Spatiotemporal regulation of heat shock protein 90-chaperoned self-DNA and CpG-oligodeoxynucleotide for type I IFN induction via targeting to static early endosome

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-oligodeoxynu...

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Published inThe Journal of immunology (1950) Vol. 184; no. 12; pp. 7092 - 7099
Main Authors Okuya, Koichi, Tamura, Yasuaki, Saito, Keita, Kutomi, Goro, Torigoe, Toshihiko, Hirata, Koichi, Sato, Noriyuki
Format Journal Article
LanguageEnglish
Published United States 15.06.2010
Subjects
Animals
Autoantigens - immunology
Cell Separation
Dendritic Cells - immunology
Dendritic Cells - metabolism
DNA - immunology
Endosomes - immunology
Endosomes - metabolism
Flow Cytometry
HSP90 Heat-Shock Proteins - immunology
HSP90 Heat-Shock Proteins - metabolism
Humans
Interferon Type I - biosynthesis
Interferon Type I - immunology
Mice
Mice, Inbred C57BL
Microscopy, Confocal
Oligodeoxyribonucleotides - immunology
Protein Transport
Toll-Like Receptor 9 - immunology
Toll-Like Receptor 9 - metabolism
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Summary: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.
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ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1000490