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CpG motif‐independent activation of TLR9 upon endosomal translocation of “natural” phosphodiester DNA
Author(s) -
Yasuda Kei,
Rutz Mark,
Schlatter Beatrix,
Metzger Jochen,
Luppa Peter B.,
Schmitz Frank,
Haas Tobias,
Heit Antje,
Bauer Stefan,
Wagner Hermann
Publication year - 2006
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200535210
Subject(s) - tlr9 , toll like receptor 9 , phosphodiester bond , dna , biology , cpg site , endosome , microbiology and biotechnology , cpg oligodeoxynucleotide , biochemistry , gene , intracellular , rna , dna methylation , gene expression
Abstract Endosomally translocated host (self) DNA activates Toll‐like receptor 9 (TLR9), while extracellular self‐DNA does not. This inconsistency reflects poor endosomal DNA translocation but also implies that host DNA contains DNA sequences that function as ligands for TLR9. Herein we report that contrary to phosphorothioate (PS)‐stabilized oligonucleotides (ODN), “natural” phosphodiester (PD) ODN lacking CpG motifs activate TLR9. CpG motif‐independent TLR9 activation of Flt3‐L‐induced dendritic cells (DC) was dependent on enforced endosomal translocation and triggered upregulation of CD40 and CD69 as well as production of IL‐6 and IFN‐α. Binding studies utilizing surface plasmon resonance technology (Biacore) revealed low TLR9 binding to single‐stranded (ss) PD‐ODN lacking CpG motifs. At higher concentrations their TLR9 binding activity compared well with TLR9 binding of canonical ss PD CpG‐ODN. These results imply that both the chemical modification of the DNA backbone as well as the amount of endosomally translocated DNA represent determining factors that allow CpG motif‐independent activation of TLR9 by ss PD‐DNA.