A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.
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.
Ivanov
Stanimir
S
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Dragoi
Ana-Maria
AM
Wang
Xin
X
Dallacosta
Corrado
C
Louten
Jennifer
J
Musco
Giovanna
G
Sitia
Giovanni
G
Yap
George S
GS
Wan
Yinsheng
Y
Biron
Christine A
CA
Bianchi
Marco E
ME
Wang
Haichao
H
Chu
Wen-Ming
WM
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*
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