Expression of TAM receptors and their ligands in unexplained recurrent pregnancy loss

Recurrent pregnancy loss (RPL) is clinically defined as two or more pregnancy failures before 20-24 weeks of gestation. Over 50% of RPL cases have no identified etiology and are classified as unexplained recurrent pregnancy loss (URPL). The TAM receptor tyrosine kinase (RTK) family, including TYRO3, AXL, MERTK, GAS6, and PROS1, plays critical roles in suppressing excessive inflammation and apoptosis. Although increased serum levels of these molecules have been observed in pregnancy complications such as preeclampsia, their role in URPL remains unexplored. We hypothesized that TAM receptors contribute to the immunoregulation of the maternal-fetal interface, playing a pivotal role in the development of semi-allogeneic fetuses and the pathogenesis of URPL. To test this hypothesis, we analyzed three groups: Control Endometrium (CE; n = 6), Terminated Pregnancy (TP; n = 6), and URPL (n = 6). AXL, MERTK, GAS6, and PROS1 mRNA levels were quantified by qPCR, and protein levels were evaluated using immunohistochemistry and immunoblotting. Our findings revealed a significant increase in AXL, MERTK, GAS6, and PROS1 expression in both maternal and fetal tissues of the URPL group compared to the CE and TP groups. These molecules exhibited intense perinuclear and cytoplasmic expression, particularly in immune cells and trophoblasts. This study demonstrates for the first time that AXL, MERTK, GAS6, and PROS1 are involved in URPL, highlighting their potential roles in fetal acceptance via decidual polyploid cells and in regulating inflammation and apoptosis during implantation.