IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy
Abstract Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2021-11-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-021-04350-y |
| _version_ | 1818916299270520832 |
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| author | Ao-Wang Qiu Da-Rui Huang Bin Li Yuan Fang Wei-Wei Zhang Qing-Huai Liu |
| author_facet | Ao-Wang Qiu Da-Rui Huang Bin Li Yuan Fang Wei-Wei Zhang Qing-Huai Liu |
| author_sort | Ao-Wang Qiu |
| collection | DOAJ |
| description | Abstract Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression. |
| first_indexed | 2024-12-20T00:15:58Z |
| format | Article |
| id | doaj.art-f4e2e18bcf584abb8e8bff654c18014f |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-12-20T00:15:58Z |
| publishDate | 2021-11-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-f4e2e18bcf584abb8e8bff654c18014f2022-12-21T20:00:22ZengNature Publishing GroupCell Death and Disease2041-48892021-11-01121111010.1038/s41419-021-04350-yIL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathyAo-Wang Qiu0Da-Rui Huang1Bin Li2Yuan Fang3Wei-Wei Zhang4Qing-Huai Liu5Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical UniversityWomen & Children Central Laboratory, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical UniversityDepartment of Ophthalmology, The First Affiliated Hospital of Nanjing Medical UniversityAbstract Diabetic retinopathy (DR), the most common and serious ocular complication, recently has been perceived as a neurovascular inflammatory disease. However, role of adaptive immune inflammation driven by T lymphocytes in DR is not yet well elucidated. Therefore, this study aimed to clarify the role of interleukin (IL)-17A, a proinflammatory cytokine mainly produced by T lymphocytes, in retinal pathophysiology particularly in retinal neuronal death during DR process. Ins2Akita (Akita) diabetic mice 12 weeks after the onset of diabetes were used as a DR model. IL-17A-deficient diabetic mice were obtained by hybridization of IL-17A-knockout (IL-17A-KO) mouse with Akita mouse. Primarily cultured retinal Müller cells (RMCs) and retinal ganglion cells (RGCs) were treated with IL-17A in high-glucose (HG) condition. A transwell coculture of RGCs and RMCs whose IL-17 receptor A (IL-17RA) gene had been silenced with IL-17RA-shRNA was exposed to IL-17A in HG condition and the cocultured RGCs were assessed on their survival. Diabetic mice manifested increased retinal microvascular lesions, RMC activation and dysfunction, as well as RGC apoptosis. IL-17A-KO diabetic mice showed reduced retinal microvascular impairments, RMC abnormalities, and RGC apoptosis compared with diabetic mice. RMCs expressed IL-17RA. IL-17A exacerbated HG-induced RMC activation and dysfunction in vitro and silencing IL-17RA gene in RMCs abolished the IL-17A deleterious effects. In contrast, RGCs did not express IL-17RA and IL-17A did not further alter HG-induced RGC death. Notably, IL-17A aggravated HG-induced RGC death in the presence of intact RMCs but not in the presence of RMCs in which IL-17RA gene had been knocked down. These findings establish that IL-17A is actively involved in DR pathophysiology and particularly by RMC mediation it promotes RGC death. Collectively, we propose that antagonizing IL-17RA on RMCs may prevent retinal neuronal death and thereby slow down DR progression.https://doi.org/10.1038/s41419-021-04350-y |
| spellingShingle | Ao-Wang Qiu Da-Rui Huang Bin Li Yuan Fang Wei-Wei Zhang Qing-Huai Liu IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy Cell Death and Disease |
| title | IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy |
| title_full | IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy |
| title_fullStr | IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy |
| title_full_unstemmed | IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy |
| title_short | IL-17A injury to retinal ganglion cells is mediated by retinal Müller cells in diabetic retinopathy |
| title_sort | il 17a injury to retinal ganglion cells is mediated by retinal muller cells in diabetic retinopathy |
| url | https://doi.org/10.1038/s41419-021-04350-y |
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