An Agonist of the Protective Factor SIRT1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury
An Agonist of the Protective Factor SIRT1 Improves Functional Recovery and Promotes Neuronal Survival by Attenuating Inflammation after Spinal Cord Injury
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DOI：
10.1523/jneurosci.3046-16.2017
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发表时间：
2017-03-11
影响因子：
5.3
通讯作者：
Zhong, Guibin
中科院分区：
文献类型：
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作者：
Chen, Haihong;Ji, Hao;Zhong, Guibin
针对创伤后炎症是改善运动功能的关键。SIRT1已被证明通过调节炎症在肝脏炎症、类风湿性关节炎和急性肺部炎症等疾病过程中发挥关键作用。然而，SIRT1在脊髓损伤（SCI）中的作用尚不清楚。我们假设SIRT1通过调节神经炎症在脊髓损伤后运动功能改善中发挥重要作用。在本研究中，我们通过药物干预（SRT1720）和Mx1-Cre/loxP重组系统敲除靶基因来研究SIRT1在SCI中的作用。首先，我们发现野生型（WT）小鼠（C57BL/6）损伤部位的SIRT1表达在脊髓损伤后4小时下降，并持续3天。此外，SIRT1激动剂SRT1720通过降低促炎细胞因子水平、M1巨噬细胞数量、巨噬细胞/小胶质细胞数量和血管周围巨噬细胞的积累，显著改善了WT小鼠损伤后28天的功能恢复。相反，给SIRT1敲除（KO）小鼠SRT1720并没有改善运动恢复或减轻炎症。此外，与WT小鼠相比，SIRT1 KO小鼠在脊髓损伤后表现出更差的运动恢复，炎症细胞因子水平升高，M1巨噬细胞和血管周围巨噬细胞增多。总之，这些发现表明SRT1720，一种SIRT1激动剂，可以通过减轻脊髓损伤后的炎症来改善功能恢复。因此，SIRT1不仅是一种保护因子，而且是一种抗炎分子，对脊髓损伤后的运动功能有有益的作用。
Targeting posttraumatic inflammation is crucial for improving locomotor function. SIRT1 has been shown to play a critical role in disease processes such as hepatic inflammation, rheumatoid arthritis, and acute lung inflammation by regulating inflammation. However, the role of SIRT1 in spinal cord injury (SCI) is unknown. We hypothesized that SIRT1 plays an important role in improving locomotor function after SCI by regulating neuroinflammation. In this study, we investigate the effect of SIRT1 in SCI using pharmacological intervention (SRT1720) and the Mx1-Cre/loxP recombination system to knock out target genes. First, we found that SIRT1 expression at the injured lesion site of wild-type (WT) mice (C57BL/6) decreased 4 h after SCI and lasted for 3 d. Moreover, administration of SRT1720, an agonist of SIRT1, to WT mice significantly improved functional recovery for up to 28 d after injury by reducing the levels of proinflammatory cytokines, the number of M1 macrophages, the number of macrophages/microglia, and the accumulation of perivascular macrophages. In contrast, administration of SRT1720 to SIRT1 knock-out (KO) mice did not improve locomotor recovery or attenuate inflammation. Furthermore, SIRT1 KO mice exhibited worse locomotor recovery, increased levels of inflammatory cytokines, and more M1 macrophages and perivascular macrophages than those of WT mice after SCI. Together, these findings indicate that SRT1720, an SIRT1 agonist, can improve functional recovery by attenuating inflammation after SCI. Therefore, SIRT1 is not only a protective factor but also an anti-inflammatory molecule that exerts beneficial effects on locomotor function after SCI.