title: Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE.
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.
authors.affiliation: Inflammation and Autoimmune Group, Research Department, MedImmune, Gaithersburg, Maryland 20878, USA.
authors.forename: Jane
authors.initials: J
authors.lastname: Tian
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Avalos
authors.forename: Su-Yau
authors.initials: SY
authors.lastname: Mao
authors.forename: Bo
authors.initials: B
authors.lastname: Chen
authors.forename: Kannaki
authors.initials: K
authors.lastname: Senthil
authors.forename: Herren
authors.initials: H
authors.lastname: Wu
authors.forename: Peggy
authors.initials: P
authors.lastname: Parroche
authors.forename: Stacey
authors.initials: S
authors.lastname: Drabic
authors.forename: Douglas
authors.initials: D
authors.lastname: Golenbock
authors.forename: Cherilyn
authors.initials: C
authors.lastname: Sirois
authors.forename: Jing
authors.initials: J
authors.lastname: Hua
authors.forename: Ling Ling
authors.initials: LL
authors.lastname: An
authors.forename: Laurent
authors.initials: L
authors.lastname: Audoly
authors.forename: Greg
authors.initials: G
authors.lastname: La Rosa
authors.forename: Angelika
authors.initials: A
authors.lastname: Bierhaus
authors.forename: Peter
authors.initials: P
authors.lastname: Naworth
authors.forename: Ann
authors.initials: A
authors.lastname: Marshak-Rothstein
authors.forename: Mary K
authors.initials: MK
authors.lastname: Crow
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Fitzgerald
authors.forename: Eicke
authors.initials: E
authors.lastname: Latz
authors.forename: Peter A
authors.initials: PA
authors.lastname: Kiener
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Coyle
mesh_terms: 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
chemical_list: 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