GAS6 as a potential target to alleviate neuroinflammation during Japanese encephalitis in mouse models

IF 9.3 1区医学 Q1 IMMUNOLOGY

Journal of Neuroinflammation Pub Date : 2024-09-19 DOI:10.1186/s12974-024-03225-1

Peiyu Bian, Haijun Zhang, Chuantao Ye, Chuanyu Luo, Hong Jiang, Yuan Wang, Yangchao Dong, Jing Yang, Fanglin Zhang, Xiaoming Wang, Ying Zhang, Zhansheng Jia, Yingfeng Lei

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Abstract

Viral encephalitis is characterized by inflammation of the brain parenchyma caused by a variety of viruses, among which the Japanese encephalitis (JE) virus (JEV) is a typical representative arbovirus. Neuronal death, neuroinflammation, and breakdown of the blood brain barrier (BBB) constitute vicious circles of JE progression. Currently, there is no effective therapy to prevent this damage. Growth arrest specific gene 6 (GAS6) is a secreted growth factor that binds to the TYRO3, AXL, and MERTK (TAM) family of receptor tyrosine kinases and has been demonstrated to participate in neuroprotection and suppression of inflammation in many central nervous system (CNS) diseases which has great potential for JE intervention. In this study, we found that GAS6 expression in the brain was decreased and was reversely correlated with viral load and neuronal loss. Mice with GAS6/TAM signalling deficiency showed higher mortality and accelerated neuroinflammation during peripheral JEV infection, accompanied by BBB breakdown. GAS6 directly promoted the expression of tight junction proteins in bEnd.3 cells and strengthened BBB integrity, partly via AXL. Mice administered GAS6 were more resistant to JEV infection due to increased BBB integrity, as well as decreased viral load and neuroinflammation. Thus, targeted GAS6 delivery may represent a strategy for the prevention and treatment of JE especially in patients with impaired BBB.

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在小鼠模型中将 GAS6 作为缓解日本脑炎期间神经炎症的潜在靶点

病毒性脑炎的特征是由多种病毒引起的脑实质炎症，其中日本脑炎病毒（JEV）是典型的虫媒病毒代表。神经元死亡、神经炎症和血脑屏障（BBB）破坏构成了日本脑炎发展的恶性循环。目前，还没有有效的疗法来预防这种损害。生长停滞特异性基因6（GAS6）是一种分泌型生长因子，可与TYRO3、AXL和MERTK（TAM）家族受体酪氨酸激酶结合，已被证实可参与多种中枢神经系统（CNS）疾病的神经保护和炎症抑制，在JE干预方面具有巨大潜力。在这项研究中，我们发现 GAS6 在大脑中的表达量减少，并且与病毒载量和神经元损失成反比。GAS6/TAM信号缺乏的小鼠在外周JEV感染过程中死亡率更高，神经炎症加速，同时伴有BBB破坏。GAS6直接促进了bEnd.3细胞中紧密连接蛋白的表达，并部分通过AXL加强了BBB的完整性。施用 GAS6 的小鼠对 JEV 感染的抵抗力更强，这是因为 BBB 的完整性提高了，病毒载量和神经炎症也减少了。因此，靶向输送 GAS6 可能是预防和治疗 JE 的一种策略，尤其是在 BBB 受损的患者中。

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

Journal of Neuroinflammation 医学-神经科学

CiteScore

15.90

自引率

3.20%

发文量

276

审稿时长

1 months

期刊介绍： The Journal of Neuroinflammation is a peer-reviewed, open access publication that emphasizes the interaction between the immune system, particularly the innate immune system, and the nervous system. It covers various aspects, including the involvement of CNS immune mediators like microglia and astrocytes, the cytokines and chemokines they produce, and the influence of peripheral neuro-immune interactions, T cells, monocytes, complement proteins, acute phase proteins, oxidative injury, and related molecular processes. Neuroinflammation is a rapidly expanding field that has significantly enhanced our knowledge of chronic neurological diseases. It attracts researchers from diverse disciplines such as pathology, biochemistry, molecular biology, genetics, clinical medicine, and epidemiology. Substantial contributions to this field have been made through studies involving populations, patients, postmortem tissues, animal models, and in vitro systems. The Journal of Neuroinflammation consolidates research that centers around common pathogenic processes. It serves as a platform for integrative reviews and commentaries in this field.