Article abstract
Nature Immunology 8, 487 - 496 (2007)
Published online: 8 April 2007 | Corrected online: 24 May 2007 | doi:10.1038/ni1457
Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE
Jane Tian1, Ana Maria Avalos2, Su-Yau Mao1, Bo Chen1, Kannaki Senthil1, Herren Wu1, Peggy Parroche3, Stacey Drabic1, Douglas Golenbock3, Cherilyn Sirois3, Jing Hua4, Ling Ling An1, Laurent Audoly1, Greg La Rosa5, Angelika Bierhaus6, Peter Naworth6, Ann Marshak-Rothstein2, Mary K Crow4, Katherine A Fitzgerald3, Eicke Latz3, Peter A Kiener1 & Anthony J Coyle1
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.
- Inflammation and Autoimmune Group, Research Department, MedImmune, Gaithersburg, Maryland 20878, USA.
- Department of Microbiology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
- Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA.
- Rheumatology Research and Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, New York 10021, USA.
- Critical Therapeutics, Lexington Massachusetts 02421, USA.
- Department of Medicine, University of Heidelberg, Heidelberg D-69115, Germany.
Correspondence to: Anthony J Coyle1 e-mail: coylea@medimmune.com
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