MiR-146a-5p improves the decidual cytokine microenvironment by regulating the toll-like receptor signaling pathway in unexplained spontaneous abortion

Abstract

Spontaneous abortion (SA) is a common pregnancy failure, but the cause of numerous cases remains unexplained. Decidual immune cells (DICs)-mediated cytokine microenvironment is involved in pregnancy and regulated by many microRNAs, but whether microRNA-146a-5p (miR-146a) regulate the decidual cytokine microenvironment and the potential mechanisms in unexplained SA pathogenesis have rarely been reported. In this study, the levels of cytokines and miR-146a in healthy and unexplained SA deciduae were first investigated, and the correlation between them was analyzed. Then, the effect of miR-146a inhibitor on cytokines was assessed in healthy deciduae-derived DICs. Third, the downstream targets and related molecular mechanisms of miR-146a were analyzed by bioinformatics, and the levels of the predicted targets in deciduae were assessed, followed by the correlation analysis between the levels of miR-146a and the targets. Finally, the effect of miR-146a on the predicted targets and inflammatory cytokines was validated in unexplained SA deciduae-derived DICs. As a result, decreased miR-146a correlated with the cytokine disorder in unexplained SA deciduae, and inhibition of miR-146a promoted pro-inflammatory response in healthy deciduae-derived DICs. One hundred four target genes and related molecular mechanisms of miR-146a were predicted, among which the toll-like receptor (TLR) pathway might be associated with the decidual cytokine regulation. Upregulation of miR-146a inhibited the expression of the predicted molecules enriched in the TLR pathway and improved the cytokine disorder in unexplained SA deciduae-derived DICs. Collectively, miR-146a improves the decidual cytokine microenvironment by regulating the TLR pathway in unexplained SA, providing novel potential targets for further therapeutic research.