Department of Biological Chemistry, The Institute of Life Sciences, The Hebrew University of Jerusalem, 91904 Jerusalem, Israel.
Immunity. 2009 Dec 18;31(6):965-73. doi: 10.1016/j.immuni.2009.09.019. Epub 2009 Dec 10.
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.
微小 RNA（miRNA）有助于神经元和免疫细胞的命运，但它们在组织间通讯中的作用仍未被探索。大脑通过迷走神经分泌乙酰胆碱（ACh）抑制外周炎症，从而阻止细胞因子的产生；因此，我们预测靶向乙酰胆碱酯酶（AChE）的 microRNAs 可以减轻炎症。在这里，我们报告说，炎症刺激诱导白细胞过表达靶向 AChE 的 miR-132。注射锁核酸（LNA）修饰的抗 miR-132 寡核苷酸可耗尽小鼠循环和组织中的 miR-132 量，同时升高 AChE。在转染的细胞中，突变的 3'UTR miR-132 结合位点增加了 AChE mRNA 的表达，而感染表达 pre-miR-132 的慢病毒的细胞则显示出 AChE 的抑制。尽管脑和骨髓中 miR-132 的大量上调，但过表达 3'UTR 空 AChE 的转基因小鼠显示出过度的炎症介质和胆碱能抗炎调节受损。我们的研究结果确定了靶向 AChE mRNA 的 miR-132 作为大脑与身体炎症分辨率的功能调节剂，为神经免疫对话的研究和治疗干预开辟了道路。
