MicroRNA-132 Potentiates Cholinergic Anti-inflammatory Signaling by Targeting Acetylcholinesterase
MicroRNA-132 Potentiates Cholinergic Anti-inflammatory Signaling by Targeting Acetylcholinesterase
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DOI：
10.1016/j.immuni.2009.09.019
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发表时间：
2009-12-18
期刊：
影响因子：
32.4
通讯作者：
Soreq, Hermona
中科院分区：
文献类型：
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作者：
Shaked, Iftach;Meerson, Ari;Soreq, Hermona
MicroRNA (miRNA) 对神经元和免疫细胞的命运都有贡献，但它们在组织间通讯中的作用仍有待探索。大脑通过迷走神经分泌乙酰胆碱 (ACh)，通过拦截细胞因子的产生来抑制外周炎症；因此，我们预测靶向乙酰胆碱酯酶（AChE）的 microRNA 可以减轻炎症。在这里，我们报告炎症刺激诱导白细胞过度表达 AChE 靶向 miR-132。注射锁核酸 (LNA) 修饰的抗 miR-132 寡核苷酸会耗尽 miR-132 量，同时升高小鼠循环和组织中的 AChE。在转染细胞中，突变的 3'UTR miR-132 结合位点增加了 AChE mRNA 表达，而用表达 pre-miR-132 的慢病毒感染的细胞则显示出 AChE 抑制。尽管大脑和骨髓中的 miR-132 显着上调，但过表达 3'UTR null AChE 的转基因小鼠显示出过多的炎症介质和受损的胆碱能抗炎调节。我们的研究结果表明，靶向 AChE mRNA 的 miR-132 是大脑与身体炎症消解的功能调节剂，为神经免疫对话的研究和治疗操作开辟了途径。
MicroRNAs (miRNAs) contribute to both neuronal and immune cell fate, but their involvement in intertissue communication remained unexplored. The brain, via vagal secretion of acetylcholine (ACh), suppresses peripheral inflammation by intercepting cytokine production; therefore, we predicted that microRNAs targeting acetylcholinesterase (AChE) can attenuate inflammation. Here, we report that inflammatory stimuli induced leukocyte overexpression of the AChE-targeting miR-132. Injected locked nucleic acid (LNA)-modified anti-miR-132 oligonucleotide depleted miR-132 amounts while elevating AChE in mouse circulation and tissues. In transfected cells, a mutated 3'UTR miR-132 binding site increased AChE mRNA expression, whereas cells infected with a lentivirus expressing pre-miR-132 showed suppressed AChE. Transgenic mice overexpressing 3'UTR null AChE showed excessive inflammatory mediators and impaired cholinergic anti-inflammatory regulation, in spite of substantial miR-132 upregulation in brain and bone marrow. Our findings identify the AChE mRNA-targeting miR-132 as a functional regulator of the brain-to-body resolution of inflammation, opening avenues for study and therapeutic manipulations of the neuro-immune dialog.