Higher activation of TLR9 in plasmacytoid dendritic cells by microbial DNA compared with self-DNA based on CpG-specific recognition of phosphodiester DNA
Coch, Christoph; Busch, Nicolas; Wimmenauer, Vera; Hartmann, Evelyn; Janke, Markus; Abdel-Mottaleb, Mona; Lamprecht, Alf; Ludwig, Janos; Barchet, Winfried; Schlee, Martin; Hartmann, Gunther;
Abstract
TLR9 detects DNA in endolysosomal compartments of human B cells and PDC. Recently, the concept of the CpG motif specificity of TLR9-mediated detection, specifically of natural phosphodiester DNA, has been challenged. Unlike in human B cells, CpG specificity of natural phosphodiester DNA recognition in human PDC has not been analyzed in the literature. Here, we found that the induction of IFN-α and TNF-α in human PDC by phosphodiester ODNs containing one or two CG dinucleotides was reduced to a lower level when the CG dinucleotides were methylated and was abolished if the CGs were switched to GCs. Consistent with a high frequency of unmethylated CG dinucleotides, bacterial DNA induced high levels of IFN-α in PDC; IFN-α was reduced but not abolished upon methylation of bacterial DNA. Mammalian DNA containing low numbers of CG dinucleotides, which are frequently methylated, induced IFN-α in PDC consistently but on a much lower level than bacterial DNA. For activation of PDC, phosphodiester ODNs and genomic DNA strictly required complexation with cationic molecules such as the keratinocyte-derived antimicrobial peptide LL37 or a scrambled derivative. In conclusion, we demonstrate that self-DNA complexed to cationic molecules activate PDC and thus, indeed, may function as DAMPs; nevertheless, the preference of PDC for CpG containing DNA provides the basis for the discrimination of microbial from self-DNA even if DNA is presented in the condensed form of a complex. © Society for Leukocyte Biology.
Other data
Title | Higher activation of TLR9 in plasmacytoid dendritic cells by microbial DNA compared with self-DNA based on CpG-specific recognition of phosphodiester DNA | Authors | Coch, Christoph; Busch, Nicolas; Wimmenauer, Vera; Hartmann, Evelyn; Janke, Markus; Abdel-Mottaleb, Mona ; Lamprecht, Alf; Ludwig, Janos; Barchet, Winfried; Schlee, Martin; Hartmann, Gunther | Keywords | IFN-α;Innate immune response | Issue Date | 1-Sep-2009 | Publisher | WILEY | Journal | Journal of Leukocyte Biology | ISSN | 07415400 | DOI | 10.1189/jlb.0509314 | PubMed ID | 19620253 | Scopus ID | 2-s2.0-70149090387 | Web of science ID | WOS:000269377200025 |
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