Spatiotemporal Regulation of Heat Shock Protein 90-Chaperoned Self-DNA and CpG-Oligodeoxynucleotide for Type I IFN Induction via Targeting to Static Early Endosome
Spatiotemporal Regulation of Heat Shock Protein 90-Chaperoned Self-DNA and CpG-Oligodeoxynucleotide for Type I IFN Induction via Targeting to Static Early Endosome
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DOI：
10.4049/jimmunol.1000490
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发表时间：
2010-06-15
影响因子：
4.4
通讯作者：
Sato, Noriyuki
中科院分区：
文献类型：
--
作者：
Okuya, Koichi;Tamura, Yasuaki;Sato, Noriyuki
最近的研究表明，早期内体中的TLR 9信号传导导致浆细胞样树突状细胞（pDC）产生IFN-α，而晚期内体中的TLR 9信号传导诱导pDC成熟、IL-6和TNF-α分泌。在这项研究中，我们表明，人类DNA以及CpG-寡脱氧核苷酸（ODNs）与热休克蛋白90（Hsp 90）的复合物刺激pDCs产生大量的IFN-α。Hsp 90-CpG-A复合物被靶向Rab 5（+），早期内体Ag 1（+）-静态早期内体被DC后内化，表明Hsp 90-陪伴的自身DNA/CpG-ODN优先分选到静态内体是通过TLR 9产生IFN-α的信号传导所需的。有趣的是，Hsp 90介导的CpG-ODN的优先静态早期内体易位触发了来自鼠常规DC的稳健IFN-α产生。因此，细胞外Hsp 90通过时空调节将惰性自身DNA/CpG-ODN转化为IFN-α产生的有效触发剂。免疫学杂志，2010，184：7092-7099。
Recent studies have suggested that TLR9 signaling in early endosomes leads to IFN-alpha production by plasmacytoid dendritic cells (pDCs), whereas TLR9 signaling in late endosomes induces pDC maturation, IL-6, and TNF-alpha secretion. In this study, we show that human DNA as well as CpG-oligodeoxynucleotides (ODNs) in complex with heat shock protein 90 (Hsp90) stimulate pDCs to produce large quantities of IFN-alpha. The Hsp90-CpG-A complexes are targeted into the Rab5(+), early endosomal Ag 1(+)-static early endosome postinternalization by DCs, suggesting that preferential sorting of Hsp90-chaperoned self-DNA/CpG-ODNs to the static endosome is required for signaling through TLR9 for IFN-alpha production. Interestingly, Hsp90-mediated preferential static early endosomal translocation of CpG-ODNs triggers robust IFN-alpha production from murine conventional DCs. Thus, extracellular Hsp90 converts inert self-DNA/CpG-ODNs into a potent trigger of IFN-alpha production via spatiotemporal regulation. The Journal of Immunology, 2010, 184: 7092-7099.