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

More than 60% of pregnancy losses occur during the first trimester, highlighting the need to understand the role of the oviduct in early pregnancy. In this study, we conditionally ablated the classical progesterone receptor (<i>Pgr</i>) in oviductal epithelial cells, called the <i>Pgr</i>^d/d mouse model. We found that 40% of embryos collected from <i>Pgr</i>^d/d females were nonviable or developmentally delayed, indicating that epithelial PGR expression is crucial for embryonic development. Single-cell RNA sequencing revealed up-regulation of proinflammatory genes, including interleukin-22 (IL-22), in the epithelial cells of <i>Pgr</i>^d/d females. Pharmacological inhibition of inflammation using nonsteroidal anti-inflammatory drugs significantly reduced IL-22 levels in the oviducts and rescued embryonic developmental rates in <i>Pgr</i>^d/d females. Coculture of wild-type zygotes with IL-22 significantly decreased the number of expanded blastocysts. Our findings suggest that progesterone signaling is vital for immunoregulation and normal preimplantation development, potentially providing insights for developing diagnostic tools and therapeutic strategies to address pregnancy failures.