Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan.
J Immunol. 2010 Jun 15;184(12):7092-9. doi: 10.4049/jimmunol.1000490. Epub 2010 May 14.
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.
最近的研究表明，早期内体中的 TLR9 信号转导导致浆细胞样树突状细胞（pDC）产生 IFN-α，而晚期内体中的 TLR9 信号转导诱导 pDC 成熟、IL-6 和 TNF-α的分泌。在这项研究中，我们表明人类 DNA 以及与热休克蛋白 90（Hsp90）结合的 CpG 寡脱氧核苷酸（ODN）刺激 pDC 产生大量 IFN-α。Hsp90-CpG-A 复合物在 DC 内化后通过 Rab5+，早期内体 Ag 1+ 被靶向到静态早期内体，这表明通过 TLR9 产生 IFN-α信号需要 HSP90 伴侣自身 DNA/CpG-ODN 优先分拣到静态内体。有趣的是，Hsp90 介导的 CpG-ODN 优先静态早期内体易位引发了来自鼠常规 DC 的强烈 IFN-α 产生。因此，细胞外 HSP90 通过时空调节将惰性自身 DNA/CpG-ODN 转化为 IFN-α 产生的有效触发物。
