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 DN...

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Bibliographic Details
Published in:Nature Immunology 2007-05, Vol.8 (5), p.487-496
Main Authors: Coyle, Anthony J, Tian, Jane, Avalos, Ana Maria, Mao, Su-Yau, Chen, Bo, Senthil, Kannaki, Wu, Herren, Parroche, Peggy, Drabic, Stacey, Golenbock, Douglas, Sirois, Cherilyn, Hua, Jing, An, Ling Ling, Audoly, Laurent, La Rosa, Greg, Bierhaus, Angelika, Naworth, Peter, Marshak-Rothstein, Ann, Crow, Mary K, Fitzgerald, Katherine A, Latz, Eicke, Kiener, Peter A
Format: Article
Language:English
Subjects:
Animals
Antigen-Antibody Complex
Autoimmune diseases
B-Lymphocytes
Biomedical and Life Sciences
Biomedicine
CpG Islands
Dendritic cells
Dendritic Cells - cytology
Dendritic Cells - metabolism
Deoxyribonucleic acid
DNA
DNA-Binding Proteins - immunology
Genetic aspects
HMGB1 Protein - biosynthesis
HMGB1 Protein - physiology
Immune complexes
Immunology
Infectious Diseases
Lupus Erythematosus, Systemic - immunology
Lupus Erythematosus, Systemic - metabolism
Lupus Erythematosus, Systemic - pathology
Mice
Mice, Inbred C57BL
Oligodeoxyribonucleotides - immunology
Physiological aspects
Receptor for Advanced Glycation End Products - biosynthesis
Receptor for Advanced Glycation End Products - physiology
Receptors, Cell Surface - metabolism
Risk factors
Systemic lupus erythematosus
Toll-Like Receptor 9 - metabolism
Toll-Like Receptor 9 - physiology
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Summary: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.
ISSN:1529-2908
1529-2916
1365-2567
DOI:10.1038/ni1457