Bta-miR-93 regulates the maternal-fetal tolerance in dairy cows via promoting Programmed Cell Death Ligand 1 mediated M2 macrophage polarization

Bovine embryo resorption is one of the key factors restricting the reproductive efficiency in dairy cattle, which mainly occurs in the early stage of maternal recognition of pregnancy, causing substantial economic losses to the dairy industry. Macrophages, the most numerous endometrial immune cells in cows during early pregnancy, are critical in developing maternal-fetal immune tolerance. However, the mechanism of their action on the maternal-fetal interface of dairy cows remains unknown. MicroRNAs have important roles in immune tolerance and macrophage polarization, but the underlying mechanisms still need further investigation. In previous laboratory studies, RNA-sequencing revealed that bta-miR-93 was dramatically reduced in bovine endometrial luminal epithelial cells (bEECs) upon IFN-tau stimulation. In the current study, it is revealed that the expression of bta-miR-93 was decreased substantially in the endometrium of pregnant cows and negatively correlated with that of Programmed Cell Death Ligand 1 (PD-L1). In vitro experiments displayed that suppression of bta-miR-93 promoted M2 polarization via promoting PD-L1/PD-1/AKT/mTOR signaling pathway in bEECs and bovine macrophage co-culture model, and vice versa. The 3'-untranslated region of PD-L1 is directly regulated by bta-miR-93. Furthermore, our in vivo studies revealed that overexpression of bta-miR-93 efficiently leads to embryo resorption and suppression of M2 polarization in mice.