Frontiers in Immunology (Apr 2020)
Mechanisms of FH Protection Against Neovascular AMD
- Céline Borras,
- Céline Borras,
- Kimberley Delaunay,
- Kimberley Delaunay,
- Kimberley Delaunay,
- Yousri Slaoui,
- Toufik Abache,
- Sylvie Jorieux,
- Marie-Christine Naud,
- Marie-Christine Naud,
- Marie-Christine Naud,
- Mohamed El Sanharawi,
- Mohamed El Sanharawi,
- Mohamed El Sanharawi,
- Emmanuelle Gelize,
- Emmanuelle Gelize,
- Emmanuelle Gelize,
- Patricia Lassiaz,
- Patricia Lassiaz,
- Patricia Lassiaz,
- Na An,
- Na An,
- Na An,
- Laura Kowalczuk,
- Laura Kowalczuk,
- Cédric Ayassami,
- Cédric Ayassami,
- Alexandre Moulin,
- Alexandre Moulin,
- Francine Behar-Cohen,
- Frédéric Mascarelli,
- Frédéric Mascarelli,
- Frédéric Mascarelli,
- Virginie Dinet,
- Virginie Dinet,
- Virginie Dinet
Affiliations
- Céline Borras
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Céline Borras
- Université Paris Diderot, Sorbonne Paris Cité, Paris, France
- Kimberley Delaunay
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Kimberley Delaunay
- INSERM, U1138, Paris, France
- Kimberley Delaunay
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Yousri Slaoui
- Laboratoire de Mathématiques et Applications UMR 7348, CNRS, Poitiers, France
- Toufik Abache
- Laboratoire Français du Fractionnement et des Biotechnologies (LFB), Lille, France
- Sylvie Jorieux
- Laboratoire Français du Fractionnement et des Biotechnologies (LFB), Lille, France
- Marie-Christine Naud
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Marie-Christine Naud
- INSERM, U1138, Paris, France
- Marie-Christine Naud
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Mohamed El Sanharawi
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Mohamed El Sanharawi
- INSERM, U1138, Paris, France
- Mohamed El Sanharawi
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Emmanuelle Gelize
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Emmanuelle Gelize
- INSERM, U1138, Paris, France
- Emmanuelle Gelize
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Patricia Lassiaz
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Patricia Lassiaz
- INSERM, U1138, Paris, France
- Patricia Lassiaz
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Na An
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Na An
- INSERM, U1138, Paris, France
- Na An
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Laura Kowalczuk
- INSERM, U1138, Paris, France
- Laura Kowalczuk
- Department of Ophthalmology of Lausanne, University Jules Gonin Eye Hospital, Lausanne, Switzerland
- Cédric Ayassami
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Cédric Ayassami
- INSERM, U1138, Paris, France
- Alexandre Moulin
- INSERM, U1138, Paris, France
- Alexandre Moulin
- Department of Ophthalmology of Lausanne, University Jules Gonin Eye Hospital, Lausanne, Switzerland
- Francine Behar-Cohen
- Ophtalmopole, Hôpital Cochin Assistance Publique Hôpitaux de Paris, Paris, France
- Frédéric Mascarelli
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Frédéric Mascarelli
- INSERM, U1138, Paris, France
- Frédéric Mascarelli
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- Virginie Dinet
- Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, France
- Virginie Dinet
- INSERM, U1138, Paris, France
- Virginie Dinet
- Université Pierre et Marie Curie - Paris6, UMRS1138, Paris, France
- DOI
- https://doi.org/10.3389/fimmu.2020.00443
- Journal volume & issue
-
Vol. 11
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 NTal region (recFH1-7), containing the CCPs1-4 C3-convertase inhibition domains and the CCP7 binding domain, exerted all differential biological effects. The CTal 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
