Experimental Autoimmune Neuritis Nerve Demyelination Is Attenuated by Blocking JAK2/STAT3 Signaling Pathway in Rats

IF 2.6 3区心理学 Q2 BEHAVIORAL SCIENCES

Brain and Behavior Pub Date : 2025-05-18 DOI:10.1002/brb3.70566

Rumeng Zhou, Shuping Liu, Yue Liu, Yin Liu, Rong Fu, Jiajia Yao, Zuneng Lu

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引用次数: 0

Abstract

Background

Guillain‒Barré syndrome (GBS) is an immune-mediated peripheral neuropathy in which inflammatory cells and cytokines participate. The JAK-STAT signaling pathway is a major pathway involved in cytokine signal transduction, but the role of this pathway in GBS is not clear. AG490 is a tyrosine kinase inhibitor that specifically inhibits JAK2 activity and downregulates STAT3 phosphorylation. The aim of this study was to investigate the function of the JAK2/STAT3 pathway in a rat model of experimental autoimmune neuritis (EAN).

Methods

Lewis rats were divided into three groups: the control, the EAN, and the AG490 groups. The EAN and AG490 groups were immunized with P2 peptide to create the EAN models, while the control group received an equal volume of vehicle solution without P2 peptide. Starting from Day 5 post-immunization (PI), the AG490 group was administered AG490 (10 mg/kg) every other day, while the control and EAN groups received an equal volume of vehicle solution without AG490. All rats were weighed and evaluated according to the EAN function score (1–10) by two investigators. Rats were sacrificed on Day 16 PI, and the sciatic nerves were examined by light microscopy, indirect immunohistochemistry, and western blotting.

Results

AG490-treated rats had improved clinical scores compared with those of EAN rats. Hematoxylin and eosin (H&E) and CD45 staining showed significant inflammatory infiltration of the sciatic nerve in the EAN group compared with the control group, and demonstrated reduced inflammatory infiltration in the AG490 group. Luxol fast blue (LFB) staining showed a reduction of myelin loss in the AG490 group compared with the EAN group. The levels of TGF-β1, IFN-γ, and IL-6 increased in the EAN group and showed a significant decrease in rats treated with AG490. The JAK2-STAT3 signaling pathway was activated in EAN rats, and the AG490 group showed decreased expression levels of JAK2, p-JAK2, and p-STAT3 compared with those of the EAN group. Immunofluorescence also showed a decrease in the levels of p-JAK2 and p-STAT3 in the sciatic nerve of EAN rats.

Conclusions

The JAK2/STAT3 signaling pathway is involved in the pathogenesis of EAN, and inhibition of this pathway can reduce the inflammatory response in EAN rats. Despite the limitations in extrapolating EAN findings to human GBS, this study provided new insights into the pathogenesis and potential therapeutic targets of human GBS.

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阻断JAK2/STAT3信号通路可减轻实验性自身免疫性神经炎大鼠神经脱髓鞘

吉兰-巴罗综合征（GBS）是一种炎症细胞和细胞因子参与的免疫介导的周围神经病变。JAK-STAT信号通路是参与细胞因子信号转导的主要通路，但该通路在GBS中的作用尚不清楚。AG490是一种酪氨酸激酶抑制剂，特异性抑制JAK2活性并下调STAT3磷酸化。本研究的目的是研究JAK2/STAT3通路在实验性自身免疫性神经炎（EAN）大鼠模型中的功能。方法将Lewis大鼠分为对照组、EAN组和AG490组。EAN组和AG490组分别用P2肽免疫建立EAN模型，对照组给予等量不含P2肽的载药液。从免疫后第5天（PI）开始，AG490组每隔一天给予AG490 (10 mg/kg)，对照组和EAN组给予等量不加AG490的载药液。所有大鼠均由两名调查员称重并根据EAN功能评分（1-10）进行评估。第16天处死大鼠，采用光镜、间接免疫组化、western blotting检查坐骨神经。结果与EAN大鼠相比，ag490治疗大鼠的临床评分明显提高。苏木精、伊红（H&；E）和CD45染色显示EAN组与对照组相比，坐骨神经有明显的炎症浸润，AG490组炎症浸润减少。Luxol快速蓝（LFB）染色显示，与EAN组相比，AG490组髓磷脂损失减少。EAN组TGF-β1、IFN-γ、IL-6水平升高，AG490组显著降低。EAN大鼠JAK2- stat3信号通路被激活，与EAN组相比，AG490组JAK2、p-JAK2和p-STAT3的表达水平下降。免疫荧光也显示EAN大鼠坐骨神经中p-JAK2和p-STAT3水平降低。结论JAK2/STAT3信号通路参与了EAN的发病过程，抑制该通路可减轻EAN大鼠的炎症反应。尽管将EAN研究结果外推到人类GBS存在局限性，但本研究为人类GBS的发病机制和潜在治疗靶点提供了新的见解。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Brain and Behavior BEHAVIORAL SCIENCES-NEUROSCIENCES

CiteScore

5.30

自引率

0.00%

发文量

352

审稿时长

14 weeks

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