatory response of early pregnancy compromises implantation and placental development, resulting in fetal growth restriction in late gestation. In a strategy to more precisely evaluate the necessity for macrophages in embryo implantation, we have employed a genetic mouse model with CD11b promoter-driven expression of the monkey diphtheria toxin (DT) receptor which allows acute systemic ablation of macrophages after administration of nanogram doses of DT. Complete ablation of uterine macrophages is achieved within 48 h of administration of DT. When macrophages are depleted during the pre-implantation phase of pregnancy, implantation failure ensues, despite normal development of pre-implantation embryos. To investigate the function of macrophages in generating endometrial receptivity, we have utilised in these in vivo experimental models as well as in vitro macrophage-epithelial cell co-culture systems. Using these approaches we have shown key roles for macrophage-derived signals in regulating expression of mRNAs encoding various adhesion and anti-adhesion molecules implicated in embryo attachment and invasion, including fucosyltransferases (FUT)-1, FUT2 and FUT4 and mucins (MUC)-1 and MUC4. In addition, qRT-PCR and proteomic experiments show macrophage depletion causes altered expression of molecular mediators of tissue remodeling and early vasculogenesis, accompanied by changes in vascular permeability in vivo at the time of implantation. Our data demonstrate that in mice, factors secreted from macrophages recruited during the inflammatory response to insemination target epithelial cells and stromal cell lineages in the endometrium to facilitate the events of embryo attachment and trophoblast invasion. In humans, dysregulation in the phenotypes or abundance of uterine macrophages might provide an explanation for some pathologies of pregnancy manifesting as implantation failure or inadequate placental development. This work was supported by Program Grant 453556 from the NHMRC of Australia.