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Journal articles
The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination
Fanny Beguier
1
Michael Housset
1
Christophe Roubeix
1
Sebastien Augustin
1
Yvrick Zagar
1
Caroline Nous
1
Thibaud Mathis
1
Chiara Eandi
2
Mustapha Benchaboune
3
Adèle Drame-Maigné
1
Wassila Carpentier
1
Solenne Chardonnet
4
Sara Touhami
1
Guillaume Blot
1
Jean Baptiste Conart
1
Hugo Charles-Messance
1
Anaïs Potey
1
Jean-François Girmens
3
Michel Paques
3
Frédéric Blond
1
Thierry Leveillard
1
Elod Koertvely
5
Jérôme Roger
6
José-Alain Sahel
1, 3
Przemyslaw Sapieha
7
Cecile Delarasse
1
Xavier Guillonneau
1
Florian Sennlaub
1
4
PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière
PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé
Fanny Beguier 1
Author
Michael Housset 1
Author
Christophe Roubeix 1
Author
Sebastien Augustin 1
Author
Mustapha Benchaboune 3
Author
Adèle Drame-Maigné 1
Author
Wassila Carpentier 1
Author
Solenne Chardonnet 4
Author IdHAL : solenne-chardonnet ORCID : https://orcid.org/0000-0001-9968-0074
Sara Touhami 1
Author Employer institution : CentraleSupélec
Guillaume Blot 1
Author
Jean Baptiste Conart 1
Author
Hugo Charles-Messance 1
Author
Thierry Leveillard 1
Author
Elod Koertvely 5
Author
Jérôme Roger 6
Author
José-Alain Sahel 1, 3
Author
Przemyslaw Sapieha 7
Author
Cecile Delarasse 1
Author
Xavier Guillonneau 1
Author
Florian Sennlaub 1
Author
1
Institut de la Vision (17 Rue Moreau, 75012 Paris - France)
- CNRS - Centre National de la Recherche Scientifique : UMR7210 (France)
- SU - Sorbonne Université : UM80 (21 rue de l’École de médecine - 75006 Paris - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : U968 (101, rue de Tolbiac, 75013 Paris - France)
2
UNITO - Università degli studi di Torino (Via Verdi, 8 10124 Torino Italie - Italy)
3
CIC Quinze-Vingts (CHNO 28, rue de Charenton, 75012 Paris - France)
- AP-HP - Assistance publique - Hôpitaux de Paris (AP-HP) (France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : CIC1423 (101, rue de Tolbiac, 75013 Paris - France)
- Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (France)
4
PASS-P3S - Plateforme Post-génomique de la Pitié-Salpêtrière (Faculté de Médecine Pitié-Salpetrière 105 Boulevard de l'Hôpital - 75013 PARIS - France)
- PASS - Unité Mixte de Service Production et Analyse de données en Sciences de la vie et en Santé (Faculté de Médecine Pitié-Salpetrière
105 Boulevard de l'Hôpital - 75013 PARIS
- France)
- SU - Sorbonne Université : UMS37 (21 rue de l’École de médecine - 75006 Paris - France)
- INSERM - Institut National de la Santé et de la Recherche Médicale : UMS37 (101, rue de Tolbiac, 75013 Paris - France)
5
pRED - Roche Pharma Research and Early Development [Basel] (Headquarter
Grenzacherstrasse 124
CH-4070 Basel - Switzerland)
- F. Hoffmann-La Roche [Basel] (F. Hoffmann-La Roche Ltd. Headquarter Grenzacherstrasse 124 CH-4070 Basel - Switzerland)
6
CERTO - Centre d'Etudes et de Recherche Thérapeutique en Ophtalmologie (Retina France, Orsay - )
7
Department of Ophthalmology [Montreal, QC, Canada] (Montreal, QC H3T 1J4. - Canada)
- University of Montreal [Canada] (Montreal, QC H3T 1J4. - Canada)
- Maisonneuve-Rosemont Hospital Research Centre [Montreal, QC, Canada] (Montreal, QC H3T 1J4. - Canada)
Abstract : A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Here, we examined the mechanisms underlying this susceptibility. We found that monocytes from homozygous carriers of the 10q26 AMD-risk haplotype expressed high amounts of the serine peptidase HTRA1, and HTRA1 located to mononuclear phagocytes (MPs) in eyes of non-carriers with AMD. HTRA1 induced the persistence of monocytes in the subretinal space and exacerbated pathogenic inflammation by hydrolyzing thrombospondin 1 (TSP1), which separated the two CD47-binding sites within TSP1 that are necessary for efficient CD47 activation. This HTRA1-induced inhibition of CD47 signaling induced the expression of pro-inflammatory osteopontin (OPN). OPN expression increased in early monocyte-derived macrophages in 10q26 risk carriers. In models of subretinal inflammation and AMD, OPN deletion or pharmacological inhibition reversed HTRA1-induced pathogenic MP persistence. Our findings argue for the therapeutic potential of CD47 agonists and OPN inhibitors for the treatment of AMD.
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Journal articles
Domain :
Complete list of metadatas
https://www.hal.inserm.fr/inserm-02933674
Contributor : Florian Sennlaub <>
Submitted on : Tuesday, September 8, 2020 - 4:36:04 PM
Last modification on : Thursday, September 10, 2020 - 3:32:36 AM
Contributor : Florian Sennlaub <>
Submitted on : Tuesday, September 8, 2020 - 4:36:04 PM
Last modification on : Thursday, September 10, 2020 - 3:32:36 AM
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Identifiers
- HAL Id : inserm-02933674, version 1
- DOI : 10.1016/j.immuni.2020.07.021
- PUBMED : 32814029
Collections
U968 | CNRS | PASS | PASS-P3S | OMIQUE | SORBONNE-UNIVERSITE | SU-MEDECINE | SU-SCIENCES
Citation
Fanny Beguier, Michael Housset, Christophe Roubeix, Sebastien Augustin, Yvrick Zagar, et al.. The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination. Immunity, 2020, 53 (2), pp.429-441.e8. ⟨10.1016/j.immuni.2020.07.021⟩. ⟨inserm-02933674⟩
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