ABSTRACT 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.
Ikezaki et al. (Sun,) studied this question.