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.
Gardai
Shyra J
SJ
Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson St., Denver, Colorado 80206, USA.
McPhillips
Kathleen A
KA
Frasch
S Courtney
SC
Janssen
William J
WJ
Starefeldt
Anna
A
Murphy-Ullrich
Joanne E
JE
Bratton
Donna L
DL
Oldenborg
Per-Arne
PA
Michalak
Marek
M
Henson
Peter M
PM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051928:CD47 Antigen / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism*; D002460:Cell Line; D004622:Embryo, Mammalian; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D019169:Jurkat Cells; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D018715:Microscopy, Video; D008954:Models, Biological; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D010586:Phagocytes / Q000276:immunology*; D010587:Phagocytosis / Q000235:genetics / Q000276:immunology; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D000911:Antibodies, Monoclonal; D051928:CD47 Antigen; D037282:Calreticulin; D011971:Receptors, Immunologic