Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy
IntroductionRetinal vascular leakage due to increased endothelial permeability is a major contributor to the pathogenesis of diabetic retinopathy (DR) and visual impairment. Pericyte loss and microglia-mediated inflammation exacerbate this vascular dysfunction. Interleukin-4 (IL-4) is known for its...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2025.1609796/full |
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| author | Jang-Hyuk Yun |
| author_facet | Jang-Hyuk Yun |
| author_sort | Jang-Hyuk Yun |
| collection | DOAJ |
| description | IntroductionRetinal vascular leakage due to increased endothelial permeability is a major contributor to the pathogenesis of diabetic retinopathy (DR) and visual impairment. Pericyte loss and microglia-mediated inflammation exacerbate this vascular dysfunction. Interleukin-4 (IL-4) is known for its anti-inflammatory and tissue-protective properties, but its role in DR remains unclear. MethodsWe evaluated IL-4 expression and signaling in the retinas of streptozotocin-induced diabetic mice. In vitro assays were conducted under high-glucose and TNF-α conditions using retinal endothelial cells, pericytes, and microglia to assess IL-4’s effects on barrier function, cell viability, and inflammatory state. Pathway-specific analyses were performed to investigate PI3K/AKT and STAT6 signaling. ResultsIL-4 expression and downstream signaling were significantly reduced in diabetic retinas. IL-4 promoted pericyte survival via PI3K/AKT activation and modulated microglial functional profiles through STAT6 signaling, favoring an anti-inflammatory phenotype. These effects contributed to restored endothelial barrier integrity and tight junction protein expression under diabetic stress conditions in vitro. ConclusionIL-4 supports retinal vascular stabilization in DR by preserving pericyte viability and modulating microglial activity. These findings highlight IL-4 as a potential therapeutic target for preventing or slowing DR progression and warrant further preclinical investigation. |
| format | Article |
| id | doaj-art-b1d972749ea1417ebd4abdcbbe7a6b4c |
| institution | DOAJ |
| issn | 1664-2392 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
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| series | Frontiers in Endocrinology |
| spelling | doaj-art-b1d972749ea1417ebd4abdcbbe7a6b4c2025-08-20T03:15:13ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922025-07-011610.3389/fendo.2025.16097961609796Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathyJang-Hyuk YunIntroductionRetinal vascular leakage due to increased endothelial permeability is a major contributor to the pathogenesis of diabetic retinopathy (DR) and visual impairment. Pericyte loss and microglia-mediated inflammation exacerbate this vascular dysfunction. Interleukin-4 (IL-4) is known for its anti-inflammatory and tissue-protective properties, but its role in DR remains unclear. MethodsWe evaluated IL-4 expression and signaling in the retinas of streptozotocin-induced diabetic mice. In vitro assays were conducted under high-glucose and TNF-α conditions using retinal endothelial cells, pericytes, and microglia to assess IL-4’s effects on barrier function, cell viability, and inflammatory state. Pathway-specific analyses were performed to investigate PI3K/AKT and STAT6 signaling. ResultsIL-4 expression and downstream signaling were significantly reduced in diabetic retinas. IL-4 promoted pericyte survival via PI3K/AKT activation and modulated microglial functional profiles through STAT6 signaling, favoring an anti-inflammatory phenotype. These effects contributed to restored endothelial barrier integrity and tight junction protein expression under diabetic stress conditions in vitro. ConclusionIL-4 supports retinal vascular stabilization in DR by preserving pericyte viability and modulating microglial activity. These findings highlight IL-4 as a potential therapeutic target for preventing or slowing DR progression and warrant further preclinical investigation. https://www.frontiersin.org/articles/10.3389/fendo.2025.1609796/fullpericytesendothelial permeabilitydiabetic retinopathyinterleukin-4signal transducer and activator of transcription 6microglia functional states |
| spellingShingle | Jang-Hyuk Yun Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy Frontiers in Endocrinology pericytes endothelial permeability diabetic retinopathy interleukin-4 signal transducer and activator of transcription 6 microglia functional states |
| title | Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| title_full | Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| title_fullStr | Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| title_full_unstemmed | Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| title_short | Interleukin-4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| title_sort | interleukin 4 prevents increased endothelial permeability by inducing pericyte survival and modulating microglial responses in diabetic retinopathy |
| topic | pericytes endothelial permeability diabetic retinopathy interleukin-4 signal transducer and activator of transcription 6 microglia functional states |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2025.1609796/full |
| work_keys_str_mv | AT janghyukyun interleukin4preventsincreasedendothelialpermeabilitybyinducingpericytesurvivalandmodulatingmicroglialresponsesindiabeticretinopathy |