LAUSR

Maternal immunotolerance toward the semi-allogeneic fetus is critical for normal pregnancy. As a secretory protein, growth arrest-specific factor 6 (GAS6) promotes cancer progression by inducing the conversion of tumour-associated macrophages to an immunosuppressive M2-like phenotype. However, little is known about whether GAS6 regulates decidual macrophages (dMφs) in early maternal-fetal interface. In this study, first-trimester decidual tissues were obtained from normal pregnant women undergoing elective terminations and patients with miscarriages. The expression of GAS6 and its receptors (AXL, TYRO3 and MERTK) in decidua and GAS6 secretion by decidual stromal cells (DSCs) was measured. Then, we investigated the effect of recombinant human GAS6 (rhGAS6) on dMφs isolated from normal pregnancy and THP-1 cells, and revealed the underlying mechanism. Both the expression of GAS6 in DSCs and MERTK in dMφs, in addition to GAS6 secretion by DSCs, was found to be significantly decreased in miscarriage patients compared to that in normal pregnancy. Additionally, we observed that rhGAS6 polarized dMφs and THP-1 cells toward an M2-like phenotype, as evidenced by the up-regulated CD163 expression. Moreover rhGAS6 enhanced the clearance of toxic cell-free hemoglobin by dMφs by up-regulating CD163 expression, and rhGAS6 also boosted cell proliferation of dMφs and THP-1 cells. Finally, we demonstrated that rhGAS6 stimulated CD163 expression and cell proliferation by activating the PI3K/Akt signaling pathway. Collectively, these findings suggest that GAS6-mediated dialogue between DSCs and dMφs is crucial for the establishment and maintenance of maternal-fetal immunotolerance, and decreased GAS6 secretion by DSCs may lead to the occurrence of miscarriage in first trimester.