A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis.
A novel SIRT6 activator ameliorates neuroinflammation and ischemic brain injury via EZH2/FOXC1 axis.
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新型 SIRT6 激活剂通过 EZH2/FOXC1 轴改善神经炎症和缺血性脑损伤
DOI：
10.1016/j.apsb.2020.11.002
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Pang T
中科院分区：
文献类型：
--
作者：
He T;Shang J;Gao C;Guan X;Chen Y;Zhu L;Zhang L;Zhang C;Zhang J;Pang T
缺血性脑卒中是全球范围内第二大死亡原因，药物治疗有限，神经炎症被认为是脑卒中进展的关键因素，但如何控制过度活跃的神经炎症仍然是一个长期的挑战。在这里，我们设计了一种新的SIRT 6激活剂MDL-811，它显着抑制脂多糖（LPS）刺激的RAW 264.7巨噬细胞和原代小鼠小胶质细胞的炎症反应，这是通过沉默SIRT 6废除。RNA-seq筛选确定叉头盒C1（Foxc 1）是MDL-811刺激诱发的关键基因，并且是MDL-811抗炎作用所必需的。我们发现MDL-811激活的SIRT 6直接与zeste增强子同源物2（EZH 2）相互作用并促进EZH 2的脱乙酰化，EZH 2可以结合Foxc 1的启动子并上调其表达以调节炎症。此外，我们的数据表明，MDL-811不仅改善了LPS诱导的神经炎症小鼠的病态行为，而且除了促进长期功能恢复外，还显著减轻了缺血性中风小鼠的脑损伤。重要的是，MDL-811在从缺血性中风患者分离的人单核细胞中也表现出强烈的抗炎作用，这是一个有趣的翻译前景的基础。总之，MDL-811可能是缺血性中风和其他与神经炎症相关的脑部疾病的替代治疗候选药物。SIRT 6激活剂MDL-811激活SIRT 6以促进EZH 2去乙酰化和进一步FOXC 1表达，从而改善神经炎症和脑缺血性损伤，并进一步改善卒中结局。
Ischemic stroke is the second leading cause of death worldwide with limited medications and neuroinflammation was recognized as a critical player in the progression of stroke, but how to control the overactive neuroinflammation is still a long-standing challenge. Here, we designed a novel SIRT6 activator MDL-811 which remarkably inhibited inflammatory response in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages and primary mouse microglia, which were abolished by silencing SIRT6. RNA-seq screening identified the forkhead box C1 (Foxc1) is a key gene evoked by MDL-811 stimulation and is required for the anti-inflammatory effects of MDL-811. We found MDL-811-activated SIRT6 directly interacted with enhancer of zeste homolog 2 (EZH2) and promoted deacetylation of EZH2 which could bind to the promoter of Foxc1 and upregulate its expression to modulate inflammation. Moreover, our data demonstrated that MDL-811 not only ameliorated sickness behaviors in neuroinflammatory mice induced by LPS, but also markedly reduced the brain injury in ischemic stroke mice in addition to promoting long-term functional recovery. Importantly, MDL-811 also exhibited strong anti-inflammatory effects in human monocytes isolated from ischemic stroke patients, underlying an interesting translational perspective. Taken together, MDL-811 could be an alternative therapeutic candidate for ischemic stroke and other brain disorders associated with neuroinflammation. SIRT6 activator MDL-811 activates SIRT6 to promote EZH2 deacetylation and further FOXC1 expression, resulting in amelioration of neuroinflammation and brain ischemic injury and further improvement of stroke outcomes.
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