Complement factor H inhibits CD47-mediated resolution of inflammation
File(s)
Accepted version
Accepted version
Author(s)
Type
Journal Article
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.
Date Issued
2017-02-21
Date Acceptance
2016-12-12
Citation
Immunity, 2017, 46 (2), pp.261-272
ISSN
1074-7613
Publisher
Elsevier
Start Page
261
End Page
272
Journal / Book Title
Immunity
Volume
46
Issue
2
Copyright Statement
© 2017 Elsevier Inc. This manuscript is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/
Sponsor
Wellcome Trust
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000396410900014&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
098476/Z/12/Z
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
MACULAR DEGENERATION
SUBRETINAL INFLAMMATION
GENE-EXPRESSION
UP-REGULATION
SPINAL-CORD
MICROGLIA
DISEASE
MACROPHAGES
ANGIOGENESIS
ACTIVATION
Animals
CD47 Antigen
Complement Factor H
Disease Models, Animal
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunohistochemistry
Inflammation
Macular Degeneration
Mice
Mice, Knockout
Peritonitis
Polymorphism, Single Nucleotide
Animals
Mice, Knockout
Mice
Peritonitis
Macular Degeneration
Disease Models, Animal
Inflammation
Complement Factor H
Enzyme-Linked Immunosorbent Assay
Flow Cytometry
Immunohistochemistry
Polymorphism, Single Nucleotide
CD47 Antigen
Immunology
1107 Immunology
Publication Status
Published
Date Publish Online
2017-02-24