Small-molecule antagonist of VLA-4 (GW559090) attenuated neuro-inflammation by targeting Th17 cell trafficking across the blood-retinal barrier in experimental autoimmune uveitis.

ABSTRACT:

Background

The integrin VLA-4 (?4?1) plays an important role in leukocyte trafficking. This study investigated the efficacy of a novel topical ?4?1 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

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⁺ T cell subsets across a central nervous system (CNS) endothelium was further assayed in vitro and quantitated by flow cytometry.

Results

There was a significant reduction in clinical and histological scores in GW₁₀- and Dex-treated groups as compared to controls either administered therapeutically or prophylactically. There were fewer CD45⁺ leukocytes infiltrating the retinae and vitreous fluids in the treated GW₁₀ group (P < 0.05). Immunofluorescence staining and flow cytometry data identified decreased levels of retinal Th17 cells (P ? 0.001) in the GW₁₀-treated eyes, leaving systemic T cell subsets unaffected. In addition, fewer Ly6C⁺ inflammatory monocyte/macrophages (P = 0.002) and dendritic cells (P = 0.017) crossed the BRB following GW₁₀ treatment. In vitro migration assays confirmed that Th17 cells were selectively suppressed by GW559090 in adhering to endothelial monolayers.

Conclusions

This ?4?1 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⁺ T cell subsets. Local ?4?1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis.

SUBMITTER: Chen YH 

PROVIDER: S-EPMC7893745 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature