Janus-like opposing roles of CD47 in autoimmune brain inflammation in humans and mice.
Comparison of transcriptomic and proteomic data from pathologically similar multiple sclerosis (MS) lesions reveals down-regulation of CD47 at the messenger RNA level and low abundance at the protein level. Immunohistochemical studies demonstrate that CD47 is expressed in normal myelin and in foamy macrophages and reactive astrocytes within active MS lesions. We demonstrate that CD47(-/-) mice are refractory to experimental autoimmune encephalomyelitis (EAE), primarily as the result of failure of immune cell activation after immunization with myelin antigen. In contrast, blocking with a monoclonal antibody against CD47 in mice at the peak of paralysis worsens EAE severity and enhances immune activation in the peripheral immune system. In vitro assays demonstrate that blocking CD47 also promotes phagocytosis of myelin and that this effect is dependent on signal regulatory protein α (SIRP-α). Immune regulation and phagocytosis are mechanisms for CD47 signaling in autoimmune neuroinflammation. Depending on the cell type, location, and disease stage, CD47 has Janus-like roles, with opposing effects on EAE pathogenesis.
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA. mayhan@stanford.edu
May H
MH
Han
Deborah H
DH
Lundgren
Siddhartha
S
Jaiswal
Mark
M
Chao
Kareem L
KL
Graham
Christopher S
CS
Garris
Robert C
RC
Axtell
Peggy P
PP
Ho
Christopher B
CB
Lock
Joslyn I
JI
Woodard
Sara E
SE
Brownell
Maria
M
Zoudilova
Jack F V
JF
Hunt
Sergio E
SE
Baranzini
Eugene C
EC
Butcher
Cedric S
CS
Raine
Raymond A
RA
Sobel
David K
DK
Han
Irving
I
Weissman
Lawrence
L
Steinman
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D001253:Astrocytes / Q000276:immunology / Q000378:metabolism; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D051928:CD47 Antigen / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D060467:Disease Resistance / Q000235:genetics / Q000276:immunology; D015536:Down-Regulation; D004660:Encephalitis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005487:Foam Cells / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000378:metabolism; D009186:Myelin Sheath / Q000276:immunology / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D059467:Transcriptome
D051928:CD47 Antigen