The Edmond and Lily Safra Center for Brain Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
The Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, The Edmond Safra Campus, Givat Ram, Jerusalem 9190401, Israel.
Sci Rep. 2017 Feb 17;7:42755. doi: 10.1038/srep42755.
MicroRNA (miR)-132 brain-to-body messages suppress inflammation by targeting acetylcholinesterase (AChE), but the target specificity of 3'-AChE splice variants and the signaling pathways involved remain unknown. Using surface plasmon resonance (SPR), we identified preferential miR-132 targeting of soluble AChE-R over synaptic-bound AChE-S, potentiating miR-132-mediated brain and body cholinergic suppression of pro-inflammatory cytokines. Inversely, bacterial lipopolysaccharide (LPS) reduced multiple miR-132 targets, suppressed AChE-S more than AChE-R and elevated inflammatory hallmarks. Furthermore, blockade of peripheral miR-132 by chemically protected AM132 antisense oligonucleotide elevated muscle AChE-R 10-fold over AChE-S, and cortical miRNA-sequencing demonstrated inverse brain changes by AM132 and LPS in immune-related miRs and neurotransmission and cholinergic signaling pathways. In neuromuscular junctions, AM132 co-elevated the nicotinic acetylcholine receptor and AChE, re-balancing neurotransmission and reaching mild muscle incoordination. Our findings demonstrate preferential miR-132-induced modulation of AChE-R which ignites bidirectional brain and body anti-inflammatory regulation, underscoring splice-variant miR-132 specificity as a new complexity level in inflammatory surveillance.
微小 RNA（miR）-132 大脑到身体的信息通过靶向乙酰胆碱酯酶（AChE）来抑制炎症，但 3'-AChE 剪接变体的靶特异性和涉及的信号通路仍不清楚。使用表面等离子体共振（SPR），我们鉴定出可溶性 AChE-R 优先靶向 miR-132，而突触结合的 AChE-S 则被增强，从而促进 miR-132 介导的大脑和身体胆碱能抑制促炎细胞因子。相反，细菌脂多糖（LPS）降低了多种 miR-132 靶标，对 AChE-S 的抑制作用大于 AChE-R，并升高了炎症标志物。此外，通过化学保护的 AM132 反义寡核苷酸阻断外周 miR-132 使肌肉 AChE-R 比 AChE-S 升高 10 倍，皮质 miRNA 测序显示 AM132 和 LPS 在免疫相关 miRs 和神经传递以及胆碱能信号通路中引起大脑的相反变化。在神经肌肉接头中，AM132 共同升高烟碱型乙酰胆碱受体和 AChE，重新平衡神经传递，达到轻度肌肉不协调。我们的研究结果表明，miR-132 优先诱导 AChE-R 的调节，从而引发双向的大脑和身体抗炎调节，突出了剪接变体 miR-132 的特异性作为炎症监测的新复杂性水平。
