Unique Roles of Infiltrating Myeloid Cells in the Murine Uterus during Early to Midpregnancy

Abstract

Leukocyte infiltration into the uterus is a characteristic feature in early to midpregnancy, but the composition and function of these leukocytes are not well understood. Using a pregnant murine model, we showed that myeloid cells and uterine NK (uNK) cells were the predominant populations in uteri during early to midgestation, whereas T and B cells were constrained. Uterine myeloid populations included cells that infiltrated from the circulation (myeloid-derived suppressor cells [MDSCs], monocyte-derived macrophages [Mφs], and dendritic cells [DCs]) or proliferated from resident precursors (resident Mφs [Re-Mφs] and DCs). CD11bhiLy6-Ghi cells, representing neutrophils in both blood and uterine MDSCs, significantly increased from embryonic days 8.5 to 9.5. To understand their putative functions, we used anti–Gr-1 Ab to deplete circulating neutrophils and uterine MDSCs. In the absence of MDSC suppression, uterine DCs, T cells, and regulatory T cells expanded. Conversely, uterine MDSCs responded to LPS-induced inflammation and transformed into CD14+-activated neutrophils, resulting in an upregulation of tolerogenic DCs. A high dose of LPS (2.5 μg/mouse) significantly increased the influx of neutrophils and production of proinflammatory cytokines, such as IL-1β and TNF-α, resulting in the reduction of Re-Mφs and uNK cells, and led to placental hemorrhages and fetal deaths. In summary, uterine MDSCs are important in early to midpregnancy by responding to the maternal immunologic milieu and protecting uNK cells and Re-Mφs via MDSC’s suppressive and anti-inflammatory functions. Upsetting this delicate immune balance by factors leading to either insufficient MDSCs or excessive neutrophil infiltration in the fetomaternal interface may contribute to pregnancy failure.

Granulocytic Myeloid-Derived Suppressor Cells Accumulate in Human Placenta and Polarize toward a Th2 Phenotype

“…These results parallel data from others showing an enrichment of Tregs in human decidua and an association between diminished Treg accumulation and pregnancy failure (32,34,35). Recently, reduced MDSCs in peripheral blood of patients with early miscarriage and a depletion of MDSCs leading to pregnancy failure in mice have also been shown (36,37). Taken together, our results add new aspects of MDSC biology in human pregnancy as being crucial during physiological conditions, that is, in human pregnancy, and point again toward a role for GRMDSCs in protecting the fetus from immune rejection.…”

“…CXCL12, the ligand for CXCR4, has been shown to be expressed by trophoblast and decidual stromal cells and to be responsible for homing of decidual NK cells (42,43). Recently, Zhao et al (37) showed an association of an upregulation of CXCL12 and an accumulation of MDSCs in the pregnant mouse uterus. Moreover, GR-MDSCs in CF patients were recently shown to express CXCR4 (16).…”

The decidua of preeclamptic-like BPH/5 mice exhibits an exaggerated inflammatory response during early pregnancy

“…Macrophages can be identified by the expression of surface markers such as CD14 and CD11b (Houser et al, 2011; Zhao et al, 2015). Houser et al used CD14, CD11b, and CD11c to characterize macrophages in first trimester human decidua.…”

Oil-Soluble Contrast Medium (OSCM) for Hysterosalpingography Modulates Dendritic Cell and Regulatory T Cell Profiles in the Peritoneal Cavity: A Possible Mechanism by Which OSCM Enhances Fertility

“…Accumulating evidence indicates that dendritic cells (DCs) (9)(10)(11)(12) and regulatory T cells (Tregs) (13)(14)(15) are crucial for the establishment and maintenance of pregnancy. For instance, Plaks et al (10) demonstrated that the depletion of DCs causes a failure of embryo implantation in mice, and the depletion of Tregs induces implantation failure and increases resorption in allogeneic, but not in syngeneic, mice (14).…”