Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells
Transcriptional profiling reveals that C5a alters microRNA in brain endothelial cells
复制标题
DOI：
10.1111/imm.12314
复制
发表时间：
2014-11-01
期刊：
影响因子：
6.4
通讯作者：
Alexander, Jessy J.
中科院分区：
文献类型：
--
作者：
Eadon, Michael T.;Jacob, Alexander;Alexander, Jessy J.
血脑屏障（BBB）紊乱是许多神经系统疾病的一个重要发生，包括系统性红斑狼疮（SLE）。我们之前的研究表明，实验性狼疮血清改变了小鼠脑内皮层的完整性，而内皮层是血脑屏障的重要组成部分。补体激活发生在狼疮中，循环补体成分增加。使用基因组学方法，我们鉴定了狼疮血清和补体蛋白 C5a 在小鼠脑内皮细胞 (bEnd3) 中改变的 microRNA (miRNA)。与对照相比，在评估的 318 个 miRNA 中，23 个 miRNA 被狼疮血清改变，32 个 miRNA 被单独的 C5a 改变。两种处理有 7 个 miRNA (P < 0.05) 差异表达：mmu-miR-133a*、mmu-miR-193*、mmu-miR-26b、mmu-miR-28*、mmu-miR-320a、mmu-miR-423-3p 和 mmu-miR-509-5p。微阵列结果通过定量 RT-PCR 进行验证。与体外结果一致，狼疮小鼠脑中 miR-26b 和 miR-28* 的表达也显着上调，而 C5a 受体抑制可降低这种表达。靶标预测分析揭示了 miR 基因靶标编码参与炎症、基质排列和细胞凋亡的成分，这些途径已知在中枢神经系统狼疮中发挥重要作用。我们的研究结果表明，本研究报告的 miRNA 可能代表中枢神经系统狼疮和其他类似神经炎症环境的新治疗靶点。
Blood-brain barrier (BBB) disturbance is a crucial occurrence in many neurological diseases, including systemic lupus erythematosus (SLE). Our previous studies showed that experimental lupus serum altered the integrity of the mouse brain endothelial layer, an important constituent of the BBB. Complement activation occurs in lupus with increased circulating complement components. Using a genomics approach, we identified the microRNA (miRNA) altered in mouse brain endothelial cells (bEnd3) by lupus serum and the complement protein, C5a. Of the 318 miRNA evaluated, 23 miRNAs were altered by lupus serum and 32 were altered by C5a alone compared with controls. Seven miRNAs (P < 0.05) were differentially expressed by both treatments: mmu-miR-133a*, mmu-miR-193*, mmu-miR-26b, mmu-miR-28*, mmu-miR-320a, mmu-miR-423-3p and mmu-miR-509-5p. The microarray results were validated by quantitative RT-PCR. In line with the in vitro results, expression of miR-26b and miR-28* were also significantly up-regulated in lupus mouse brain which was reduced by C5a receptor inhibition. Target prediction analysis revealed miR gene targets encoding components involved in inflammation, matrix arrangement, and apoptosis, pathways known to play important roles in central nervous system lupus. Our findings suggest that the miRNAs reported in this study may represent novel therapeutic targets in central nervous system lupus and other similar neuroinflammatory settings.