Abstract
Decidual macrophages (dMϕ) 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-β (MNSFβ) in embryonic implantation and pregnancy success. MNSFβ is a ubiquitously expressed ubiquitin-like protein that also exhibits immune regulatory potential, but its function in human dMϕ remains unknown. Here, we observed that the proportion of CD11chigh (CD11cHI) dMϕ was significantly increased in dMϕ derived from patients with recurrent pregnancy loss (RPL dMϕ) compared to those derived from normal pregnant women (Control dMϕ). The production of MNSFβ and TNFα by RPL dMϕ was also significantly increased compared to that by Control dMϕ. Conditioned medium from RPL dMϕ 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 TNFα. Bioinformatics analysis indicated a potential interaction between MNSFβ and RC3H1, a suppressor of TNFα transcription. Immunoprecipitation experiments with human Mϕ differentiated from the human monocyte cell line Thp1 (Thp1-derived Mϕ) proved the binding of MNSFβ to RC3H1. Specific knockdown of MNSFβ in Thp1-derived Mϕ led to a marked decrease in TNFα production, which could be reversed by inhibiting RC3H1 expression. Interestingly, a significant decrease in the protein level of RC3H1 was observed in RPL dMϕ. Together, our findings indicate that aberrantly increased MNSFβ expression in dMϕ may promote TNFα 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.
Highlights
The establishment and maintenance of maternal–fetal tolerance, mediated by fetal and maternal cells, including extravillous trophoblasts (EVTs), decidual stromal cells (DSCs), and decidual immune cells (DICs), are crucial for successful human pregnancy [1]
The results showed that the monoclonal nonspecific suppressor factor-b (MNSFb) protein signals were widely distributed in human decidual tissues, including decidual macrophages, during the first trimester (Figure 1A)
The invasion of HTR8/SVneo cells was enhanced by treatment with the conditioned media (CM) of MNSFb-knockdown Mf, and this stimulatory effect could be eliminated by the addition of TNFa (Figure 5C); these results further indicated that dMf could inhibit the invasion of EVTs by secreting TNFa
Summary
The establishment and maintenance of maternal–fetal tolerance, mediated by fetal and maternal cells, including extravillous trophoblasts (EVTs), decidual stromal cells (DSCs), and decidual immune cells (DICs), are crucial for successful human pregnancy [1]. The most abundant cell types among DICs are decidual NK cells (dNK, 50%–70%), decidual macrophages (dMf, 20%–30%), and T cells (10%–15%) [2]. MNSFb was originally identified as an inhibitor of the T-cellmediated immune response [7] because it inhibits the proliferation of T and B cells and the secretion of interleukin (IL-4) from type 2 helper T cells and bone marrow-derived mast cells [8, 9]. It has been reported that MNSFb promotes the apoptosis [10] but inhibits the phagocytosis [11] and TNFa production [12] of murine macrophages
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