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-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.