Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis.
Animals
Autoimmune Diseases
/ drug therapy
Blood-Retinal Barrier
/ drug effects
Cells, Cultured
Dose-Response Relationship, Drug
Drug Delivery Systems
/ methods
Female
Humans
Integrin alpha4beta1
/ antagonists & inhibitors
Mice
Mice, Inbred C57BL
Mice, Transgenic
Phenylalanine
/ administration & dosage
Piperidines
/ administration & dosage
Th17 Cells
/ drug effects
Uveitis
/ drug therapy
Experimental autoimmune uveitis
Inflammatory monocytes/macrophages
Integrin (α4β1
Leukocyte migration
Th17 cells
Uveitis
VLA-4)
Journal
Journal of neuroinflammation
ISSN: 1742-2094
Titre abrégé: J Neuroinflammation
Pays: England
ID NLM: 101222974
Informations de publication
Date de publication:
18 Feb 2021
18 Feb 2021
Historique:
received:
20
09
2020
accepted:
11
01
2021
entrez:
19
2
2021
pubmed:
20
2
2021
medline:
28
10
2021
Statut:
epublish
Résumé
The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets. Mice (female; B10.RIII or C57Bl/6; aged 6-8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4 There was a significant reduction in clinical and histological scores in GW This α4β1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4
Sections du résumé
BACKGROUND
BACKGROUND
The integrin VLA-4 (α4β1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical α4β1 integrin inhibitor (GW559090, GW) in a mouse model for non-infectious posterior uveitis (experimental autoimmune uveitis; EAU) and its effect on intraocular leukocyte subsets.
METHODS
METHODS
Mice (female; B10.RIII or C57Bl/6; aged 6-8 weeks) were immunized with specific interphotoreceptor retinoid-binding protein (IRBP) peptides to induce EAU. Topically administered GW (3, 10, and 30 mg/ml) were given twice daily either therapeutically once disease was evident, or prophylactically, and compared with vehicle-treated (Veh) and 0.1% dexamethasone-treated (Dex) controls. Mice were sacrificed at peak disease. The retinal T cell subsets were investigated by immunohistochemistry and immunofluorescence staining. The immune cells within the retina, blood, and draining lymph nodes (dLNs) were phenotyped by flow cytometry. The effect of GW559090 on non-adherent, adherent, and migrated CD4
RESULTS
RESULTS
There was a significant reduction in clinical and histological scores in GW
CONCLUSIONS
CONCLUSIONS
This α4β1 integrin inhibitor may exert a modulatory effect in EAU progression by selectively blocking Th17 cell migration across the blood-retinal barrier without affecting systemic CD4
Identifiants
pubmed: 33602234
doi: 10.1186/s12974-021-02080-8
pii: 10.1186/s12974-021-02080-8
pmc: PMC7893745
doi:
Substances chimiques
GW559090
0
Integrin alpha4beta1
0
Piperidines
0
Phenylalanine
47E5O17Y3R
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
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