title: A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.
abstract: CpG-DNA or its synthetic analog CpG-ODN activates innate immunity through Toll-like receptor 9 (TLR9). However, the mechanism of TLR9 activation by CpG-DNA remains elusive. Here we have identified HMGB1 as a CpG-ODN-binding protein. HMGB1 interacts and preassociates with TLR9 in the endoplasmic reticulum-Golgi intermediate compartment (ERGIC), and hastens TLR9's redistribution to early endosomes in response to CpG-ODN. CpG-ODN stimulates macrophages and dendritic cells to secrete HMGB1; in turn, extracellular HMGB1 accelerates the delivery of CpG-ODNs to its receptor, leading to a TLR9-dependent augmentation of IL-6, IL-12, and TNFalpha secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFalpha, and iNOS response to CpG-ODN. However, lack of intracellular TLR9-associated HMGB1 can be compensated by extracellular HMGB1. Thus, the DNA-binding protein HMGB1 shuttles in and out of immune cells and regulates inflammatory responses to CpG-DNA.
authors.affiliation: Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
authors.forename: Stanimir
authors.initials: S
authors.lastname: Ivanov
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Dragoi
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Corrado
authors.initials: C
authors.lastname: Dallacosta
authors.forename: Jennifer
authors.initials: J
authors.lastname: Louten
authors.forename: Giovanna
authors.initials: G
authors.lastname: Musco
authors.forename: Giovanni
authors.initials: G
authors.lastname: Sitia
authors.forename: George S
authors.initials: GS
authors.lastname: Yap
authors.forename: Yinsheng
authors.initials: Y
authors.lastname: Wan
authors.forename: Christine A
authors.initials: CA
authors.lastname: Biron
authors.forename: Marco E
authors.initials: ME
authors.lastname: Bianchi
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Chu
mesh_terms: D000818:Animals; D037281:Calnexin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D018899:CpG Islands; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005109:Extracellular Matrix / Q000378:metabolism; D005434:Flow Cytometry; D006056:Golgi Apparatus / Q000187:drug effects / Q000378:metabolism; D024243:HMGB1 Protein / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D047468:Immunoprecipitation; D018664:Interleukin-12 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D037241:Mannose-Binding Lectins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D022142:Secretory Vesicles / Q000187:drug effects / Q000378:metabolism; D051217:Toll-Like Receptor 9 / Q000235:genetics / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; C515307:ERGIC-53 protein, mouse; D024243:HMGB1 Protein; D015850:Interleukin-6; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D009838:Oligodeoxyribonucleotides; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D037281:Calnexin; D018664:Interleukin-12; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse