Impact of the Reticular Stress and Unfolded Protein Response on the inflammatory response in endometrial stromal cells

E Grasso,R Ramhorst,C Pérez Leirós,T F Lobo,G Martínez,M Irigoyen,E Soczewski,G Salamone,R Mattar,C Ruhlmann,L Gallino,L Fernández,S Daher,S Gori,D Vota

doi:10.1038/s41598-018-29779-8

Abstract

During decidualization, endometrial stromal cells undergo reticular stress (RS) and unfolded protein response (UPR), allowing the endoplasmic reticulum-expansion and immunomodulators production. Physiological RS generates the activation of sensing proteins, inflammasome activation and mature-IL-1β secretion, associated with pro-implantatory effects. We focus on the impact of RS and UPR on decidualized cells and whether they induce a physiological sterile inflammatory response through IL-1β production. Human endometrial stromal cell line (HESC) after decidualization treatment with MPA + dibutyryl-cAMP (Dec) increased the expression of RS-sensors (ATF6, PERK and IRE1α) and UPR markers (sXBP1 and CHOP) in comparison with Non-dec cells. Then we found increased NLRP3 expression in Dec cells compared with Non-dec cells. In fact STF-083010 (an IRE1α inhibitor) prevented this increase. Downstream, increased levels of active caspase-1 on Dec cells were detected by FAM-Flica Caspase-1 associated with an increase in IL-1β production. Moreover, the treatment with STF-083010 decreased the invasion index observed in Dec cells, evaluated by an in vitro model of implantation. In endometrial biopsies from recurrent spontaneous abortion patients an increased expression of IRE1α was found in comparison with fertile women; while recurrent implantation failure samples showed a lower expression of sXBP1, TXNIP and NLRP3 than fertile women, suggesting that RS/UPR tenors might condition endometrial receptivity.

Highlights

Embryo implantation in humans involves the generation of an inflammatory response associated with the invasion of the blastocyst into the decidua
We investigated if alterations in the reticular stress (RS)/unfolded protein response (UPR) levels and interleukin 1β (IL-1β) production, either reduced or exacerbated levels, might precondition the endometrium from patients with recurrent implantation failures (RIF) or recurrent spontaneous abortions (RSA)
In the context of fetal-maternal interaction, our findings indicate that decidualization pre-conditions the uterus to an inflammatory response needed for trophoblast cell invasion

Summary

Introduction

Embryo implantation in humans involves the generation of an inflammatory response associated with the invasion of the blastocyst into the decidua. We evaluated the induction of the RS and UPR processes during the decidualization as an inductor of a sterile and physiological inflammatory response with NLRP3 inflammasome activation, Caspase-1 maturation and IL-1β production.

Results

Conclusion