Increased miR-6875-5p inhibits plasmacytoid dendritic cell differentiation via the STAT3/E2-2 pathway in recurrent spontaneous abortion

Abstract

Recurrent spontaneous abortion (RSA) is a common complication of early pregnancy. Dendritic cells (DCs) are thought to confer fetal-maternal immunotolerance and play a crucial role in ensuring a successful pregnancy. A decrease of plasmacytoid dendritic cells (pDCs) was found to be involved in RSA, but the underlying mechanisms of decreased pDC in RSA remain unclear. MicroRNAs (miRNAs) play critical roles in RSA as well as the development, differentiation and functional regulation of pDCs; however, the regulatory effect of miRNAs on pDC in RSA has not been fully investigated. Here we demonstrated that both the proportion of pDC and signal transducer and activator of transcription (STAT3)/transcription factor 4 (Tcf4/E2-2) expression decreased in the peripheral blood mononuclear cells and decidua of patients with RSA compared to those with normal pregnancy (NP), and there was a significantly positive correlation between pDC and STAT3 mRNA. MiRNA microarray assay and quantitative reverse transcription PCR results showed that miR-6875-5p expression was markedly increased in women with RSA and negatively correlated with mRNA expression level of STAT3. Up-regulated miR-6875-5p could sensitively discriminate patients with RSA from NP subjects. Overexpression of miR-6875-5p significantly down-regulated the mRNA expression of STAT3 and E2-2 as well as the protein and phosphorylation level of STAT3, while miR-6875-5p knockdown showed opposite results. Dual luciferase reporter verified that miR-6875-5p regulated STAT3 expression by directly binding to its 3'untranslated region. Overall, our results suggested that increased miR-6875-5p is involved in RSA by decreasing the differentiation of pDCs via inhibition of the STAT3/E2-2 signaling pathway. miR-6875-5p may be explored as a promising diagnostic marker and therapeutic target for RSA.

DNA Methylation of Window of Implantation Genes in Cervical Secretions Predicts Ongoing Pregnancy in Infertility Treatment

“…Impaired STAT3 expression is a possible cause of altered endometrial receptivity and decidualization via different pathways [ 49 , 50 , 51 , 52 , 53 , 54 ]. Both STAT3 and TCF4 are downregulated in the decidua of patients with recurrent spontaneous abortion compared with those with normal pregnancy [ 55 ]. In a mouse model, an impaired LIF/STAT3 pathway resulted in the failure of decidualization and embryo implantation [ 56 ].…”

Research on the Mechanism of Asperosaponin VI for Treating Recurrent Spontaneous Abortion by Bioinformatics Analysis and Experimental Validation

“…RSA results from impaired trophoblast function, and further study has shown that STAT3 expression could a ect trophoblast cell proliferation and migration [41]. Existing studies have con rmed that the reduction of plasmacytoid dendritic cells in RSA could be mediated by the regulation of STAT3 expression [42]. STAT3 signaling has been veri ed to exert anti-in ammatory IL-10 expression in decidua cells to protect pregnancy [43].…”

Emerging role of miRNAs, lncRNAs, and circRNAs in pregnancy-associated diseases

“…It was demonstrated thatupregulated miR-365 in the decidua of RSA patients compared to that of normal pregnant women could cause DCs apoptosis throughsuppressing serum and glucocorticoid-regulated kinase-1, which may be a potential underlying mechanism of early RSA [37] . Our recent research demonstrated increased miR-6875-5p in plasmacytoid DCs of RSA patients inhibited the cell differentiation via the STAT3/transcription factor 4 ( Tcf4/E2-2 ) signaling [38] . Additionally, a study distinguished 32 upregulated miRNAs in the decidua of RSA patients compared to normal pregnant women through deep sequencing; Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses predicted that these miRNAs are mainly involved in the regulation of trophoblast cells apoptosis and death [39] .…”