Chen Jing, Chen Yu-Qing, Shi Yu-Jiao, Ding Shu-Qin, Shen Lin, Wang Rui, Wang Qi-Yi, Zha Cheng, Ding Hai, Hu Jian-Guo, Lü He-Zuo
Clinical Laboratory; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical College; Department of Immunology, Bengbu Medical College, and Anhui Key Laboratory of Infection and Immunity at Bengbu Medical College, Bengbu, Anhui Province, China.
Clinical Laboratory; Anhui Key Laboratory of Tissue Transplantation, the First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui Province, China.
Neural Regen Res. 2021 Sep;16(9):1836-1847. doi: 10.4103/1673-5374.306096.
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.
炎症是脊髓损伤后神经元损伤的主要原因。我们推测，抑制半胱天冬酶-1的激活可能会减轻脊髓损伤后的神经炎症，从而对受损脊髓产生保护作用。使用Infinite Horizon冲击器建立T9挫伤性脊髓损伤小鼠模型，并在脊髓损伤后连续7天给予半胱天冬酶-1的选择性抑制剂VX-765。结果显示：（1）VX-765抑制脊髓损伤诱导的半胱天冬酶-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，M1细胞增加主要源于局部小胶质细胞而非浸润的巨噬细胞。（3）促炎性Th1Th17细胞在Th亚群中占主导。VX-765抑制总巨噬细胞浸润、M1巨噬细胞/小胶质细胞、Th1和Th1Th17亚群分化以及细胞毒性T细胞激活；增加M2小胶质细胞；并促进Th2和调节性T细胞分化。（4）VX-765减少纤维化面积，促进白质髓鞘形成，减轻运动神经元损伤，并改善功能恢复。这些发现表明，VX-765可通过抑制半胱天冬酶-1/白细胞介素-1β/白细胞介素-18来减轻脊髓损伤后的神经炎症并改善神经功能恢复。这可能是治疗脊髓损伤的一种潜在策略。本研究于2017年2月23日获得蚌埠医学院动物护理伦理委员会批准（批准号：2017-037）。
