miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation
miR-142-3p Is a Key Regulator of IL-1β-Dependent Synaptopathy in Neuroinflammation
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miR-142-3p 是神经炎症中 IL-1β 依赖性突触病的关键调节因子
DOI：
10.1523/jneurosci.0851-16.2016
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发表时间：
2017
期刊：
影响因子：
--
通讯作者：
D. Centonze
中科院分区：
文献类型：
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作者：
G. Mandolesi;F. De Vito;A. Musella;A. Gentile;S. Bullitta;D. Fresegna;H. Sepman;C. Di Sanza;N. Haji;F. Mori;F. Buttari;E. Perlas;M. Ciotti;E. Hornstein;I. Bozzoni;C. Presutti;D. Centonze
MicroRNA (miRNA) 在多种生理和病理过程的转录后基因调控中发挥着重要作用。在多发性硬化症 (MS)（一种中枢神经系统慢性炎症和退行性疾病）及其小鼠模型实验性自身免疫性脑脊髓炎 (EAE) 中，miRNA 失调主要与免疫系统功能障碍和白质 (WM) 病理有关。然而，人们对它们在灰质病理学中的作用知之甚少。在这里，我们探索了 miRNA 参与炎症驱动的突触结构和功能改变，统称为突触病，这是一种导致 MS/EAE 兴奋性毒性神经变性的神经病理过程。特别是，我们观察到 miR-142-3p 在活动性 MS 患者的 CSF 和 EAE 大脑中增加。我们提出 miR-142-3p 作为 IL-1β 依赖性胶质细胞谷氨酸-天冬氨酸转运蛋白 (GLAST) 下调的分子介导物，从而导致 EAE 小脑中谷氨酸能传递的增强。 IL-1β介导的突触异常以及EAE的临床和神经病理学表现在miR-142敲除小鼠中消失。此外，我们观察到，通过预防性局部治疗或治疗性全身策略，体内抑制 miR-142-3p 可以消除 EAE 野生型小鼠中 IL-1β 和 GLAST 依赖性突触病。一致地，miR-142-3p 是 MS 患者脑脊液引起的谷氨酸突触改变的原因，并且 CSF 中 miR-142-3p 的水平与预期 MS 疾病进展相关。我们的研究结果强调 miR-142-3p 作为 IL-1β 介导的突触功能障碍的关键分子参与者，可能导致 EAE 和 MS 疾病中的兴奋性毒性损伤。抑制 miR-142-3p 可能对 MS 具有神经保护作用。意义陈述 目前的研究表明谷氨酸兴奋性毒性在多发性硬化症（MS）及其小鼠模型实验性自身免疫性脑脊髓炎（EAE）的发生和进展中的作用。 MS/EAE 中炎症和突触改变之间的分子机制仍不清楚。在这里，我们确定 miR-142-3p 是 MS 和 EAE 典型的炎症依赖性突触病的决定分子。 miR-142-3p 在 MS 患者的 CSF 和 EAE 小脑中上调。在EAE大脑和MS嵌合离体模型中局部抑制miR-142-3p，恢复了EAE/MS典型的谷氨酸突触增强。我们证明，miR-142-3p 通过靶向谷氨酸-天冬氨酸转运蛋白（GLAST）促进 IL-1β 依赖性谷氨酸功能障碍，GLAST 是参与谷氨酸稳态的关键神经胶质转运蛋白。最后，我们建议 miR-142-3p 作为复发缓解型多发性硬化症患者的负面预后因素。
MicroRNAs (miRNA) play an important role in post-transcriptional gene regulation of several physiological and pathological processes. In multiple sclerosis (MS), a chronic inflammatory and degenerative disease of the CNS, and in its mouse model, the experimental autoimmune encephalomyelitis (EAE), miRNA dysregulation has been mainly related to immune system dysfunction and white matter (WM) pathology. However, little is known about their role in gray matter pathology. Here, we explored miRNA involvement in the inflammation-driven alterations of synaptic structure and function, collectively known as synaptopathy, a neuropathological process contributing to excitotoxic neurodegeneration in MS/EAE. Particularly, we observed that miR-142-3p is increased in the CSF of patients with active MS and in EAE brains. We propose miR-142-3p as a molecular mediator of the IL-1β-dependent downregulation of the glial glutamate-aspartate transporter (GLAST), which causes an enhancement of the glutamatergic transmission in the EAE cerebellum. The synaptic abnormalities mediated by IL-1β and the clinical and neuropathological manifestations of EAE disappeared in miR-142 knock-out mice. Furthermore, we observed that in vivo miR-142-3p inhibition, either by a preventive and local treatment or by a therapeutic and systemic strategy, abolished IL-1β- and GLAST-dependent synaptopathy in EAE wild-type mice. Consistently, miR-142-3p was responsible for the glutamatergic synaptic alterations caused by CSF of patients with MS, and CSF levels of miR-142-3p correlated with prospective MS disease progression. Our findings highlight miR-142-3p as key molecular player in IL-1β-mediated synaptic dysfunction, possibly leading to excitotoxic damage in both EAE and MS diseases. Inhibition of miR-142-3p could be neuroprotective in MS. SIGNIFICANCE STATEMENT Current studies suggest the role of glutamate excitotoxicity in the development and progression of multiple sclerosis (MS) and of its mouse model experimental autoimmune encephalomyelitis (EAE). The molecular mechanisms linking inflammation and synaptic alterations in MS/EAE are still unknown. Here, we identified miR-142-3p as a determinant molecular actor in inflammation-dependent synaptopathy typical of both MS and EAE. miR-142-3p was upregulated in the CSF of MS patients and in EAE cerebellum. Inhibition of miR-142-3p, locally in EAE brain and in a MS chimeric ex vivo model, recovered glutamatergic synaptic enhancement typical of EAE/MS. We proved that miR-142-3p promoted the IL-1β-dependent glutamate dysfunction by targeting glutamate-aspartate transporter (GLAST), a crucial glial transporter involved in glutamate homeostasis. Finally, we suggest miR-142-3p as a negative prognostic factor in patients with relapsing-remitting multiple sclerosis.
影响因子：
14.5
作者：
Baranzini, Sergio E.;Srinivasan, Radhika;Pelletier, Daniel
通讯作者：
Pelletier, Daniel
MicroRNA：突触活性中基因表达的元控制者出现，作为人类疾病的遗传和诊断标记。
影响因子：
13.5
作者：
Ceman, Stephanie;Saugstad, Julie
通讯作者：
Saugstad, Julie