Endosomal translocation of vertebrate DNA activates dendritic cells via TLR9-dependent and -independent pathways.

Mitochondrial Transcription Factor A, an Endogenous Danger Signal, Promotes TNFα Release via RAGE- and TLR9-Responsive Plasmacytoid Dendritic Cells

OBJECTIVE Mitochondrial transcription factor A (TFAM) is normally bound to and remains associated with mitochondrial DNA (mtDNA) when released from damaged cells. We hypothesized that TFAM, bound to mtDNA (or equivalent CpG-enriched DNA), amplifies TNFα release from TLR9-expressing plasmacytoid dendritic cells (pDCs) by engaging RAGE. MATERIALS AND METHODS Murine Flt3 ligand-expanded splenocy...

Comment on "TLR9-dependent activation of dendritic cells by DNA from Leishmania major favors Th1 cell development and the resolution of lesions".

In its vertebrate host, Leishmania encounters cells that express TLRs. Using genetically resistant C57BL/6 mice deficient in either TLR2, 4, or 9, we show in this study that only TLR9-deficient mice are more susceptible to infection with Leishmania major. TLR9-deficient mice resolved their lesions and controlled parasites growth with much lower efficiency than wild-type C57BL/6 mice. The absenc...

Vaccination with plasmid DNA activates dendritic cells via Toll-like receptor 9 (TLR9) but functions in TLR9-deficient mice.

We analyzed whether the immunobiology of vaccinating plasmid DNA containing a transcription unit for OVA is influenced by immunostimulatory CpG motifs in the plasmid backbone. Indeed, plasmid DNA differentially activated in vitro myeloid and plasmacytoid dendritic cells (DCs) provided they expressed the CpG-DNA receptor, Toll-like receptor 9 (TLR9). Dependent on the DC subset, activation result...

Nuclear Translocation of IRF7 Endosomal Translocation of TLR9 and Mediating of Plasmacytoid Dendritic Cells by SCARB2/LIMP-2 Regulates IFN Production

The tyrosine kinase inhibitor dasatinib suppresses cytokine production by plasmacytoid dendritic cells by targeting endosomal transport of CpG DNA.

Plasmacytoid dendritic cells (pDCs) produce a vast amount of interferon (IFN)-α in response to nucleic acids from viruses and damaged self-cells through Toll-like receptor (TLR)7 and TLR9. Pharmaceutical agents that suppress IFN-α production by pDCs are instrumental in elucidating the mechanisms behind IFN-α production, and in developing novel therapies for inflammatory disorders that involve p...