Mechanisms of FH Protection Against Neovascular AMD.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_D229AC094087
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Mechanisms of FH Protection Against Neovascular AMD.
Journal
Frontiers in immunology
Author(s)
Borras C., Delaunay K., Slaoui Y., Abache T., Jorieux S., Naud M.C., Sanharawi M.E., Gelize E., Lassiaz P., An N., Kowalczuk L., Ayassami C., Moulin A., Behar-Cohen F., Mascarelli F., Dinet V.
ISSN
1664-3224 (Electronic)
ISSN-L
1664-3224
Publication state
Published
Issued date
2020
Peer-reviewed
Oui
Volume
11
Pages
443
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
A common allele (402H) of the complement factor H (FH) gene is the major risk factor for age-related macular degeneration (AMD), the leading cause of blindness in the elderly population. Development and progression of AMD involves vascular and inflammatory components partly by deregulation of the alternative pathway of the complement system (AP). The loss of central vision results from atrophy and/or from abnormal neovascularization arising from the choroid. The functional link between FH, the main inhibitor of AP, and choroidal neovascularization (CNV) in AMD remains unclear. In a murine model of CNV used as a model for neovascular AMD (nAMD), intraocular human recombinant FH (recFH) reduced CNV as efficiently as currently used anti-VEGF (vascular endothelial growth factor) antibody, decreasing deposition of C3 cleavage fragments, membrane attack complex (MAC), and microglia/macrophage recruitment markers in the CNV lesion site. In sharp contrast, recFH carrying the H402 risk variant had no effect on CNV indicating a causal link to disease etiology. Only the recFH NT <sup>al</sup> region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CT <sup>al</sup> region (recFH7-20) containing the CCP7 and CCPs19-20 binding domains was antiangiogenic but did not reduce the microglia/macrophage recruitment. The antiangiogenic effect of both recFH1-20 and recFH-CCP7-20 resulted from thrombospondin-1 (TSP-1) upregulation independently of the C3 cleavage fragments generation. This study provides insight on the mechanistic role of FH in nAMD and invites to reconsider its therapeutic potential.
Keywords
AMD, FH Y402H polymorphism, TSP-1, complement factor H, therapeutic target
Pubmed
Open Access
Yes
Create date
25/04/2020 17:32
Last modification date
15/01/2021 7:12
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