中国神经再生研究(英文版) ›› 2021, Vol. 16 ›› Issue (9): 1836-1847.doi: 10.4103/1673-5374.306096

• 原著:脊髓损伤修复保护与再生 • 上一篇    下一篇

VX-765可改善脊髓损伤后的神经炎症反应

  

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

    中国国家自然科学基金项目(8177232182072416

VX-765 reduces neuroinflammation after spinal cord injury in mice

Jing Chen1, 2, 3, #, Yu-Qing Chen1, 2, 3, #, Yu-Jiao Shi1, 2, #, Shu-Qin Ding1, Lin Shen2, Rui Wang2, Qi-Yi Wang2, Cheng Zha2, Hai Ding2, Jian-Guo Hu1, 2, *, He-Zuo Lü1, 2, 3, *#br#   

  1. 1Clinical Laboratory, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; 2Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China; 3Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, Anhui Province, China
  • Online:2021-09-15 Published:2021-02-05
  • Contact: He-Zuo Lü, MD, PhD, lhz233003@163.com; Jian-Guo Hu, MD, PhD, jghu9200@163.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, Nos. 81772321, 82072416 (both to HZL).

摘要:

炎症是损伤脊髓继续发生神经元损伤的主要因素。假设可通过抑制caspase-1激活来改善脊髓损伤厚的神经炎症,从而产生对损伤脊髓的保护作用。为此,实验使用Infinite Horizon撞击器建立T9挫伤性脊髓损伤小鼠模型,并在损伤后连续7d腹腔注射caspase-1选择性抑制剂VX-765。结果发现:(1)给予VX-765可抑制脊髓损伤诱导的caspase-1激活以及白细胞介素1β和白细胞介素18的分泌;(2)脊髓损伤后,增加的M1细胞主要来源于局部小胶质细胞,而不是浸润巨噬细胞;(3)促炎性Th1Th17细胞在Th细胞亚群中占主导地位。VX-765可抑制局部巨噬细胞浸润,M1巨噬细胞/小胶质细胞、Th1和Th1Th17亚群分化和细胞毒性T细胞活化,增加M2小胶质细胞,并促进向Th2和Treg的分化;(4)VX-765还可缩小脊髓损伤部位的纤维化,促进白质髓鞘形成,减轻运动神经元损伤,并改善小鼠的神经功能;(5)实验结果表明VX-765可通过抑制caspase-1/白细胞介素1β/白细胞介素18轴来改善脊髓损伤后神经炎症以及神经功能,可能成为治疗脊髓损伤的潜在策略。实验于2017年2月23日经蚌埠医学院动物伦理委员会皮质,批准号2017-037。

https://orcid.org/0000-0002-3889-835X (He-Zuo Lü); https://orcid.org/0000-0002-9055-874X (Jian-Guo Hu)

关键词:

炎性小体, 免疫细胞亚群, 白细胞浸润, 巨噬细胞, 小胶质细胞, 免疫功能, 脊髓损伤, 通路

Abstract: Inflammation is a major cause of neuronal injury after spinal cord injury. We hypothesized that inhibiting caspase-1 activation may reduce neuroinflammation after spinal cord injury, thus producing a protective effect in the injured spinal cord. A mouse model of T9 contusive spinal cord injury was established using an Infinite Horizon Impactor, and VX-765, a selective inhibitor of caspase-1, was administered for 7 successive days after spinal cord injury. The results showed that: (1) VX-765 inhibited spinal cord injury-induced caspase-1 activation and interleukin-1β and interleukin-18 secretion. (2) After spinal cord injury, an increase in M1 cells mainly came from local microglia rather than infiltrating macrophages. (3) Pro-inflammatory Th1Th17 cells were predominant in the Th subsets. VX-765 suppressed total macrophage infiltration, M1 macrophages/microglia, Th1 and Th1Th17 subset differentiation, and cytotoxic T cells activation; increased M2 microglia; and promoted Th2 and Treg differentiation. (4) VX-765 reduced the fibrotic area, promoted white matter myelination, alleviated motor neuron injury, and improved functional recovery. These findings suggest that VX-765 can reduce neuroinflammation and improve nerve function recovery after spinal cord injury by inhibiting caspase-1/interleukin-1β/interleukin-18. This may be a potential strategy for treating spinal cord injury. This study was approved by the Animal Care Ethics Committee of Bengbu Medical College (approval No. 2017-037) on February 23, 2017. 

Key words: immune cell subsets, immune function, inflammasomes, leukocyte infiltration, macrophages, microglia,  , pathways, spinal cord injury