IL-17A 通过 Act1/TRAF6/NF-κB 通路增强青光眼的炎症反应

IF 4.4 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY Neurochemistry international Pub Date : 2024-06-01 DOI:10.1016/j.neuint.2024.105787

Yunfan Zheng , Zhenni Mou , Sisi Tan, Xiaochen Wang, Jingchang Yuan, Hong Li

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引用次数: 0

摘要

目的研究白细胞介素17A（IL-17A）和IL-17A中和抗体（IL-17Ab）在青光眼中的可能作用及其潜在机制。方法建立了两种青光眼动物模型，即慢性眼压过高（COH）和N-甲基-D-天冬氨酸（NMDA）诱导的视网膜神经节细胞（RGC）损伤，并用IL-17A或IL-17Ab进行玻璃体内注射治疗。用回弹式眼压计测量眼压（IOP）。视网膜和RGC损伤通过HE染色、TUNLE检测和Brn3a免疫荧光染色进行评估。流式细胞术检测了外周血中IL-17A+CD4+T细胞的频率。通过免疫荧光染色、Western Blot 和 qPCR 检测视网膜中神经胶质纤维酸性蛋白（GFAP）的表达。通过 Western Blot 和 qPCR 检测视网膜中 Act1/TRAF6/NF-κB 的 RNA 和蛋白表达。静脉注射IL-17A后，视网膜中RGC数量减少，RGC凋亡增加，Müller细胞胶质病变更加明显。此外，外周炎症加剧。而玻璃体内注射IL-17Ab可减轻相关表现和外周炎症，减轻Müller细胞的胶质增生。在 COH 模型中，注射 IL-17A 后眼压升高，而玻璃体内注射 IL-17Ab 则使眼压降低。此外，IL-17A通过与IL-17A受体结合，激活Act1/TRAF6/NF-κB通路，促进RGC的凋亡。IL-17Ab能中和IL-17A的促炎作用，对青光眼有保护作用。这些发现揭示了IL-17A在青光眼发病机制中的重要作用，为青光眼的预防和治疗指明了新的方向，也为其他视网膜疾病的进一步研究提供了参考。

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IL-17A enhances the inflammatory response of glaucoma through Act1/TRAF6/NF-κB pathway

Objectives

To investigate the possible roles of Interleukin 17A (IL-17A) and IL-17A neutralizing antibodies (IL-17Ab) in glaucoma and the potential mechanisms.

Methods

The two glaucoma animal models, chronic ocular hypertension (COH) and N-methyl-D-aspartate (NMDA)-induced retinal ganglion cell (RGC) damage, were established and treated with intravitreal injection of IL-17A or IL-17Ab. Intraocular pressure (IOP) was measured by a rebound tonometer. The retina and RGC injury were evaluated by HE staining, TUNLE assay and Brn3a immunofluorescence staining. The frequency of IL-17A⁺CD4⁺T cells in peripheral blood was detected by flow cytometry. The expression of glial fibrillary acidic protein (GFAP) was detected by immunofluorescence staining, Western Blot and qPCR in retina. The RNA and protein expression of Act1/TRAF6/NF-κB were detected by Western Blot and qPCR in retina.

Results

The expression of IL-17A increased in glaucoma models. After intravitreal injection of IL-17A, in the retina, the number of RGCs decreased, the apoptosis of RGCs increased, the Müller cell gliosis was more obvious. In addition, peripheral inflammation aggravated. Whereas the intravitreal injection of IL-17Ab alleviated the relevant manifestations and peripheral inflammation, reduced the gliosis of Müller cells. In the COH model, IOP increased after the injection of IL-17A, while the intravitreal injection of IL-17Ab led to a decrease in IOP. Furthermore, IL-17A promotes the apoptosis of RGCs by binding to IL-17A receptor, activating Act1/TRAF6/NF-κB pathways.

Conclusion

IL-17A plays a role in and aggravates RGC damage in glaucoma. IL-17Ab can neutralize the pro-inflammatory effect of IL-17A and have a protective function in glaucoma. These findings reveal the importance of IL-17A in the pathogenesis of glaucoma, which will shed light on a novel direction for the prevention and treatment of glaucoma, and also provide a reference for further research on other retinal diseases.

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来源期刊

Neurochemistry international 医学-神经科学

CiteScore

8.40

自引率

2.40%

发文量

128

审稿时长

37 days

期刊介绍： Neurochemistry International is devoted to the rapid publication of outstanding original articles and timely reviews in neurochemistry. Manuscripts on a broad range of topics will be considered, including molecular and cellular neurochemistry, neuropharmacology and genetic aspects of CNS function, neuroimmunology, metabolism as well as the neurochemistry of neurological and psychiatric disorders of the CNS.