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.
Tian
Jane
J
Inflammation and Autoimmune Group, Research Department, MedImmune, Gaithersburg, Maryland 20878, USA.
Avalos
Ana Maria
AM
Mao
Su-Yau
SY
Chen
Bo
B
Senthil
Kannaki
K
Wu
Herren
H
Parroche
Peggy
P
Drabic
Stacey
S
Golenbock
Douglas
D
Sirois
Cherilyn
C
Hua
Jing
J
An
Ling Ling
LL
Audoly
Laurent
L
La Rosa
Greg
G
Bierhaus
Angelika
A
Naworth
Peter
P
Marshak-Rothstein
Ann
A
Crow
Mary K
MK
Fitzgerald
Katherine A
KA
Latz
Eicke
E
Kiener
Peter A
PA
Coyle
Anthony J
AJ
D000818:Animals; D000936:Antigen-Antibody Complex; D001402:B-Lymphocytes; D018899:CpG Islands; D004268:DNA-Binding Proteins / Q000276:immunology; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000502:physiology*; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D000067759:Receptor for Advanced Glycation End Products / Q000096:biosynthesis / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000378:metabolism* / Q000502:physiology
C000593871:AGER protein, human; D000936:Antigen-Antibody Complex; D004268:DNA-Binding Proteins; D024243:HMGB1 Protein; D009838:Oligodeoxyribonucleotides; D000067759:Receptor for Advanced Glycation End Products; D011956:Receptors, Cell Surface; D051217:Toll-Like Receptor 9