中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (12): 2453-2464.doi: 10.4103/1673-5374.313049

• 原著:退行性病与再生 • 上一篇    下一篇

SOCS1/JAK2/STAT3轴可通过诱导炎症反应参与蛛网膜下腔出血后的早期脑损伤

  

  • 出版日期:2021-12-15 发布日期:2021-05-15
  • 基金资助:

    国家自然科学基金项目（81500375）；中央高校基本科研业务费专项资金（WK91100000112）；安徽省自然科学基金（1508085QH184）；山东省自然科学基金（ZR1015HQ001）

SOCS1/JAK2/STAT3 axis regulates early brain injury induced by subarachnoid hemorrhage via inflammatory responses

Yang Wang1, #, Xiang-Qian Kong2, 3, #, Fei Wu1, #, Bin Xu4, De-Jun Bao1, Chuan-Dong Cheng1, Xiang-Ping Wei1, Yong-Fei Dong1, *, Chao-Shi Niu1, 5, *   

  1. 1Department of Neurosurgery, First Affiliated Hospital of University of Science and Technology of China, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui Province, China; 2Department of Vascular Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong Province, China; 3Department of Vascular Surgery, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province, China; 4Anhui Medical College, Anhui Provincial Medical Genetics Center, Hefei, Anhui Province, China; 5Anhui Province Key Laboratory of Brain Function and Brain Disease, Hefei, Anhui Province, China
  • Online:2021-12-15 Published:2021-05-15
  • Contact: Yong-Fei Dong, MD, dyf.w@163.com; Chao-Shi Niu, PhD, ah_neurosurgery@163.com.
  • Supported by:
    This study was supported by the National Natural Science Foundation of China, No. 81500375 (to XQK); the Fundamental Research Funds for the Central Universities, No. WK9110000112 (to YW); the Anhui Provincial Natural Science Foundation of China, No. 1508085QH184 (to YW); and Shandong Provincial Natural Science Foundation of China, No. ZR2015HQ001 (to XQK).

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摘要：

SOCS1/JAK2/STAT3轴与肿瘤的生长进展密切相关，并在多种疾病中参与炎症细胞因子的分泌，但在蛛网膜下腔出血中SOCS1/JAK2/STAT3轴的作用尚待研究。实验首先将自体血注入视交叉池建立蛛网膜下腔出血大鼠模型，并以小干扰JAK2/STAT3 RNA与过表达JAK2/STAT3进行干预。结果发现①蛛网膜下腔出血模型大鼠脑组织中JAK2、STAT3表达上调，SOCS1表达下调，并在蛛网膜下腔出血诱导后48h达到峰值；同时JAK2和SOCS1的相互作用减弱，而JAK2和STAT3的相互作用增强；②Si-JAK2和Si-STAT3可缓解蛛网膜下腔出血后皮质神经元细胞凋亡和坏死、血脑屏障破坏、脑水肿以及认知功能障碍，同时下调JAK2，STAT3的磷酸化水平和总水平，并上调SOCS1水平，而Over-JAK2和Over-STAT3则能产生相反的效果，两者均能加重蛛网膜下腔出血引起的早期脑损伤；③Si-JAK2和Si-STAT3还可抑制M1型小胶质细胞转化和促炎因子(诱导型一氧化氮合酶、白细胞介素1β、肿瘤坏死因子α)的释放，同时也增加抗炎因子(精氨酸酶1、白细胞介素10、白细胞介素4)的释放；④然后以氧血红蛋白刺激的原代神经元模拟体外蛛网膜下腔出血，并以JAK2抑制剂AG490进行干预，结果同样验证了抑制JAK2和STAT3表达介导的神经元保护作用；⑤表明SOCS1/JAK2/STAT3轴可通过诱导炎症反应在体内外参与蛛网膜下腔出血后的早期脑损伤。动物实验于2017年5月24日经安徽医科大学和中国科学技术大学附属第一医院动物伦理委员会批准，批准号LLSC-20180202。

https://orcid.org/0000-0001-8508-567X (Chao-Shi Niu)

关键词: 蛛网膜下腔出血, SOCS1/JAK2/STAT3轴, 脑损伤, 小胶质细胞, 炎症, 细胞因子, 体内模型, 体外模型

Abstract: The SOCS1/JAK2/STAT3 axis is strongly associated with tumor growth and progression, and participates in cytokine secretion in many diseases. However, the effects of the SOCS1/JAK2/STAT3 axis in experimental subarachnoid hemorrhage remain to be studied. A subarachnoid hemorrhage model was established in rats by infusing autologous blood into the optic chiasm pool. Some rats were first treated with JAK2/STAT3 small interfering RNA (Si-JAK2/Si-STAT3) or overexpression plasmids of JAK2/STAT3. In the brains of subarachnoid hemorrhage model rats, the expression levels of both JAK2 and STAT3 were upregulated and the expression of SOCS1 was downregulated, reaching a peak at 48 hours after injury. Simultaneously, the interactions between JAK2 and SOCS1 were reduced. In contrast, the interactions between JAK2 and STAT3 were markedly enhanced. Si-JAK2 and Si-STAT3 treatment alleviated cortical neuronal cell apoptosis and necrosis, destruction of the blood–brain barrier, brain edema, and cognitive functional impairment after subarachnoid hemorrhage. This was accompanied by decreased phosphorylation of JAK2 and STAT3 protein, decreased total levels of JAK2 and STAT3 protein, and increased SOCS1 protein expression. However, overexpression of JAK2 and STAT3 exerted opposite effects, aggravating subarachnoid hemorrhage-induced early brain injury. Si-JAK2 and Si-STAT3 inhibited M1-type microglial conversion and the release of pro-inflammatory factors (inducible nitric oxide synthase, interleukin-1β, and tumor necrosis factor-α) and increased the release of anti-inflammatory factors (arginase-1, interleukin-10, and interleukin-4). Furthermore, primary neurons stimulated with oxyhemoglobin were used to simulate subarachnoid hemorrhage in vitro, and the JAK2 inhibitor AG490 was used as an intervention. The in vitro results also suggested that neuronal protection is mediated by the inhibition of JAK2 and STAT3 expression. Together, our findings indicate that the SOCS1/JAK2/STAT3 axis contributes to early brain injury after subarachnoid hemorrhage both in vitro and in vivo by inducing inflammatory responses. This study was approved by the Animal Ethics Committee of Anhui Medical University and the First Affiliated Hospital of University of Science and Technology of China (approval No. LLSC-20180202) on March 1, 2018.

Key words: brain injury, cytokines, in vitro model, in vivo model, inflammation, microglia, SOCS1/JAK2/STAT3 axis, subarachnoid hemorrhage

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