Mechanisms of FH Protection Against Neovascular AMD
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 al...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00443/full |
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Article |
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DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
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 |
| spellingShingle |
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 Mechanisms of FH Protection Against Neovascular AMD Frontiers in Immunology AMD complement factor H FH Y402H polymorphism TSP-1 therapeutic target |
| author_facet |
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 |
| author_sort |
Céline Borras |
| title |
Mechanisms of FH Protection Against Neovascular AMD |
| title_short |
Mechanisms of FH Protection Against Neovascular AMD |
| title_full |
Mechanisms of FH Protection Against Neovascular AMD |
| title_fullStr |
Mechanisms of FH Protection Against Neovascular AMD |
| title_full_unstemmed |
Mechanisms of FH Protection Against Neovascular AMD |
| title_sort |
mechanisms of fh protection against neovascular amd |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2020-04-01 |
| description |
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. |
| topic |
AMD complement factor H FH Y402H polymorphism TSP-1 therapeutic target |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2020.00443/full |
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doaj-3646d397d2b940178ae9e6eb1094d66d2020-11-25T03:31:59ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-04-011110.3389/fimmu.2020.00443513435Mechanisms of FH Protection Against Neovascular AMDCéline Borras0Céline Borras1Kimberley Delaunay2Kimberley Delaunay3Kimberley Delaunay4Yousri Slaoui5Toufik Abache6Sylvie Jorieux7Marie-Christine Naud8Marie-Christine Naud9Marie-Christine Naud10Mohamed El Sanharawi11Mohamed El Sanharawi12Mohamed El Sanharawi13Emmanuelle Gelize14Emmanuelle Gelize15Emmanuelle Gelize16Patricia Lassiaz17Patricia Lassiaz18Patricia Lassiaz19Na An20Na An21Na An22Laura Kowalczuk23Laura Kowalczuk24Cédric Ayassami25Cédric Ayassami26Alexandre Moulin27Alexandre Moulin28Francine Behar-Cohen29Frédéric Mascarelli30Frédéric Mascarelli31Frédéric Mascarelli32Virginie Dinet33Virginie Dinet34Virginie Dinet35Centre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceUniversité Paris Diderot, Sorbonne Paris Cité, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceLaboratoire de Mathématiques et Applications UMR 7348, CNRS, Poitiers, FranceLaboratoire Français du Fractionnement et des Biotechnologies (LFB), Lille, FranceLaboratoire Français du Fractionnement et des Biotechnologies (LFB), Lille, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceINSERM, U1138, Paris, FranceDepartment of Ophthalmology of Lausanne, University Jules Gonin Eye Hospital, Lausanne, SwitzerlandCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceINSERM, U1138, Paris, FranceDepartment of Ophthalmology of Lausanne, University Jules Gonin Eye Hospital, Lausanne, SwitzerlandOphtalmopole, Hôpital Cochin Assistance Publique Hôpitaux de Paris, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceCentre de Recherche des Cordeliers, Inserm UMR1138, Université de Paris, Sorbonne Université, Paris, FranceINSERM, U1138, Paris, FranceUniversité Pierre et Marie Curie - Paris6, UMRS1138, Paris, FranceA 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.00443/fullAMDcomplement factor HFH Y402H polymorphismTSP-1therapeutic target |