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

Abstract

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.

Neurotrophins: are they involved in immune tolerance in pregnancy?

“…113 Elevated levels of BDNF enhance the ability of cells to migrate and invade by regulating the activation of RhoA, 115 a protein that regulates signaling pathways associated with cytoskeletal remodeling during cell migration. 11,116 It was found that the change in the expression and activation of various Rho isoforms under the influence of other growth factors, in particular IGF1, EGF and TGFβ, plays a role in the organization of the actin skeleton of trophoblast cells and modulates the migration of HTR-8/SVneo, Jeg-3, and JAR cells. [117][118][119][120] However, the possibility of activation of Rho-dependent migration of trophoblast cells during the induction of NTs has not yet been studied.…”

“…Despite the fact that several hypotheses have been proposed for the development of immune tolerance during normal pregnancy, 1–5 there is still no understanding of the exact mechanisms. Therefore, research aimed at studying the relationship between invasive trophoblast cells and maternal NK cells, in particular decidual NK (dNK) cells, is of particular interest 6–11 …”

“…Therefore, research aimed at studying the relationship between invasive trophoblast cells and maternal NK cells, in particular decidual NK (dNK) cells, is of particular interest. [6][7][8][9][10][11] It is generally accepted that a decrease in the cytotoxicity of NK cells in the decidua to a level at which they do not cause cytolysis of trophoblasts is a necessary for their normal invasion; however, data on changes in the cytotoxic activity of dNK cells are contradictory. 9 was reported that dNK cells have a high cytotoxic potential, expressing granzymes, perforin and granulysin while having a reduced cytotoxic function.…”

Immune Cell Functionality during Decidualization and Potential Clinical Application

“…Reasons for this imbalance can be manifold, including systemic immune alterations, genetic constitution, inflammatory effectors including immune disorders, stress, diet, physical exercises, and obesity, or altered activators including paternal factors, HLA matching, genetics of the embryo, and more. On a cellular basis, not only local immune cells but also trophoblast cells, as well as decidual epithelial and stromal cells, affect the balance by activating and inhibiting soluble and cell-to-cell-contact-mediated factors and receptors [ 24 , 42 , 51 , 52 , 97 , 98 , 99 , 100 ].…”

“…Similarly, to immune cells in the decidua, angiogenetic and invasive processes can be supported by immune cells in the tumor microenvironment. Both tumor and trophoblastic cells express immune inhibitory ligands, including B7 family molecules such as programmed cell death ligand (PD-L) 1, PD-L2, CD80, and CD86 [ 23 , 24 ], and T cell immunoglobulin and mucin-domain containing-3 ligand (TIM-3L) [ 25 ]. Similar to the immune cells, such as macrophages and NK cells, which support trophoblast invasion, the presence of tumor-associated macrophages (TAMs) is associated with tumor progression and metastasis [ 26 , 27 ].…”