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Complement factor H inhibits CD47-Mediated resolution of inflammation

Calippe, Bertrand, Augustin, Sebastien, Beguier, Fanny, Charles-Messance, Hugo, Poupel, Lucie, Conart, Jean-Baptiste, Hu, Shulong J., Lavalette, Sophie, Fauvet, Alexandre, Rayes, Julie, Levy, Olivier, Raoul, William, Fitting, Catherine, Denèfle, Thomas, Pickering, Matthew C., Harris, Claire, Jorieux, Sylvie, Sullivan, Patrick M., Sahel, José-Alain, Karoyan, Philippe, Sapieha, Przemyslaw, Guillonneau, Xavier, Gautier, Emmanuel L. and Sennlaub, Florian 2017. Complement factor H inhibits CD47-Mediated resolution of inflammation. Immunity 46 (2) , pp. 261-272. 10.1016/j.immuni.2017.01.006

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: Elsevier (Cell Press)
ISSN: 1074-7613
Date of Acceptance: 12 December 2016
Last Modified: 11 Jun 2020 11:45
URI: http://orca.cf.ac.uk/id/eprint/105592

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