Decreased B7-H3 promotes unexplained recurrent miscarriage via RhoA/ROCK2 signaling pathway and regulates the secretion of decidual NK cells.

The cause for at least 50% of recurrent miscarriages (RM) is unclear, defined as unexplained recurrent miscarriages (uRM). B7-H1 (PD-L1), a molecule of the B7 family, promotes tumor development by modulating immune evasion, and recent researchers have also attached importance to the role of B7-H3, another molecule of B7 family, in tumor. Based on the similarity between growth and immune response in tumors and pregnancy, we first explored the role of B7-H3 in uRM. We found reduced levels of B7-H3 in villus tissue of uRM patients, and it was mainly expressed on the cell membrane of extravillous trophoblasts (EVT). Further, the HTR-8/SVneo and JEG-3 cells were selected to explore the role of B7-H3 in proliferation, apoptosis, tube formation, migration, and invasion. We found that B7-H3 regulated trophoblast migration and invasion via RhoA/ROCK2 signaling pathway. Inflammatory cytokines were detected through ELISA after co-culturing with decidual natural killer cells (dNK) and B7-H3-knockout JEG-3. Results showed that B7-H3 inhibited IL-8 and IP-10 secretion from dNK. In a CBA/J × DBA/2 abortion-prone mice model, treatment with B7-H3-Fc protein successfully reduced the rate of embryo resorption. In conclusion, our results revealed a possible mechanism by which decreased B7-H3 on trophoblasts of uRM inhibited trophoblast migration and invasion and increased IL-8 and IP-10 secretion from dNK. Furthermore, B7-H3 may be a promising new therapeutic target in uRM patients.