Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes.
Evidence for miR-181 involvement in neuroinflammatory responses of astrocytes.
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作者：
Hutchison ER;Kawamoto EM;Taub DD;Lal A;Abdelmohsen K;Zhang Y;Wood WH 3rd;Lehrmann E;Camandola S;Becker KG;Gorospe M;Mattson MP
炎症是中枢神经系统(CNS)急性损伤和阿尔茨海默病等退行性疾病的常见组成部分。神经胶质细胞在局部中枢神经系统炎症中发挥重要作用，因此，了解microRNAs在损伤和疾病环境中神经胶质细胞反应性中的作用可能会使新的治疗干预措施成为可能。在这里，我们表明miR-181家族是发育调节的，与神经元相比，它在星形胶质细胞中的含量很高。在培养的星形胶质细胞中，miR-181c的过度表达导致在脂多糖(LPS)作用下细胞死亡增加。我们发现，在缺乏炎性细胞因子肿瘤坏死因子α受体的野生型小鼠和转基因小鼠中，miR-181在体内脑细胞中的表达在内毒素(一种炎症模型)的反应中发生了变化。敲除miR-181可促进内毒素诱导的促炎细胞因子(肿瘤坏死因子-α、IL-6、IL-1β、IL-8)和HMGB1的产生，而miR-181的过表达则导致抗炎细胞因子IL-10的表达显著增加。为了评估miR-181对星形胶质细胞转录组的影响，我们对miR-181b/c水平降低的星形胶质细胞进行了基因阵列和通路分析。为了检查潜在的miR-181靶点，我们使用了miR-181c的生物素下拉和微阵列分析。我们验证了MeCP2和XIAP mRNAs作为miR-181的靶标。这些发现表明miR-181在星形胶质细胞对炎症环境的反应中发挥重要作用。进一步了解miR-181在炎症事件和中枢神经系统损伤中的作用可能会导致具有炎症成分的中枢神经系统疾病的新疗法。
Inflammation is a common component of acute injuries of the central nervous system (CNS) and degenerative disorders such as Alzheimer’s disease. Glial cells play important roles in local CNS inflammation, and an understanding of the roles for microRNAs in glial reactivity in injury and disease settings may therefore enable novel therapeutic interventions. Here we show that the miR-181 family is developmentally regulated and present in high amounts in astrocytes compared to neurons. Over-expression of miR-181c in cultured astrocytes results in increased cell death when exposed to lipopolysaccharide (LPS). We show that miR-181 expression is altered in brain cells in vivo in response to LPS, a model of inflammation, in both wild-type mice and transgenic mice lacking both receptors for the inflammatory cytokine TNF-α. Knockdown of miR-181 enhanced LPS-induced production of pro-inflammatory cytokines (TNF-α, IL-6, IL-1β, IL-8) and HMGB1, while over-expression of miR-181 resulted in a significant increase in the expression of the anti-inflammatory cytokine IL-10. To assess the effects of miR-181 on the astrocyte transcriptome, we performed gene array and pathway analysis on astrocytes with reduced levels of miR-181b/c. To examine the pool of potential miR-181 targets, we employed a biotin pull-down of miR-181c and microarray analysis. We validated both MeCP2 and XIAP mRNAs as targets of miR-181. These findings suggest that miR-181 plays important roles in the response of astrocytes to inflammatory settings. Further understanding of the role of miR-181 in inflammatory events and CNS injury could lead to novel therapies for CNS disorders with an inflammatory component.