Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE
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.
Jane Tian, Ana Maria Avalos, Su-Yau Mao, Bo Chen, Kannaki Senthil, Herren Wu, Peggy Parroche, Stacey Drabic, Douglas T. Golenbock, Cherilyn M. Sirois, Jing Hua, Ling Ling An, Laurent Audoly, Greg La Rosa, Angelika Bierhaus, Peter Naworth, Ann Marshak-Rothstein, Mary K. Crow, Katherine A. Fitzgerald, Eicke Latz, Peter A. Kiener, and Anthony J. Coyle. "Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE" Nature immunology 8.5 (2007): 487-496.
Available at: http://works.bepress.com/katherine_fitzgerald/93