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. A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation.

The 10q26 Risk Haplotype of Age-Related Macular Degeneration Aggravates Subretinal Inflammation by Impairing Monocyte Elimination

Eandi C.;
2020

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. A minor haplotype of the 10q26 locus conveys the strongest genetic risk for age-related macular degeneration (AMD). Beguier et al. provide a mechanistic understanding of this susceptibility by linking this risk haplotype to overexpression of the peptidase HTRA1 and thereby to the accumulation of macrophages in the subretinal space and pathogenic inflammation.
53
2
429
441.e8
10q26; age-related macular degeneration; CD47; choroidal neovascularization; high-temperature requirement a serine peptidase 1; monocytes; mononuclear phagocytes; neuro-inflammation; osteopontin; thrombospondin 1
Beguier F.; Housset M.; Roubeix C.; Augustin S.; Zagar Y.; Nous C.; Mathis T.; Eandi C.; Benchaboune M.; Drame-Maigne 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.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1753357
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