Sirtuin4 suppresses the anti-neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord
Sirtuin4 suppresses the anti-neuroinflammatory activity of infiltrating regulatory T cells in the traumatically injured spinal cord
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Sirtuin4 抑制创伤性损伤脊髓中浸润调节性 T 细胞的抗神经炎症活性
DOI：
10.1111/imm.13123
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发表时间：
2019-10-13
期刊：
影响因子：
6.4
通讯作者：
Zhang, Liqun
中科院分区：
文献类型：
--
作者：
Lin, Wenping;Chen, Wenkai;Zhang, Liqun
创伤性脊髓损伤（SCI）后神经炎症是影响脊髓实质损伤和恢复的重要过程。浸润性调节性T （Treg）细胞是抑制脊髓损伤后神经炎症的有效抗炎细胞。为了了解浸润性Treg细胞活性的分子机制，我们使用小鼠脊髓压迫损伤模型来分析Sirtuins （SIRTs）在浸润性Treg细胞功能调节中的作用。我们发现SIRT4和SIRT6在浸润的Treg细胞中表达上调。通过慢病毒介导的基因表达或RNA干扰，我们发现SIRT4显著抑制Treg细胞中Foxp3、白介素-10和转化生长因子- β的表达，而SIRT6对Treg细胞的影响很小。与此一致的是，SIRT4过表达削弱了Treg细胞对脂多糖刺激的脊髓CD11b（+）髓样细胞的抑制作用。SIRT4敲低可增强损伤脊髓实质浸润性Treg细胞的抗炎活性。此外，SIRT4过表达阻断体外常规T细胞生成Treg细胞。此外，SIRT4下调Treg细胞中5 ' amp活化蛋白激酶（AMPK）信号，而AMPK激动剂AICAR恢复了SIRT4过表达Treg细胞中Foxp3和白介素-10的表达。总之，我们的研究揭示了脊髓损伤后神经炎症调节的新机制。
The neuroinflammation following traumatic spinal cord injury (SCI) is a critical process that impacts both the injury and the recovery of spinal cord parenchyma. Infiltrating regulatory T (Treg) cells are potent anti-inflammatory cells that restrain post-SCI neuroinflammation. To understand the molecular mechanisms underlying the activity of infiltrating Treg cells, we used a mouse spinal cord compression injury model to analyze the role of Sirtuins (SIRTs) in the modulation of infiltrating Treg cell functions. We found that the expressions of SIRT4 and SIRT6 were up-regulated in infiltrating Treg cells. Using lentivirus-mediated gene expression or RNA interference, we revealed that SIRT4 substantially inhibited the expression of Foxp3, interleukin-10, and transforming growth factor-beta in Treg cells, whereas SIRT6 had little effect on Treg cells. Consistently, SIRT4 overexpression weakened the suppressive effect of Treg cells on lipopolysaccharide-stimulated spinal cord CD11b(+) myeloid cells. Knock-down of SIRT4 enhanced the anti-inflammatory activity of infiltrating Treg cells in the parenchyma of injured spinal cords. Additionally, SIRT4 overexpression blocked in vitro Treg cell generation from conventional T cells. Furthermore, SIRT4 down-regulated 5 ' AMP-activated protein kinase (AMPK) signaling in Treg cells, whereas the AMPK agonist AICAR restored the expression of Foxp3 and interleukin-10 in SIRT4-overexpressing Treg cells. In conclusion, our research unveils a new mechanism by which the post-SCI neuroinflammation is regulated.