Deletion of BMP4 impairs trophoblast function and decidual macrophage polarization via autophagy leading to recurrent spontaneous abortion.

Abstract

Bone morphogenetic protein 4 (BMP4) is widely involved in the regulation of cell proliferation and differentiation, but its role in Recurrent Spontaneous Abortion (RSA) remains unclear. RSA is a disease that affects roughly 1-2% of partner pairs, but its pathogenesis is still unclear. In recent years, many studies have focused on the role of decidual macrophages in RSA. In this study, we found decreased expression levels of BMP4 in villous tissues of RSA patients and found that low expression of RUNX2 leads to down-regulation of BMP4, which impairs trophoblast function. More importantly, we found in both co-culture system and human recombinant BMP4 protein models that BMP4 overexpression polarizes THP-1-derived macrophages toward M2, and down-regulation of BMP4 leads to macrophage polarization toward M1. Mechanically, we found that BMP4 promotes macrophage polarization via regulating autophagy level. The recovery experiment was further confirmed that 3-MA (autophagy inhibitor) inhibit THP-1-derived macrophage polarization toward M2 induced by BMP4 overexpression and exogenous addition of rBMP4, and rapamycin (autophagy agonists) inhibit macrophages polarization toward M1 from down-regulation of BMP4. Our study further reveals the mechanism of maternal-fetal interface cell interactions in RSA, which can help in the diagnosis and treatment of RSA.