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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
1 Institut de la Vision
2 UNITO - Università degli studi di Torino
3 Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts
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
5 pRED - Roche Pharma Research and Early Development [Basel]
6 CERTO - Centre d'Etudes et de Recherche Thérapeutique en Ophtalmologie
7 Department of Ophthalmology [Montreal, QC, 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.
Keywords : 10q26 CD47 age-related macular degeneration choroidal neovascularization high-temperature requirement a serine peptidase 1 monocytes mononuclear phagocytes neuro-inflammation osteopontin thrombospondin 1
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https://www.hal.inserm.fr/inserm-02933674
Contributor : Florian Sennlaub <>
Submitted on : Tuesday, September 8, 2020 - 4:36:04 PM
Last modification on : Thursday, February 18, 2021 - 10:42:07 AM
Long-term archiving on: : Saturday, December 5, 2020 - 12:22:12 AM

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INSERM | U968 | CNRS | PASS | PASS-P3S | SORBONNE-UNIVERSITE | SU-MEDECINE | SU-TI

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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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