miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling.
miR-1224 contributes to ischemic stroke-mediated natural killer cell dysfunction by targeting Sp1 signaling.
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miR-1224通过靶向Sp1信号传导导致缺血性中风介导的自然杀伤细胞功能障碍
DOI：
10.1186/s12974-021-02181-4
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发表时间：
2021-06-12
影响因子：
9.3
通讯作者：
Zhang XA
中科院分区：
文献类型：
--
作者：
Feng Y;Li Y;Zhang Y;Zhang BH;Zhao H;Zhao X;Shi FD;Jin WN;Zhang XA
背景脑缺血通过作用于神经源性和细胞内途径，损害自然杀伤 (NK) 细胞介导的免疫防御。关于缺血性中风后调节 NK 细胞活化和细胞毒性的转录后机制知之甚少。方法使用 NanoString nCounter® miRNA 阵列面板，我们探索了大脑中动脉闭塞小鼠脾脏 NK 细胞的 microRNA (miRNA) 谱。应用差异基因表达和功能/通路分析来研究预测的miRNA靶基因的主要功能。进行 miR-1224 抑制剂/模拟物转染和 NK 细胞被动转移，以确认脑缺血后 miR-1224 对 NK 细胞的影响。结果我们观察到几种 miRNA 在应对缺血时出现显着失调。在这些 miRNA 中，miR-1224 在缺血性中风后 3 天显着增加。将 miR-1224 模拟物转染 NK 细胞会导致 NK 细胞活性受到抑制，而 miR-1224 抑制剂则增强 NK 细胞活性和细胞毒性，尤其是在外周细胞。用 miR-1224 抑制剂处理的 NK 细胞的被动转移可防止缺血性中风后肺部细菌负荷的积累，这表明 NK 细胞的免疫防御能力增强。转录因子 Sp1 在转录水平上控制 NK 细胞释放细胞因子/趋化因子，是 miR-1224 的预测靶标。 miR-1224对NK细胞活性的抑制作用在Sp1敲除小鼠中被阻断。结论这些发现表明miR-1224可能以Sp1依赖性方式作为NK细胞活化的负调节因子。这种机制可能是预防中风后感染（特别是在外周）并保护大脑免疫防御的新靶标。
BackgroundBrain ischemia compromises natural killer (NK) cell-mediated immune defenses by acting on neurogenic and intracellular pathways. Less is known about the posttranscriptional mechanisms that regulate NK cell activation and cytotoxicity after ischemic stroke.MethodsUsing a NanoString nCounter® miRNA array panel, we explored the microRNA (miRNA) profile of splenic NK cells in mice subjected to middle cerebral artery occlusion. Differential gene expression and function/pathway analysis were applied to investigate the main functions of predicted miRNA target genes. miR-1224 inhibitor/mimics transfection and passive transfer of NK cells were performed to confirm the impact of miR-1224 in NK cells after brain ischemia.ResultsWe observed striking dysregulation of several miRNAs in response to ischemia. Among those miRNAs, miR-1224 markedly increased 3 days after ischemic stroke. Transfection of miR-1224 mimics into NK cells resulted in suppression of NK cell activity, while an miR-1224 inhibitor enhanced NK cell activity and cytotoxicity, especially in the periphery. Passive transfer of NK cells treated with an miR-1224 inhibitor prevented the accumulation of a bacterial burden in the lungs after ischemic stroke, suggesting an enhanced immune defense of NK cells. The transcription factor Sp1, which controls cytokine/chemokine release by NK cells at the transcriptional level, is a predicted target of miR-1224. The inhibitory effect of miR-1224 on NK cell activity was blocked in Sp1 knockout mice.ConclusionsThese findings indicate that miR-1224 may serve as a negative regulator of NK cell activation in an Sp1-dependent manner; this mechanism may be a novel target to prevent poststroke infection specifically in the periphery and preserve immune defense in the brain.
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影响因子：
168.9
作者：
Kalra, Lalit;Irshad, Saddif;Rebollo-Mesa, Irene
通讯作者：
Rebollo-Mesa, Irene
影响因子：
2.6
作者：
Li, Bo;Wu, Pingping;Zeng, Gaofeng
通讯作者：
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影响因子：
8.3
作者：
Liesz, Arthur;Hagmann, Sebastien;Veltkamp, Roland
通讯作者：
Veltkamp, Roland
影响因子：
3.2
作者：
de Knegt, Gerjo J.;Dickinson, Laura;de Steenwinkel, Jurriaan E. M.
通讯作者：
de Steenwinkel, Jurriaan E. M.
影响因子：
6
作者：
Curtale G
通讯作者：
Curtale G