Accuri C6 Flow Cytometer System
Originally published online as doi:10.1189/jlb.0509314 on July 20, 2009

Published online before print July 20, 2009
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(Journal of Leukocyte Biology. 2009;86:663-670.)
© 2009 Society for Leukocyte Biology

Higher activation of TLR9 in plasmacytoid dendritic cells by microbial DNA compared with self-DNA based on CpG-specific recognition of phosphodiester DNA

Christoph Coch*,1, Nicolas Busch*,1, Vera Wimmenauer*, Evelyn Hartmann{dagger}, Markus Janke*, Mona Mohamed Ahmed Abdel-Mottaleb{ddagger}, Alf Lamprecht{ddagger}, Janos Ludwig*, Winfried Barchet*, Martin Schlee*,1 and Gunther Hartmann*,1,2

* Institute of Clinical Chemistry and Pharmacology, and
{dagger} Clinic and Policlinic for Otolaryngology/Ear, Nose and Throat Surgery, University Hospital of Bonn, Bonn, Germany; and
{ddagger} Laboratory of Pharmaceutical Engineering and Biopharmaceutics, Institute of Pharmacy, University of Bonn, Bonn, Germany

2. Correspondence: Institut für Klinische Chemie und Pharmakologie, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, D-53127 Bonn, Germany. E-mail: gunther.hartmann{at}ukb.uni-bonn.de

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-{alpha} and TNF-{alpha} 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-{alpha} in PDC; IFN-{alpha} was reduced but not abolished upon methylation of bacterial DNA. Mammalian DNA containing low numbers of CG dinucleotides, which are frequently methylated, induced IFN-{alpha} 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.

Key Words: IFN-{alpha} • innate immune response




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