Progesterone signaling in oviductal epithelial cells modulates the immune response to support preimplantation embryonic development

More than 60% of pregnancy loss occurs during the first trimester. As we lack a complete understanding of the environment within the oviduct (Fallopian tube in humans) and its role in regulating early pregnancy, it is difficult to provide diagnostic tools for oviductal origin of early pregnancy loss. To determine the role of progesterone (P4), we conditionally ablated the classical P4 receptor (Pgr) in oviductal epithelial cells using the Wnt7aCre/+;Pgrf/f (hereafter Pgrd/d) mouse model. Approximately 40% of embryos collected from Pgrd/d females at 3.5 days post-coitus were nonviable or developmentally delayed suggesting that epithelial PGR expression in the oviduct is required for normal embryonic development. Single-cell RNA-sequencing analysis showed an upregulation of genes involved in proinflammatory pathway (i.e., interleukin 22 (IL-22) and genes in IL-22 signaling) in secretory epithelial cells of Pgrd/d females as compared to controls. A loss of PGR in the epithelial cells resulted in an increase immune cell recruitment into the oviduct as compared to controls. Conversely, ovariectomized wild-type (WT) females treated with exogenous P4 showed a reduced expression of inflammatory response genes. Pharmacological inhibition of inflammation using non-steroidal anti-inflammatory drugs significantly reduced IL-22 levels in the oviducts and rescued embryo developmental rates in Pgrd/d females. Co-culture of WT zygotes with IL-22 significantly decreased the number of expanded blastocysts. Our findings indicate that P4 signaling through the classical PGR in oviductal epithelial cells is required for the immunoregulatory function and is indispensable for normal preimplantation embryonic development. These data may contribute to an understanding of the mechanisms underlying pre-implantation pregnancy failure, which can inform the development of targeted diagnostic tools and therapeutic interventions to improve reproductive outcomes when embryonic aneuploidy is not present.