Bta-miR-93 regulates the maternal-fetal tolerance in dairy cows via promoting PD-L1-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 (MRP), 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-τ stimulation. In 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 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 macrophages (BoMac) co-culture model, and vice versa. The 3'-UTR 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. Overall, the findings suggested that reduced bta-miR-93 levels were found to be implicated in pregnancy immune tolerance by boosting M2 macrophage polarization via promoting PD-L1/PD-1/AKT/mTOR signaling pathway. Bta-miR-93 might be investigated as auspicious identification signal for a successful pregnancy and a potential therapeutic target for reproductive disorders.