中国神经再生研究(英文版)

中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (9): 2029-2035.doi: 10.4103/1673-5374.335165

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

芦可替尼可降低创伤性脊髓损伤后的继发性病变

  

  • 出版日期:2022-09-15 发布日期:2022-03-05

Ruxolitinib attenuates secondary injury after traumatic spinal cord injury

Zhan-Yang Qian1, 2, #, Ren-Yi Kong3, #, Sheng Zhang3, #, Bin-Yu Wang3, Jie Chang3, Jiang Cao3, Chao-Qin Wu3, Zi-Yan Huang3, Ao Duan3, Hai-Jun Li4, 5, *, Lei Yang4, 5, *, Xiao-Jian Cao3, *   

  1. 1Spine Center, Zhongda Hospital of Southeast University, Nanjing, Jiangsu Province, China; 2Medical School, Southeast University, Nanjing, Jiangsu Province, China; 3Department of Orthopedics, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China; 4Department of Orthopedics, Hospital Affiliated 5 to Nantong University (Taizhou People’s Hospital), Taizhou, Jiangsu Province, China; 5Taizhou Clinical Medical School of Nanjing Medical University, Taizhou People’s Hospital, Taizhou, Jiangsu Province, China
  • Online:2022-09-15 Published:2022-03-05
  • Contact: Xiao-Jian Cao, MD, PhD, xiaojiancao001@163.com; Lei Yang, PhD, leiyang@njmu.edu.cn; Hai-Jun Li, MD, PhD, 13901436563@139.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 81871773 (to XJC), 81672152 (to XJC), 81802149 (to LY); Primary Research and Development Plan of Jiangsu Province of China, No. BE2018132 (to XJC); and Scientific Research Project of Health Commission of Jiangsu Province of China, No. LGY2020068 (to HJL).

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摘要：

脊髓损伤后过度的炎症反应会诱导小胶质细胞的活化，进而导致长期的神经功能障碍。但是目前与小胶质细胞激活诱导的神经炎症相关机制仍不清楚。芦可替尼是一种JAK1/2选择性抑制剂，最近有研究认为其可抑制由SARS-CoV-2引起的肺部炎症风暴。然而其是否也在脊髓损伤后的炎症破坏中起作用尚未见报道。（1）实验首先以芦可替尼预先干预小胶质细胞24h，在以干扰素γ激活细胞6h。结果发现芦可替尼可有效抑制干扰素γ诱导的小胶质细胞中JAK和STAT的磷酸化，并减少促炎基因肿瘤坏死因子α、白细胞介素1β和白细胞介素6和增殖基因Ki67的表达。（2）进一步体内实验中，对脊髓损伤小鼠模型连续3d灌胃芦可替尼进行治疗，可见芦可替尼可通过抑制干扰素γ/JAK/STAT通路激活抑制小胶质细胞增殖，且小胶质细胞会向心迁移到受伤病灶，并保持局限于胶质瘢痕中，使得轴突保留和脱髓鞘较少；同时也会减弱炎症因子肿瘤坏死因子α、白细胞介素1β和白细胞介素6的蛋白表达，并促进脊髓损伤小鼠模型的神经运动功能的恢复。表明芦可替尼通过抑制干扰素γ/JAK/STAT信号通路抑制神经炎症，从而降低脊髓损伤后继发性病变，而产生神经保护效果的。

https://orcid.org/0000-0001-5567-0536 (Xiao-Jian Cao); https://orcid.org/0000-0001-5677-9955 (Lei Yang)

关键词: 芦可替尼, 炎症, 小胶质细胞, 胶质瘢痕, 干扰素γ, JAK, STAT, 脊髓损伤, 功能恢复

Abstract: Excessive inflammation post-traumatic spinal cord injury (SCI) induces microglial activation, which leads to prolonged neurological dysfunction. However, the mechanism underlying microglial activation-induced neuroinflammation remains poorly understood. Ruxolitinib (RUX), a selective inhibitor of JAK1/2, was recently reported to inhibit inflammatory storms caused by SARS-CoV-2 in the lung. However, its role in disrupting inflammation post-SCI has not been confirmed. In this study, microglia were treated with RUX for 24 hours and then activated with interferon-γ for 6 hours. The results showed that interferon-γ-induced phosphorylation of JAK and STAT in microglia was inhibited, and the mRNA expression levels of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-1β, interleukin-6, and cell proliferation marker Ki67 were reduced. In further in vivo experiments, a mouse model of spinal cord injury was treated intragastrically with RUX for 3 successive days, and the findings suggest that RUX can inhibit microglial proliferation by inhibiting the interferon-γ/JAK/STAT pathway. Moreover, microglia treated with RUX centripetally migrated toward injured foci, remaining limited and compacted within the glial scar, which resulted in axon preservation and less demyelination. Moreover, the protein expression levels of tumor necrosis factor-α, interleukin-1β, and interleukin-6 were reduced. The neuromotor function of SCI mice also recovered. These findings suggest that RUX can inhibit neuroinflammation through inhibiting the interferon-γ/JAK/STAT pathway, thereby reducing secondary injury after SCI and producing neuroprotective effects. 

Key words: functional recovery, glial scar, inflammation, interferon-γ, JAK/STAT signaling, microglia, Ruxolitinib, spinal cord injury