MNSFβ Regulates TNFα Production by Interacting with RC3H1 in Human Macrophages, and Dysfunction of MNSFβ in Decidual Macrophages Is Associated With Recurrent Pregnancy Loss

Decidual macrophages (dM phi) are the second largest population of leukocytes at the maternal-fetal interface and play critical roles in maintaining pregnancy. Our previous studies demonstrated the active involvement of monoclonal nonspecific suppressor factor-beta (MNSF beta) in embryonic implantation and pregnancy success. MNSF beta is a ubiquitously expressed ubiquitin-like protein that also exhibits immune regulatory potential, but its function in human dM phi remains unknown. Here, we observed that the proportion of CD11c(high) (CD11cHI) dM phi was significantly increased in dM phi derived from patients with recurrent pregnancy loss (RPL dM phi) compared to those derived from normal pregnant women (Control dM phi). The production of MNSF beta and TNF alpha by RPL dM phi was also significantly increased compared to that by Control dM phi. Conditioned medium from RPL dM phi exerted an inhibitory effect on the invasiveness of human trophoblastic HTR8/SVneo cells, and this effect could be partially reversed by a neutralizing antibody against TNF alpha. Bioinformatics analysis indicated a potential interaction between MNSF beta and RC3H1, a suppressor of TNF alpha transcription. Immunoprecipitation experiments with human M phi differentiated from the human monocyte cell line Thp1 (Thp1-derived M phi) proved the binding of MNSF beta to RC3H1. Specific knockdown of MNSF beta in Thp1-derived M phi led to a marked decrease in TNF alpha production, which could be reversed by inhibiting RC3H1 expression. Interestingly, a significant decrease in the protein level of RC3H1 was observed in RPL dM phi. Together, our findings indicate that aberrantly increased MNSF beta expression in dM phi may promote TNF alpha production via its interaction with RC3H1, and these phenomena could result in the disruption of the immune balance at the maternal-fetal interface and thus pregnancy loss.

Automated summary

Decidual macrophages (dM phi) play critical roles in maintaining pregnancy at the maternal-fetal interface, and aberrantly increased expression of MNSF beta in dM phi from patients with recurrent pregnancy loss (RPL) may promote TNF alpha production via its interaction with RC3H1, potentially disrupting the immune balance and leading to pregnancy loss.