miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production
miR-155 modulates microglia-mediated immune response by down-regulating SOCS-1 and promoting cytokine and nitric oxide production
复制标题
DOI：
10.1111/j.1365-2567.2011.03514.x
复制
发表时间：
2012-01-01
期刊：
影响因子：
6.4
通讯作者：
Pedroso de Lima, Maria C.
中科院分区：
文献类型：
--
作者：
Cardoso, Ana L.;Guedes, Joana R.;Pedroso de Lima, Maria C.
先天免疫是大脑抵御外部和内源性威胁的第一道防线，小胶质细胞被认为是这一过程的关键介质。最近的研究表明，在先天免疫应答过程中，microRNAs （miRNAs）可能在基因表达调控中起决定性作用。这项工作的主要目的是研究特定的miRNA miR-155对小胶质细胞介导的免疫反应的调节的贡献。为此，在N9小胶质细胞中进行了体外研究，以评估小胶质细胞激活后该miRNA水平的变化。在小胶质细胞暴露于脂多糖后，观察到miR-155表达的强烈上调，这与细胞因子信号传导1 （SOCS-1）蛋白抑制因子水平的降低是一致的，SOCS-1蛋白是炎症过程的关键抑制剂，也是miR-155的预测靶点。通过抗mirna寡核苷酸敲低miR-155可上调SOCS-1 mRNA和蛋白水平，显著降低一氧化氮的产生、炎症细胞因子和诱导型一氧化氮合酶的表达。最后，用从小胶质细胞中获得的条件培养基处理神经元原代培养物，其中miR-155在细胞激活前被抑制，减少炎症介导的神经元细胞死亡。总体而言，我们的研究结果表明，miR-155在小胶质细胞中具有促炎作用，并且通过调节SOCS-1对免疫反应的进展是必要的，这表明，在慢性炎症背景下，miR-155抑制可能具有神经保护作用。
Innate immunity constitutes the first line of defence against both external and endogenous threats in the brain, and microglia cells are considered key mediators of this process. Recent studies have shown that microRNAs (miRNAs) may play a determinant role in the regulation of gene expression during innate immune responses. The major goal of this work was to investigate the contribution of a specific miRNA miR-155 to the modulation of the microglia-mediated immune response. For this purpose, in vitro studies were performed in N9 microglia cells to evaluate changes in the levels of this miRNA following microglia activation. A strong up-regulation of miR-155 expression was observed following microglia exposure to lipopolysaccharide, which was consistent with a decrease in the levels of the suppressor of cytokine signalling 1 (SOCS-1) protein, a key inhibitor of the inflammatory process and a predicted target of miR-155. The miR-155 knockdown by anti-miRNA oligonucleotides up-regulated SOCS-1 mRNA and protein levels and significantly decreased the production of nitric oxide and the expression of inflammatory cytokines and inducible nitric oxide synthase. Finally, treatment of neuronal primary cultures with conditioned medium obtained from microglia cells, in which miR-155 was inhibited before cell activation, decreased inflammatory-mediated neuronal cell death. Overall, our results show that miR-155 has a pro-inflammatory role in microglia and is necessary for the progression of the immune response through the modulation of SOCS-1, suggesting that, in a chronic inflammatory context, miR-155 inhibition can have a neuroprotective effect.