Trophoblasts protect the inner cell mass from macrophage destruction

Several mechanisms have been suggested to account for the survival of the semiallogeneic fetus in the maternal uterus. However, no data are available to explain how the blastocyst resists the high number of macrophages in the uterus at the time of implantation. The present study examines the in vitro development of murine 3.5-day-old syngeneic or semiallogeneic blastocysts in the presence of nonactivated or lipopolysaccharide (LPS)-activated macrophages. It was found that the in vitro development of blastocysts was undisturbed by the presence of nonactivated or LPS-activated macrophages. The outgrowing trophoblasts were not only nonadhesive to the macrophages but also repelled them actively, thus preventing them from reaching the inner cell mass (ICM). Removing the zona pellucida by use of pronase or killing the ICM by irradiation did not alter the repulsion of macrophages by the trophoblasts. On the other hand, removal of the trophectoderm by antibody and complement treatment rendered the macrophages adhesive and destructive to the ICM. Four of 15 ICM (27%) were destroyed by nonactivated macrophages, and all of the ICM (15/15) were destroyed by LPS-activated macrophages. It is noteworthy that the addition of colchicine, cytochalasin B, proteinase inhibitors, anti-transforming growth factor-beta (TGF beta) antibodies, and indomethacin had no effect on the repulsion of macrophages by the trophoblasts. Therefore, it seems that microtubular proteins, microfilaments, extracellular matrix-degrading enzymes, TGF beta, and prostaglandins are not involved in the repulsion process. These results indicate that trophoblasts protect the ICM from the destructive action of macrophages by a repulsion mechanism of an as yet unknown nature.