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

J Tian, AM Avalos, SY Mao, B Chen, K Senthil… - Nature …, 2007 - nature.com
J Tian, AM Avalos, SY Mao, B Chen, K Senthil, H Wu, P Parroche, S Drabic, D Golenbock
Nature immunology, 2007nature.com
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 …
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.
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