Exacerbated endoplasmic reticulum stress transmitted by endometrial stromal cells alters the conditioning of tolerogenic dendritic cells affecting trophoblast migration.

Abstract

Endometrial stromal cells acquire a secretory profile associated with endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) related to the onset of a sterile inflammatory response essential for sustaining embryo implantation. However, exacerbated stromal ERS/UPR is associated with reproductive complications. Given the ability of dendritic cells (DCs) to sense stress signals and be conditioned by stromal cells, here we investigated the transmission of ERS (TERS) from stromal cells to monocytes and its impact on tolerogenic DCs conditioning. Blood monocytes were differentiated into DCs (rhGM-CSF+rhIL-4, 5 d) in the presence or absence of conditioned media derived from either thapsigargin-treated (stressed) or nonstressed human endometrial stromal cell line. Soluble factors released by stressed stromal cells impaired CD1a+CD14- DC differentiation and induced a proinflammatory profile, increasing the CD86high cell population, COX-2 expression, and tumor necrosis factor (TNF)-α, interleukin (IL)-8 and IL-1β secretion. Additionally, TERS was observed in these cultures, with increased expression of IRE1α, PERK, and ATF4. Even the splicing of the adaptive UPR marker XBP1 was increased though at low levels, its nuclear translocation was unchanged. These effects on spliced XBP1, coupled with a decreased GRP78/BiP and heightened CHOP expression, suggest the triggering of terminal UPR over adaptive UPR, confirmed by the induction of lytic cell death in stressed cultures. Finally, exacerbated TERS negatively impacted trophoblast migration in a blastocyst-like spheroid in vitro model. These findings suggest that exacerbated stromal ERS can be transmitted to monocytes, altering their differentiation, immune profile, and viability, which could ultimately impair trophoblast migration.