Small-Molecule Antagonist of VLA-4 (GW559090) Attenuated Neuro-Inflammation by Targeting Th17 Cell Trafficking across the Blood-Retinal Barrier in Experimental Autoimmune Uveitis
| العنوان: | Small-Molecule Antagonist of VLA-4 (GW559090) Attenuated Neuro-Inflammation by Targeting Th17 Cell Trafficking across the Blood-Retinal Barrier in Experimental Autoimmune Uveitis |
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| المؤلفون: | Malihe Eskandarpour, Yi Hsing Chen, Virginia L. Calder, G. Galatowicz, Xiaozhe Zhang, John Greenwood, Susan Lightman |
| المصدر: | Journal of Neuroinflammation, Vol 18, Iss 1, Pp 1-13 (2021) Journal of Neuroinflammation |
| بيانات النشر: | Research Square Platform LLC, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Leukocyte migration, Endothelium, T cell, Phenylalanine, Experimental autoimmune uveitis, Immunology, Blood–retinal barrier, Mice, Transgenic, Pharmacology, Integrin alpha4beta1, lcsh:RC346-429, Flow cytometry, Autoimmune Diseases, Uveitis, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mice, 0302 clinical medicine, Immune system, Drug Delivery Systems, Piperidines, Blood-Retinal Barrier, medicine, Animals, Humans, Integrin (α4β1, Th17 cells, Cells, Cultured, lcsh:Neurology. Diseases of the nervous system, Inflammatory monocytes/macrophages, medicine.diagnostic_test, Dose-Response Relationship, Drug, business.industry, General Neuroscience, Research, VLA-4), VLA-4, medicine.disease, Mice, Inbred C57BL, medicine.anatomical_structure, Neurology, 030221 ophthalmology & optometry, Female, business, 030217 neurology & neurosurgery |
| الوصف: | 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 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 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+ T cell subsets. Local α4β1 integrin-directed inhibition could be clinically relevant in treating a Th17-dominant form of uveitis. |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::71c36b21dd9b2dbdb62eb1c3a7cf8e9dTest https://doi.org/10.21203/rs.3.rs-65522/v1Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....71c36b21dd9b2dbdb62eb1c3a7cf8e9d |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |