Toll 样受体对 RNA 识别的抑制：核苷修饰的影响与 RNA 的进化起源
Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA
DNA 和 RNA 能通过 Toll 样受体（识别病原体分子的先天免疫感受器）激活哺乳动物免疫系统，但含甲基化 CpG 的 DNA 不具刺激性。天然 RNA 中的部分核苷也是甲基化或修饰的，但其免疫调节作用此前未被检验。本研究发现 RNA 通过人类 TLR3、TLR7 和 TLR8 传递信号，而掺入修饰核苷 m5C、m6A、m5U、s2U 或假尿苷后这种活性被消除。树突状细胞（免疫系统中呈递抗原、启动免疫反应的细胞）接触这类修饰 RNA 后，表达的细胞因子和活化标志物显著少于接触未修饰 RNA 时。细菌和线粒体 RNA 能强烈激活树突状细胞和 TLR 表达细胞，而富含修饰核苷的哺乳动物总 RNA 则不能。作者结论是核苷修饰抑制了 RNA 激活树突状细胞的能力，先天免疫系统可能借此识别缺乏修饰的 RNA，从而选择性应对细菌或坏死组织。
为什么推荐给您：揭示核苷修饰抑制 RNA 免疫激活，奠定 mRNA 疫苗修饰核苷这一核心平台技术。
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人体免疫系统靠 Toll 样受体识别外来的 DNA 和 RNA。
摘要Abstract
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.