Endoplastmatic reticulum stress induces and inaflammatory response during decidualization Potential regulation by miR-17-5p, miR-21-5p AND miR-193b-3p

E SOCZEWSKI, J M MURRIETA-COXCA, P FUENTES-ZACARIAS, R GUTIÉRREZ-SAMUDIO, L MIRANDA, E GRASSO, M MARTÍ, C PÉREZ LEIRÓS, D MORALES-PRIETO, U MARKERT, R RAMHORST.

Congreso; Reunión Anual Conjunta SAIC-SAI-SAFIS; 2022

Considering the differentiation of endometrial stromal cells involve the induction of the endoplasmic Reticulum Stress (RS) and Unfolded Protein Response (UPR), here we identified and explored the contribution of miRNAs in the regulation of these processes. We used an in vitro model of decidualization based on the endometrial stromal cell line St-T1b, treated with 8-Br-cAMP during 5 days, or Thapsigargin (Tg, a RS-inducer). After decidualization St-T1b, increased the RS-sensors, ATF6, PERK and IRE1, and the UPR marker, C/EBP Homologous Protein (CHOP) in comparison with non-decidualized cells. Moreover, thioredoxin-interacting protein (TXNIP), a link between the RS-pathway and inflammation increased in decidualized cells, and also the inflammasome NLRP3 and IL-1β expression. Then, by performing an in silico analysis using miRNet 2.0 we identified three miRNAs able to regulate the RS/UPR pathways and the inflammation associated to embryo implantation: miR-17-5p, miR-21-5p and miR-193b-3p. The three miRNA significantly decreased in non-decidualized cells in the presence of Tg. Finally, to validate the present results we used endometrial biopsies from patients with recurrent pregnancy loss (RPL) and recurrent in vitro fertilization failures (RIF). Using in situ hybridization technique in endometrial samples we confirmed the localized of the three miRNAs in stromal and epithelial glandular cells from group of patients. In fact, stromal cells from RPL patients displayed lower intensity in comparison with those from RIF patients indicating an alteration in the regulation of the RS/UPR processes. The key message is that decidualization is accompanied by the induction RS/UPR processes associated with a sterile inflammatory response to sustain embryo implantation. We identified novels miRNAs, miR-17-5p, miR-21-5p, and miR-193b-3p that might be involved in the regulation of these processes and are differentially expressed in endometrium from RPL and RIF patients.