Endoplasmic Reticulum Stress-Induced Membrane Exposure of Calreticulin Serves as a Guide for Phagocytic Removal of Stressed-But-Viable Cytotrophoblasts.

AIM: Calreticulin (CRT), a protein in the endoplasmic reticulum (ER), plays critical roles in protein quality control and homeostasis of cytosolic and ER calcium levels. We previously reported that ER stress, a risk factor for poor placentation and preeclampsia, induced extracellular release of CRT in a cytotrophoblast (CTB) BeWo cell model; extracellular CRT impaired CTB syncytialization. Several stresses, including ER stress, reportedly exposed CRT on membranes, but the roles of membrane-exposed CRT in CTBs have remained unclear.

METHODS

We investigated whether ER stress-induced membrane exposure of CRT in CTBs and whether membrane-exposed CRT acted as a guide for phagocytic removal of stressed CTBs.

RESULTS

Immunohistochemical analysis of preeclamptic placentas demonstrated increased expression of immunoglobulin heavy chain-binding protein, which indicated enhanced ER stress in preeclamptic placentas. The ER stress inducers thapsigargin and tunicamycin-induced membrane exposure of CRT in BeWo cells and primary human CTBs. Phorbol ester-differentiated THP-1 cells phagocytosed ER-stressed and CRT-exposing CTBs, which were blocked by an anti-CRT antibody.

CONCLUSIONS

Our results thus propose a pathway for removal of damaged CTBs and thus for maintaining pregnancy. Because ER stress is a risk factor for poor placentation, investigation of physiological and pathological roles of CRT exposure-mediated phagocytic removal deserves future study.