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

Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism Binding Sites / physiology CD47 Antigen / metabolism COS Cells Cell Line Chlorocebus aethiops Chromosomes, Human, Pair 10 / genetics Eye / pathology Genetic Predisposition to Disease / genetics High-Temperature Requirement A Serine Peptidase 1 / genetics Humans Macrophages / immunology Macular Degeneration / genetics Mice Mice, Inbred C57BL Mice, Knockout Monocytes / metabolism Osteopontin / metabolism Signal Transduction / genetics

10q26 CD47 age-related macular degeneration choroidal neovascularization high-temperature requirement a serine peptidase 1 monocytes mononuclear phagocytes neuro-inflammation osteopontin thrombospondin 1

Journal

Immunity

ISSN: 1097-4180

Titre abrégé: Immunity

Pays: United States

ID NLM: 9432918

Informations de publication

Date de publication:
18 08 2020

Historique:

received: 12 03 2019

revised: 06 03 2020

accepted: 24 07 2020

entrez: 20 8 2020

pubmed: 20 8 2020

medline: 14 4 2021

Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.immuni.2020.07.021 PMID: 32814029

pubmed: 32814029

pii: S1074-7613(20)30328-9

doi: 10.1016/j.immuni.2020.07.021

pii:

doi:

Substances chimiques

Basic Helix-Loop-Helix Leucine Zipper Transcription Factors 0

CD47 Antigen 0

CD47 protein, human 0

SPZ1 protein, human 0

Osteopontin 106441-73-0

High-Temperature Requirement A Serine Peptidase 1 EC 3.4.21.-

HTRA1 protein, human EC 3.4.21.-

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

429-441.e8

Commentaires et corrections

Type : CommentIn

Informations de copyright

Déclaration de conflit d'intérêts

Declaration of Interests The authors declare no competing interests.