F11r Deficiency–Mediated Disruption of Crosstalk Between Decidual Epithelial Cells and Macrophages is Detrimental to Female Pregnancy

Complex intercellular interactions occur at the maternal-fetal interface during pregnancy. Human uterine decidual epithelial cells play a crucial role in maternal immune tolerance and placental development. Macrophages are major cells at the maternal-fetal interface regulating tissue remodeling and immune response. The role of F11 receptor (F11r) in regulating the biological functions of epithelial cells and immune cells is particularly prominent. Thus, this study was to determine the mechanism by which F11r mediates the interaction of decidual epithelial cells with macrophages. F11r knockout (KO) mice were obtained using CRISPR/Cas9 technology. On Day 12.5 of gestation, single-cell RNA sequencing (scRNA-seq) was performed and reproduction was recorded at the uterine implantation sites in the WT and the KO groups, respectively. F11r KO mice have increased embryo resorption after natural mating. Decidual epithelial cells were classified into three subtypes based on scRNA-seq data: Epi1, Epi2, and Epi3. In F11r KO mice, Epi2, located at an early stage of differentiation, prematurely differentiates to an immunoregulatory cell fate and participates in the regulation of the immune response. In addition, the interaction between epithelial cell subpopulations and macrophage subpopulations was disturbed in the KO group. Specifically, Csf1-Csf1r interactions between Epi1 and C1q+ macrophages were reduced in the F11r KO group. However, Spp1-cd44 interactions were enhanced between subclusters of decidual epithelial cells (Epi1, 2, and 3) and macrophage subclusters (C1q+, Cxcl10+, and Spp1+ macrophages). In conclusion, we elucidated the immunomodulatory mechanisms by which F11r mediates decidual epithelial-macrophage interactions at the maternal-fetal interface from cellular and molecular perspectives.