Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction
Spatiotemporal regulation of MyD88-IRF-7 signalling for robust type-I interferon induction
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DOI：
10.1038/nature03547
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发表时间：
2005-04-21
期刊：
影响因子：
64.8
通讯作者：
Taniguchi, T
中科院分区：
文献类型：
--
作者：
Honda, K;Ohba, Y;Taniguchi, T
通过激活Toll-like受体9（TLR9）的激活，可靠的I型干扰素（IFN-Alpha/beta）在浆细胞类树突状细胞中诱导构成免疫力的关键方面（1-6）。它绝对取决于转录因子IRF-7，它与适配器MyD88（参考文献7）相互作用并激活。质细胞类动物树突状细胞，但没有其他细胞类型（例如常规树突细胞）能够激活MyD88 IRF-7依赖性IFN诱导途径仍然未知。在这里，我们表明MyD88 IRF-7信号的时空调节对于响应TLR9激活而对高级IFN诱导至关重要。 The IFN-inducing TLR9 ligand, A/D-type CpG oligodeoxynucleotide (CpG-A)(3,4,8-11), is retained for long periods in the endosomal vesicles of plasmacytoid dendritic cells, together with the MyD88-IRF- 7复合物。但是，在常规的树突状细胞中，CpG-A迅速转移到溶酶体囊泡中。我们进一步表明，如果使用阳离子脂质操纵CpG-A进行内体保留，则常规的树突状细胞也可以安装强大的IFN诱导。该策略还使我们能够通过原本不活跃的TLR9配体B/K型寡脱氧核苷酸（CPG-B）证明IFN途径的内体激活（3,4,8-12）。因此，我们的研究提供了对太空中TLR9信号的调节的见解，有可能提出一种新的治疗干预途径。
Robust type-I interferon (IFN-alpha/beta) induction in plasmacytoid dendritic cells, through the activation of Toll-like receptor 9 (TLR9), constitutes a critical aspect of immunity(1-6). It is absolutely dependent on the transcription factor IRF-7, which interacts with and is activated by the adaptor MyD88 (ref. 7). How plasmacytoid dendritic cells, but not other cell types (such as conventional dendritic cells), are able to activate the MyD88 IRF-7-dependent IFN induction pathway remains unknown. Here we show that the spatiotemporal regulation of MyD88 IRF-7 signalling is critical for a high-level IFN induction in response to TLR9 activation. The IFN-inducing TLR9 ligand, A/D-type CpG oligodeoxynucleotide (CpG-A)(3,4,8-11), is retained for long periods in the endosomal vesicles of plasmacytoid dendritic cells, together with the MyD88-IRF-7 complex. However, in conventional dendritic cells, CpG-A is rapidly transferred to lysosomal vesicles. We further show that conventional dendritic cells can also mount a robust IFN induction if CpG-A is manipulated for endosomal retention using a cationic lipid. This strategy also allows us to demonstrate endosomal activation of the IFN pathway by the otherwise inactive TLR9 ligand B/K-type oligodeoxynucleotide (CpG-B)(3,4,8-12). Thus, our study offers insights into the regulation of TLR9 signalling in space, potentially suggesting a new avenue for therapeutic intervention.