Upregulation of OTULIN Alleviated Recurrent Pregnancy Loss by Suppressing Trophoblast Dysfunction and NF-κB Signaling Pathway

Abstract

Recurrent pregnancy loss (RPL) is one of obstetrical diseases with no effective therapy methods. Trophoblast cell dysfunction and inflammation induce embryo implantation insufficiency, thereby resulting in RPL. OTU deubiquitinase with linear linkage specificity (OTULIN) plays a role in regulating the immune response and cell death. However, the role of OTULIN in RPL remains unclear. Spontaneous abortion mouse model and lipopolysaccharide-treated HTR-8/SVneo cells were used to investigate the role of OTULIN in RPL. OTULIN expression was downregulated in the labyrinth trophoblast of RPL mice and LPS-treated trophoblast cells. The embryonic reabsorption rate was decreased in OTULIN-overexpressed spontaneous abortion mice, accompanied with the increase in placental/fetus weight ratio. OTULIN overexpression significantly inhibited apoptosis in vivo and in vitro, as evidenced by the decrease in the activity of caspase 3. The expression of pro-inflammatory cytokines was decreased with OTULIN overexpression. Moreover, OTULIN overexpression decreased p-IκBα/IκBα and p-p65/p65 ratio. The nuclear translocation of NF-κB was suppressed via OTULIN overexpression both in vivo and in vitro. Our study suggested that OTULIN deficiency might cause inflammation and trophoblast abnormalities in RPL. The supplementation with OTULIN might alleviate the development of RPL via inhibiting NF-κB mediated inflammation response.