Endoplasmic Reticulum Stress through ATF6a pathway is associated with an inflammatory response in endometrial stromal cells: potential regulation by miRNAs

SOCZEWSKI, E.; GUTIERREZ-ZAMUDIO L.; FERNÁNDEZ, L.; MORALES-PRIETO, D.; MARKERT, U.; MIRANDA L.; GRASSO, E.; MARTI, M; PEREZ LEIRÓS, C.; MURRIETA-COXCA JM.; GALLINO, L.; GORI, S.; FAVARO, R.; RAMHORST, R.

Congreso; Reunión conjunta de la Sociedad Chilena de Ciencias Fisiológicas (SCHCF) y la Asociación Latinoamericana de Ciencias Fisiológicas (ALACF); 2020

Introduction: During decidualization, endometrial stromal cells undergo endoplasmic reticulum stress (ERS) and unfolded protein response (UPR), which will allow them to expand their endoplasmic reticulum with the corresponding machinery for protein folding. These processes are directed by miRNAs that regulate the expression or stability of their transcription factors.Objectives: we focus on the role of ERS/UPR during decidualization to induce a physiological sterileinflammatory response and whether it might be regulated by miRNAs.Methods: We used an in vitro model of decidualization represented by human telomerase immortalized endometrial stromal cell line St-T1b ; and endometrial biopsies from patients with recurrent spontaneous abortions (RSA) and recurrent in vitro fertilization failures (RIF). Statistical analysis: Student?s t test. Mean±S.E.M. of at least 4 independent experiments. The study was approved by the respective local ethic committee (Friederich Schiller Universität).Results: We evaluated the expression of the ERS-sensor ATF6 and the UPR marker, CHOP. Both markers increased in decidualized cells, and Tg (ERS inducer) induced even higher levels in comparison with non-decidualized cells. Then, we evaluated the modulation of TXNIP, a link between the ERS-pathway and inflammation. TXNIP increased in decidualized cells, and also the inflammasome NLRP3 and IL-1b expression. Then, using an in silico analysis using miRTarBase v8.0 we selected two miRNAs able to regulate the ERS and UPR pathways: miR-193b-3p and miR-21-5p. Both miRNAs significantly decreased in non-decidualized cells in the presence of Tg. Finally, we studied the expression and localization of miRNAs through an In Situ Hybridization (ISH) technique in endometrial samples. Both miRNAs were expressed in stromal cells and endometrial glands in samples from RSA and RIF patients at similar levels.Conclusion:The present results suggest that decidualization in St-T1b cells is accompanied by an ERS and UPR associated with a sterile inflammatory response potentially regulated by miR-193b-3p and miR-21-5p.We acknowledge DAAD for financial support of Elizabeth Soczewski's short-term stay in Placenta-Labor. This work was funded by Deutsche Forschungsgemeinschaft and the National Agency of Sciences and Technology from Argentina.