Surface‐exposed calreticulin in the interaction between dying cells and phagocytes

Phagocytosis is essential for pathogen elimination and for the removal of apoptotic corpses, a process that has been long considered immunologically silent. The phagocytic uptake of apoptotic/necrotic cells involves a plethora of molecules, including immunoglobulins, lectins, components of the complement system (all of which act as opsonins), as well as the phospholipid phosphatidylserine (PS) and the endoplasmic reticulum chaperone calreticulin (CRT), both of which can be exposed on the surface of dying cells. For a long time, surface-exposed CRT was believed to participate in phagocytosis, mostly as a (co)receptor for specific opsonins. Recently, this view has been challenged by the observations that, similar to PS, CRT acts as a facultative recognition ligand on apoptotic cells, and that cytotoxic agents such as anthracyclines induce the exposure of CRT on the surface of dying tumor cells, thereby generating an engulfment signal that stimulates the uptake of apoptotic corpses and the presentation of the corresponding antigens by dendritic cells. Here, we summarize the current knowledge on the role of CRT and CRT-interacting proteins during corpse removal.