Suppression of RNA recognition by Toll-like receptors:: The impact of nucleoside modification and the evolutionary origin of RNA
Suppression of RNA recognition by Toll-like receptors:: The impact of nucleoside modification and the evolutionary origin of RNA
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DOI：
10.1016/j.immuni.2005.06.008
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发表时间：
2005-08-01
期刊：
影响因子：
32.4
通讯作者：
Weissman, D
中科院分区：
文献类型：
--
作者：
Karikó, K;Buckstein, M;Weissman, D
DNA和RNA通过激活Toll样受体(TLRs)刺激哺乳动物的先天免疫系统。然而，含有甲基化CpG基序的DNA并不具有刺激性。自然产生的RNA中的部分核苷也被甲基化或以其他方式修饰，但这些改变的免疫调节效果仍未得到测试。我们发现通过人TLR3、TLR7和TLR8的RNA信号，但掺入修饰的核苷M5C、M6A、M5U、S2U或假尿苷会抑制活性。接触这种修饰RNA的树突状细胞(DC)比未修饰RNA处理的DC表达的细胞因子和激活标志物明显减少。表达DC和TLR的细胞可被细菌和线粒体RNA有效激活，但不能被哺乳动物总RNA激活，哺乳动物总RNA富含修饰的核苷。我们的结论是，核苷修饰抑制了RNA激活DC的潜力。因此，先天免疫系统可能会检测到缺乏核苷修饰的RNA，作为选择性地对细菌或坏死组织做出反应的一种手段。
DNA and RNA stimulate the mammalian innate immune system through activation of Toll-like receptors (TLRs). DNA containing methylated CpG motifs, however, is not stimulatory. Selected nucleosides in naturally occurring RNA are also methylated or otherwise modified, but the immunomodulatory effects of these alterations remain untested. We show that RNA signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity. Dendritic cells (DCs) exposed to such modified RNA express significantly less cytokines and activation markers than those treated with unmodified RNA. DCs and TLR-expressing cells are potently activated by bacterial and mitochondrial RNA, but not by mammalian total RNA, which is abundant in modified nucleosides. We conclude that nucleoside modifications suppress the potential of RNA to activate DCs. The innate immune system may therefore detect RNA lacking nucleoside modification as a means of selectively responding to bacteria or necrotic tissue.