The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination
Open accessAbstract
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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The minor haplotype of chromosome10q26, a strong risk factor for age-related macular degeneration, results in inhibition of CD47-signalling leading to chronic subretinal inflammation.
“Indicative of the importance of this immunosuppressor function is the recent proof that the minor haplotype of chromosome10q26, a strong risk factor for the development of age-related macular degeneration (AMD), results in inhibition of CD47-signalling leading to chronic subretinal inflammation [63].”
From Risk mitigation of immunogenicity: a key to personalized retinal gene therapy (2021) · cites this paper as [63]
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References 66 · Cited by 87
- Authors
- Beguier, F., Housset, M., Roubeix, C., Augustin, S., Zagar, Y., Nous, C., Mathis, T., Eandi, C., Benchaboune, M., Drame-Maigné, A., Carpentier, W., Chardonnet, S., Touhami, S., Blot, G., Conart, J. B., Charles-Messance, H., Potey, A., Girmens, J.-F., Paques, M., Blond, F., Leveillard, T., Koertvely, E., Roger, J. E., Sahel, J.-A., Sapieha, P., Delarasse, C., Guillonneau, X., & Sennlaub, F.
- Affiliations
- Centre National de la Recherche Scientifique (FR)
- University of Turin (IT)
- Inserm (FR)
- Hôpital Maisonneuve-Rosemont (CA)
- Corresponding author
- Sennlaub, Florian
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2020-08
- Volume
- 53
- Issue
- 2
- Pages
- 429-441.e8
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W3067969185
- Cited by
- 87
- References
- 66
- Citations by year
- 2026: 6 · 2025: 6 · 2024: 21 · 2023: 12 · 2022: 19 · 2021: 20 · 2020: 3
- FWCI
- 10.71
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 383 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion)
- Funders
- Agence Nationale de la Recherche (ANR-10-LABX-65, ANR-15-CE14-0015-01, ANR-18-IAHU-0001)
- Institut Carnot Santé Animale
- Institut National de la Santé et de la Recherche Médicale
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Health Sciences › Medicine › Ophthalmology › Ocular Diseases and Behçet’s Syndrome
- Keywords
- age-related macular degeneration, HTRA1, thrombospondin-1, osteopontin, monocyte-derived macrophages, genetic susceptibility
- MeSH terms
- High-Temperature Requirement A Serine Peptidase 1, Animals, Binding Sites, Cell Line, Chlorocebus aethiops, Chromosomes, Human, Pair 10, Eye, Humans, Macrophages, Macular Degeneration, Mice, Inbred C57BL, Monocytes, Signal Transduction, Mice, Knockout, COS Cells, Genetic Predisposition to Disease, Mice, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, CD47 Antigen, Osteopontin
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