Abstract |
Variants of the CFH gene, encoding complement factor H (CFH), show strong association with age-related macular degeneration (AMD), a major cause of blindness. Here, we used murine models of AMD to examine the contribution of CFH to disease etiology. Cfh deletion protected the mice from the pathogenic subretinal accumulation of mononuclear phagocytes (MP) that characterize AMD and showed accelerated resolution of inflammation. MP persistence arose secondary to binding of CFH to CD11b, which obstructed the homeostatic elimination of MPs from the subretinal space mediated by thrombospsondin-1 (TSP-1) activation of CD47. The AMD-associated CFH(H402) variant markedly increased this inhibitory effect on microglial cells, supporting a causal link to disease etiology. This mechanism is not restricted to the eye, as similar results were observed in a model of acute sterile peritonitis. Pharmacological activation of CD47 accelerated resolution of both subretinal and peritoneal inflammation, with implications for the treatment of chronic inflammatory disease.
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Authors | Bertrand Calippe, Sebastien Augustin, Fanny Beguier, Hugo Charles-Messance, Lucie Poupel, Jean-Baptiste Conart, Shulong J Hu, Sophie Lavalette, Alexandre Fauvet, Julie Rayes, Olivier Levy, William Raoul, Catherine Fitting, Thomas Denèfle, Matthew C Pickering, Claire Harris, Sylvie Jorieux, Patrick M Sullivan, José-Alain Sahel, Philippe Karoyan, Przemyslaw Sapieha, Xavier Guillonneau, Emmanuel L Gautier, Florian Sennlaub |
Journal | Immunity
(Immunity)
Vol. 46
Issue 2
Pg. 261-272
(02 21 2017)
ISSN: 1097-4180 [Electronic] United States |
PMID | 28228282
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2017 Elsevier Inc. All rights reserved. |
Chemical References |
- CD47 Antigen
- Complement Factor H
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Topics |
- Animals
- CD47 Antigen
(immunology)
- Complement Factor H
(genetics, immunology)
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Flow Cytometry
- Immunohistochemistry
- Inflammation
(genetics, immunology)
- Macular Degeneration
(genetics, immunology)
- Mice
- Mice, Knockout
- Peritonitis
(genetics, immunology)
- Polymorphism, Single Nucleotide
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