miR-146a-5p enhances embryo survival in unexplained recurrent spontaneous abortion by promoting M2 polarization of decidual macrophages

Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions in the reproductive field, and macrophage M1/M2 polarization disorder is involved in URSA pathogenesis, although the relevant mechanisms are undefined. miR-146a-5p possesses an immunoregulatory role and is expressed in decidual immune cells, and this study aims to investigate its effect on decidual macrophage polarization and therapeutic prospects in URSA, which has never been reported. The levels of M1/M2 markers in the deciduae and the miR-146a-5p expression in the decidual macrophages of URSA and healthy pregnant women were first detected and analyzed. Then, the in vitro effect of miR-146a-5p on the M1/M2 polarization and the secretion of inflammatory cytokines was investigated in Tamm-Horsfall protein-1 (THP-1)-induced macrophages. Finally, the in vivo immunotherapeutic effect of miR-146a-5p on embryo survival and the potential mechanisms were evaluated in a murine model of immune-based URSA. As a result, the abnormal M1/M2 polarization, which showed a shift towards the M1 phenotype and correlated with the decreased expression of miR-146a-5p, was verified in human URSA decidual macrophages. miR-146a-5p could inhibit M1 polarization, promote M2 polarization, and result in an anti-inflammatory microenvironment in THP-1-induced macrophages. The intravenous injection of exogenous miR-146a-5p in the first trimester of pregnant URSA mice significantly reduced the embryo resorption rate and promoted the M2 polarization of decidual macrophages. In conclusion, miR-146a-5p enhances embryo survival in URSA by promoting decidual macrophage polarization toward an M2 phenotype, giving new ideas and potential targets for subsequent research on the pathogenesis and immunotherapeutic strategies of URSA.