神经胶质细胞炎症反应的RNA调控及其作为中枢神经系统疾病治疗靶点的潜力

RNA Regulation of Inflammatory Responses in Glia and Its Potential as a Therapeutic Target in Central Nervous System Disorders

神经炎症的一个主要标志是小胶质细胞和星形胶质细胞的激活以及炎症介质(如IL-1β、TNF-α、iNOS和IL-6)的诱导。神经炎症会导致从急性中枢神经系统创伤到慢性神经退行性疾病等多种神经系统疾病的进展。mRNA稳定性的转录后调控途径和翻译效率是这些炎症介质表达的主要驱动因素。这一调节水平的一个共同元素以富含腺嘌呤和尿苷的元素(ARE)为中心,该元素存在于编码这些炎症介质的mRNA的3’非翻译区(UTR)中。(ARE)-结合蛋白(AUBPs)——如人类抗原R(HuR)、三四脯氨酸(TTP)和KH型剪接调节蛋白(KSRP)——是指导这些转录后通路的关键节点,可以促进(HuR)或抑制(TTP和KSRP)胶质细胞产生炎症介质。本综述将讨论ARE介导的RNA调节的基本概念及其对胶质细胞驱动的神经炎症性疾病的影响。还将讨论针对这种新的基因调控水平以达到治疗效果的策略,并对其治疗神经系统疾病潜力的初步研究进行回顾性分析。

A major hallmark of neuroinflammation is the activation of microglia and astrocytes with the induction of inflammatory mediators such as IL-1 β, TNF-α, i NOS, and IL-6. Neuroinflammation contributes to disease progression in a plethora of neurological disorders ranging from acute CNS trauma to chronic neurodegenerative disease. Posttranscriptional pathways of m RNA stability and translational efficiency are major drivers for the expression of these inflammatory mediators. A common element in this level of regulation centers around the adenine-and uridine-rich element(ARE) which is present in the 3’ untranslated region(UTR) of the mRNAs encoding these inflammatory mediators.(ARE)-binding proteins(AUBPs) such as Human antigen R(HuR), Tristetraprolin(TTP) and KH-type splicing regulatory protein(KSRP) are key nodes for directing these posttranscriptional pathways and either promote(HuR) or suppress(TTP and KSRP) glial production of inflammatory mediators. This review will discuss basic concepts of ARE-mediated RNA regulation and its impact on glial-driven neuroinflammatory diseases. We will discuss strategies to target this novel level of gene regulation for therapeutic effect and review exciting preliminary studies that underscore its potential for treating neurological disorders.