Cell-surface calreticulin initiates clearance of viable or apoptotic cells through trans-activation of LRP on the phagocyte

• Apoptotic-cell removal is critical for development, tissue homeostasis, and resolution of inflammation. Although many candidate systems exist, only phosphatidylserine has been identified as a general recognition ligand on apoptotic cells. We demonstrate here that calreticulin acts as a second general recognition ligand by binding and activating LDL-receptor-related protein (LRP) on the engulfing cell. Since surface calreticulin is also found on viable cells, a mechanism preventing inadvertent uptake was sought. Disruption of interactions between CD47 (integrin-associated protein) on the target cell and SIRPalpha (SHPS-1), a heavily glycosylated transmembrane protein on the engulfing cell, permitted uptake of viable cells in a calreticulin/LRP-dependent manner. On apoptotic cells, CD47 was altered and/or lost and no longer activated SIRPalpha. These changes on the apoptotic cell create an environment where "don't eat me" signals are rendered inactive and "eat me" signals, including calreticulin and phosphatidylserine, congregate together and signal for removal.

Keyword

Animals

Antibodies; Monoclonal/metabolism

Antigens; CD47/metabolism

Apoptosis/genetics/*immunology

Calreticulin/*metabolism

Cell Line

Embryo

Fibroblasts/cytology/metabolism

Heterozygote

Humans

Jurkat Cells

Macrophages/immunology

Mice

Mice; Knockout

Microscopy; Video

Models; Biological

Neutrophils/cytology/metabolism

Phagocytes/*immunology

Phagocytosis/genetics/immunology

Receptors; Immunologic/genetics/*metabolism

Trans-Activation (Genetics)

Publication and Content Type

ref (subject category)

art (subject category)