Hsp90 controls immune response through spatio-temporal regulation of chaperoned molecule via targeting dendritic cells

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Recent studies have suggested that Toll-like recepor 9 (TLR9) signaling in early endosomes leads to interferon-a production by plasmacytoid dendritic cells (pDCs), whereas TLR9 signaling in late endosomes induces pDC maturation, IL-6 and TNF-a secretion. Here 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-a. The Hsp90-CpG-A complexes are targeted into the Rab5^+, EEA1^+- "static" early endosome after internalization 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-a production. Thus, extracellular Hsp90 converts inert self-DNA/CpG-ODNs into a potent trigger of IFN-a production via spatiotemporal regulation.