Decidual IDO⁺ macrophage promotes the proliferation and restricts the apoptosis of trophoblasts

Indoleamine 2, 3-dioxygenase (IDO), a tryptophan-catabolizing enzyme, is essential in physiological immunoregulation. The present research was conducted to elucidate the expression and roles of IDO in decidual macrophages (dMφ) during early pregnancy. Here, we observed a remarkable decrease of IDO⁺ dMφ from patients with unexplained recurrent spontaneous abortion (URSA). IDO⁺ dMφ displayed M2 phenotype with higher CD206, CD209 and CD163, and lower CD86. Interestingly, treatment with 1-methyl-d-tryptophan (1-MT, an IDO pathway inhibitor) led to the M1 bias of dMφ. Further analysis of the cytokine array and the qPCR showed decreased levels of trophoblast proliferation or invasion-related molecules (e.g., CXCL12 and BMP2) in 1-MT-treated dMφ. The data of co-culture system showed that 1-MT-pretreated dMφ decreased the proliferation and the expression of Ki-67 and Bcl-2, and increased cell apoptosis of HTR-8/Snveo cells. Additionally, the expression of IDO in U937 cells was up-regulated by decidual stromal cells (DSC) and HTR-8/Snveo cells in vitro, as well as estradiol and medroxyprogesterone. These data suggest that endocrine environment, DSC and trophoblasts should contribute to the high level of IDO in dMφ, and IDO⁺ dMφ with M2 dominant phenotype promote the survival of trophoblasts during early pregnancy. The abnormal lower level of IDO should trigger the dysfunction of dMφ, further suppress the survival of trophoblasts and increase the risk of miscarriage.