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Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction
PURPOSE: Inflammation triggers the activation of CD4(+)T cells and the breakdown of blood–retinal barrier, thus contributing to the pathology of experimental autoimmune uveitis (EAU). We explored the anti-inflammatory effect of hydroxychloroquine (HCQ) on EAU and the potential mechanisms active in T...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989724/ https://www.ncbi.nlm.nih.gov/pubmed/35401507 http://dx.doi.org/10.3389/fimmu.2022.859260 |
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author | Hu, Yunwei Li, Zuoyi Chen, Guanyu Li, Zhuang Huang, Jun Huang, Haixiang Xie, Yanyan Chen, Qian Zhu, Wenjie Wang, Minzhen Chen, Jianping Su, Wenru Chen, Xiaoqing Liang, Dan |
author_facet | Hu, Yunwei Li, Zuoyi Chen, Guanyu Li, Zhuang Huang, Jun Huang, Haixiang Xie, Yanyan Chen, Qian Zhu, Wenjie Wang, Minzhen Chen, Jianping Su, Wenru Chen, Xiaoqing Liang, Dan |
author_sort | Hu, Yunwei |
collection | PubMed |
description | PURPOSE: Inflammation triggers the activation of CD4(+)T cells and the breakdown of blood–retinal barrier, thus contributing to the pathology of experimental autoimmune uveitis (EAU). We explored the anti-inflammatory effect of hydroxychloroquine (HCQ) on EAU and the potential mechanisms active in T cells and retinal vascular endothelial cells (RVECs). METHODS: C57BL/6J mice were immunized with interphotoreceptor retinoid binding protein 1-20 (IRBP(1–20)) to induce EAU and then treated with the vehicle or HCQ (100 mg/kg/day). On day 7, 14, 21, 30 and 60 after immunization, clinical scores were evaluated. On day 14, histopathological scores were assessed, and retinas, spleens, and lymph nodes were collected for quantitative polymerase chain reaction or flow cytometry analysis. RVEC dysfunction was induced by tumor necrosis factor α (TNF-α) stimulation. The expression of cytokines, chemokines, adhesion molecules, and lectin-like oxidized LDL receptor-1 (LOX-1)/nuclear factor κB (NF-κB) was measured in RVECs with or without HCQ. RESULTS: HCQ treatment protected mice from uveitis, evidenced by reduced expression of inflammatory factors, chemokines, and adhesion molecules in the retina. In systemic immune response, HCQ inhibited the activation of naïve CD4(+)T cells and frequencies of T effector cells, and promoted T regulatory cells. HCQ decreased IRBP(1-20)–specific T cell responses and proliferation of CD4(+)T cells in vitro. Further studies established that TNF-α induced RVECs to express inflammatory cytokines, chemokines, and adhesion molecules, whereas HCQ alleviated the alterations via the LOX-1/NF-κB pathways. CONCLUSIONS: HCQ alleviates EAU by regulating the Teff/Treg balance and ameliorating RVECs dysfunction via the LOX-1/NF-κB axis. HCQ may be a promising therapeutic candidate for uveitis. |
format | Online Article Text |
id | pubmed-8989724 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89897242022-04-09 Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction Hu, Yunwei Li, Zuoyi Chen, Guanyu Li, Zhuang Huang, Jun Huang, Haixiang Xie, Yanyan Chen, Qian Zhu, Wenjie Wang, Minzhen Chen, Jianping Su, Wenru Chen, Xiaoqing Liang, Dan Front Immunol Immunology PURPOSE: Inflammation triggers the activation of CD4(+)T cells and the breakdown of blood–retinal barrier, thus contributing to the pathology of experimental autoimmune uveitis (EAU). We explored the anti-inflammatory effect of hydroxychloroquine (HCQ) on EAU and the potential mechanisms active in T cells and retinal vascular endothelial cells (RVECs). METHODS: C57BL/6J mice were immunized with interphotoreceptor retinoid binding protein 1-20 (IRBP(1–20)) to induce EAU and then treated with the vehicle or HCQ (100 mg/kg/day). On day 7, 14, 21, 30 and 60 after immunization, clinical scores were evaluated. On day 14, histopathological scores were assessed, and retinas, spleens, and lymph nodes were collected for quantitative polymerase chain reaction or flow cytometry analysis. RVEC dysfunction was induced by tumor necrosis factor α (TNF-α) stimulation. The expression of cytokines, chemokines, adhesion molecules, and lectin-like oxidized LDL receptor-1 (LOX-1)/nuclear factor κB (NF-κB) was measured in RVECs with or without HCQ. RESULTS: HCQ treatment protected mice from uveitis, evidenced by reduced expression of inflammatory factors, chemokines, and adhesion molecules in the retina. In systemic immune response, HCQ inhibited the activation of naïve CD4(+)T cells and frequencies of T effector cells, and promoted T regulatory cells. HCQ decreased IRBP(1-20)–specific T cell responses and proliferation of CD4(+)T cells in vitro. Further studies established that TNF-α induced RVECs to express inflammatory cytokines, chemokines, and adhesion molecules, whereas HCQ alleviated the alterations via the LOX-1/NF-κB pathways. CONCLUSIONS: HCQ alleviates EAU by regulating the Teff/Treg balance and ameliorating RVECs dysfunction via the LOX-1/NF-κB axis. HCQ may be a promising therapeutic candidate for uveitis. Frontiers Media S.A. 2022-03-25 /pmc/articles/PMC8989724/ /pubmed/35401507 http://dx.doi.org/10.3389/fimmu.2022.859260 Text en Copyright © 2022 Hu, Li, Chen, Li, Huang, Huang, Xie, Chen, Zhu, Wang, Chen, Su, Chen and Liang https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Immunology Hu, Yunwei Li, Zuoyi Chen, Guanyu Li, Zhuang Huang, Jun Huang, Haixiang Xie, Yanyan Chen, Qian Zhu, Wenjie Wang, Minzhen Chen, Jianping Su, Wenru Chen, Xiaoqing Liang, Dan Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title | Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title_full | Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title_fullStr | Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title_full_unstemmed | Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title_short | Hydroxychloroquine Alleviates EAU by Inhibiting Uveitogenic T Cells and Ameliorating Retinal Vascular Endothelial Cells Dysfunction |
title_sort | hydroxychloroquine alleviates eau by inhibiting uveitogenic t cells and ameliorating retinal vascular endothelial cells dysfunction |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8989724/ https://www.ncbi.nlm.nih.gov/pubmed/35401507 http://dx.doi.org/10.3389/fimmu.2022.859260 |
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