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 (9): 1848-1855.doi: 10.4103/1673-5374.303039

• 原著:周围神经损伤修复保护与再生 • 上一篇    下一篇

脊髓损伤后高迁移率蛋白1介导星形胶质细胞的炎症反应

  

  • 出版日期:2021-09-15 发布日期:2021-02-05
  • 基金资助:

    中国国家重点研究开发计划项目（2018YFC1105603），国家自然科学基金项目（31871211），江苏省高等学校优先级学术计划研发项目，中国博士后科学基金项目（2020M681689），南通市基础科研项目（JC2018065）

High mobility group box 1 mediates inflammatory response of astrocytes via cyclooxygenase 2/prostaglandin E2 signaling following spinal cord injury

Hong-Hua Song1, 2, #, Tian-Cheng Song1, #, Ting Yang1, Chun-Shuai Sun1, Bing-Qiang He1, Hui Li1, Ying-Jie Wang1, Yu Li3, Hao Wu4, Yu-Ming Hu5, Yong-Jun Wang1, *    

  1. 1Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu Province, China; 2Center of Special Inspection, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China; 3Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China; 4Department of Otolaryngology Head Neck Surgery, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China; 5Department of Rehabilitation Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, China
  • Online:2021-09-15 Published:2021-02-05
  • Contact: Yong-Jun Wang, PhD, wyjbs@ntu.edu.cn.
  • Supported by:
    This study was supported by the National Key Research and Development Program of China, No. 2018YFC1105603 (to YJunW), the National Natural Science Foundation of China, No. 31871211 (to YJunW), the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) (to YJunW), the China Postdoctoral Science Foundation, No. 2020M681689 (to YMH), and the Basic Scientific Research Projects of Nantong of China, No. JC2018065 (to HHS).

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摘要：

高迁移率蛋白1可与免疫细胞的模式识别受体相互作用，激活炎症反应。而星形胶质细胞还可通过表达与模式识别受体在创伤性中枢神经系统的神经炎症中发挥积极作用。但高迁移率蛋白1与星形胶质细胞炎症反应之间的潜在关系仍有待研究。（1）实验通过挫伤T8-10建立脊髓损伤大鼠模型，对损伤脊髓进行转录组测序，发现高迁移率蛋白1/Toll样受体4轴可通过调节环氧合酶2/前列腺素E2信号传导参与激活星形胶质细胞的炎症反应。Toll样受体4和环氧合酶2均分布于星形胶质细胞，且在脊髓损伤后两者的表达上调；（2）利用重组高迁移率蛋白1刺激原代星形胶质细胞，发现环氧合酶2和微粒前列腺素E合酶1表达上调，而环氧合酶1、微粒前列腺素E合酶2或胞质前列腺素E合酶表达没有明显变化。同时为响应重组高迁移率蛋白1的刺激，星形胶质细胞中前列腺素E2表达显著增加；（3）Toll样受体4受体白术内酯I和Toll样受体2受体C29均能降低高迁移率蛋白1介导的环氧合酶2 /前列腺素E2的表达；（4）高迁移率蛋白1不能显著改变星形胶质细胞中肿瘤坏死因子α或白介素1β的表达水平；（5）结果阐明了脊髓损伤后高迁移率蛋白1通过调节环氧合酶2 /前列腺素E2信号通路介导星形胶质细胞的炎症反应。实验于2018年12月4日经南通大学实验动物伦理委员会批准，批准号20181204-001。

https://orcid.org/0000-0001-5040-8926 (Yong-Jun Wang)

关键词:

中枢神经系统, 脊髓, 脊髓损伤, 炎症, 星形胶质细胞, 损伤, 修复, 通路, 蛋白

Abstract: High mobility group box 1 (HMGB1) interacts with pattern-recognition receptors of immune cells to activate the inflammatory response. Astrocytes play a positive role in the inflammatory response of the central nervous system by expressing a broad range of pattern-recognition receptors. However, the underlying relationship between HMGB1 and the inflammatory reaction of astrocytes remains unclear. In this study, we established rat models of spinal cord injury via laminectomy at the T8–10 level, and the injured spinal cord was subjected to transcriptome sequencing. Our results showed that the HMGB1/Toll-like receptor 4 (TLR4) axis was involved in the activation of astrocyte inflammatory response through regulation of cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE2) signaling. Both TLR4 and COX2 were distributed in astrocytes and showed elevated protein levels following spinal cord injury. Stimulation of primary astrocytes with recombinant HMGB1 showed that COX2 and microsomal PGE synthase (mPGES)-1, rather than COX1, mPGES-2, or cytosolic PGE synthase, were significantly upregulated. Accordingly, PGE2 production in astrocytes was remarkably increased in response to recombinant HMGB1 challenges. Pharmacologic blockade of TLR2/4 attenuated HMGB1-mediated activation of the COX2/PGE2 pathway. Interestingly, HMGB1 did not impact the production of tumor necrosis factor-α or interleukin-1β in astrocytes. Our results suggest that HMGB1 mediates the astrocyte inflammatory response through regulating the COX2/PGE2 signaling pathway. The study was approved by the Laboratory Animal Ethics Committee of Nantong University, China (approval No. 20181204-001) on December 4, 2018.

Key words: astrocytes, COX2, HMGB1, inflammation, spinal cord injury