Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE

Nat Immunol. 2007 May;8(5):487-96. doi: 10.1038/ni1457. Epub 2007 Apr 8.


Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9-MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigen-Antibody Complex
  • B-Lymphocytes
  • CpG Islands
  • DNA-Binding Proteins / immunology
  • Dendritic Cells / cytology
  • Dendritic Cells / metabolism
  • HMGB1 Protein / biosynthesis
  • HMGB1 Protein / physiology*
  • Lupus Erythematosus, Systemic / immunology*
  • Lupus Erythematosus, Systemic / metabolism
  • Lupus Erythematosus, Systemic / pathology
  • Mice
  • Mice, Inbred C57BL
  • Oligodeoxyribonucleotides / immunology*
  • Receptor for Advanced Glycation End Products / biosynthesis
  • Receptor for Advanced Glycation End Products / physiology*
  • Receptors, Cell Surface / metabolism
  • Toll-Like Receptor 9 / metabolism*
  • Toll-Like Receptor 9 / physiology


  • AGER protein, human
  • Antigen-Antibody Complex
  • DNA-Binding Proteins
  • HMGB1 Protein
  • Oligodeoxyribonucleotides
  • Receptor for Advanced Glycation End Products
  • Receptors, Cell Surface
  • Toll-Like Receptor 9