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 (Pgr) in oviductal epithelial cells called Pgrd/d
mouse model. We found that 40% of embryos collected from Pgrd/d females
were non-viable or developmentally delayed, indicating that epithelial PGR
expression is crucial for embryonic development. Single-cell
RNA-sequencing revealed upregulation of proinflammatory genes, including
interleukin 22 (IL-22), in the epithelial cells of Pgrd/d females.
Pharmacological inhibition of inflammation using non-steroidal
anti-inflammatory drugs significantly reduced IL-22 levels in the oviducts
and rescued embryonic developmental rates in Pgrd/d females. Co-culture 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.