Granzyme B degrades extracellular matrix and promotes inflammation and choroidal neovascularization.
Age-related macular degeneration
Angiogenesis
Choroidal neovascularization
Extracellular matrix
Granzyme B
Inflammation
Mast cell
Journal
Angiogenesis
ISSN: 1573-7209
Titre abrégé: Angiogenesis
Pays: Germany
ID NLM: 9814575
Informations de publication
Date de publication:
18 Mar 2024
18 Mar 2024
Historique:
received:
25
09
2023
accepted:
11
02
2024
medline:
19
3
2024
pubmed:
19
3
2024
entrez:
18
3
2024
Statut:
aheadofprint
Résumé
Age-related macular degeneration (AMD) is a common retinal neurodegenerative disease among the elderly. Neovascular AMD (nAMD), a leading cause of AMD-related blindness, involves choroidal neovascularization (CNV), which can be suppressed by anti-angiogenic treatments. However, current CNV treatments do not work in all nAMD patients. Here we investigate a novel target for AMD. Granzyme B (GzmB) is a serine protease that promotes aging, chronic inflammation and vascular permeability through the degradation of the extracellular matrix (ECM) and tight junctions. Extracellular GzmB is increased in retina pigment epithelium (RPE) and mast cells in the choroid of the healthy aging outer retina. It is further increased in donor eyes exhibiting features of nAMD and CNV. Here, we show in RPE-choroidal explant cultures that exogenous GzmB degrades the RPE-choroid ECM, promotes retinal/choroidal inflammation and angiogenesis while diminishing anti-angiogenic factor, thrombospondin-1 (TSP-1). The pharmacological inhibition of either GzmB or mast-cell degranulation significantly reduces choroidal angiogenesis. In line with our in vitro data, GzmB-deficiency reduces the extent of laser-induced CNV lesions and the age-related deterioration of electroretinogram (ERG) responses in mice. These findings suggest that targeting GzmB, a serine protease with no known endogenous inhibitors, may be a potential novel therapeutic approach to suppress CNV in nAMD.
Identifiants
pubmed: 38498232
doi: 10.1007/s10456-024-09909-9
pii: 10.1007/s10456-024-09909-9
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIH HHS
ID : S10RR024585
Pays : United States
Organisme : NIH HHS
ID : S10RR024585
Pays : United States
Informations de copyright
© 2024. The Author(s).
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