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

Jane Tian, MedImmune
Ana Maria Avalos, Boston University
Su-Yau Mao, MedImmune
Bo Chen, MedImmune
Kannaki Senthil, MedImmune
Herren Wu, MedImmune
Peggy Parroche, University of Massachusetts Medical School
Stacey Drabic, MedImmune
Douglas T. Golenbock, University of Massachusetts Medical School
Cherilyn M. Sirois, University of Massachusetts Medical School
Jing Hua, Hospital for Special Surgery
Ling Ling An, MedImmune
Laurent Audoly, MedImmune
Greg La Rosa, Critical Therapeutics
Angelika Bierhaus, University of Heidelberg
Peter Naworth, University of Heidelberg
Ann Marshak-Rothstein, Boston University
Mary K. Crow, Hospital for Special Surgery
Katherine A. Fitzgerald, University of Massachusetts Medical School
Eicke Latz, University of Massachusetts Medical School
Peter A. Kiener, MedImmune
Anthony J. Coyle, MedImmune

Abstract

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.