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PMID: 17548579 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.

Blood ·Vol. 110 ·No. 6 ·2007-09-15 ·Pages 1970-81

Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, Sitia G, Yap GS, Wan Y, Biron CA, Bianchi ME, Wang H, Chu WM

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.

MeSH Terms
Animals Calnexin/metabolism Cell Nucleus/metabolism CpG Islands Endoplasmic Reticulum/drug effects,metabolism Enzyme-Linked Immunosorbent Assay Extracellular Matrix/metabolism Flow Cytometry Golgi Apparatus/drug effects,metabolism HMGB1 Protein/genetics,physiology Immunoblotting Immunoprecipitation Interleukin-12/metabolism Interleukin-6/metabolism Lysosomes/metabolism Macrophages/cytology,drug effects,metabolism Mannose-Binding Lectins/metabolism Membrane Proteins/metabolism Mice Mice, Knockout Nitric Oxide Synthase Type II/metabolism Oligodeoxyribonucleotides/pharmacology Secretory Vesicles/drug effects,metabolism Toll-Like Receptor 9/genetics,physiology Tumor Necrosis Factor-alpha/metabolism
Chemicals
CPG-oligonucleotide ERGIC-53 protein, mouse HMGB1 Protein Interleukin-6 Mannose-Binding Lectins Membrane Proteins Oligodeoxyribonucleotides Tlr9 protein, mouse Toll-Like Receptor 9 Tumor Necrosis Factor-alpha Calnexin Interleukin-12 Nitric Oxide Synthase Type II Nos2 protein, mouse
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Ivanov Stanimir
Department of Molecular Microbiology and Immunology, Brown University, Providence, RI 02912, USA.
Dragoi Ana-Maria
Wang Xin
Dallacosta Corrado
Louten Jennifer
Musco Giovanna
Sitia Giovanni
Yap George S
Wan Yinsheng
Biron Christine A
Bianchi Marco E
Wang Haichao
Chu Wen-Ming
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Article Info
Journal
Blood
Abbr.
Blood
ISSN
0006-4971
DOI
10.1182/blood-2006-09-044776
Published
2007-09-15
Epub
2007-00-04
Pages
1970-81
Language
English
Region
United States
NLM ID
7603509
PMCID
PMC1976374
Subset
IM
Grants
NIAID NIH HHS · AI54128 · United States
NIAID NIH HHS · AI55677 · United States
NIAID NIH HHS · R56 AI055677 · United States
NIAID NIH HHS · R01 AI054128 · United States
NIAID NIH HHS · R01 AI055677 · United States
External Links
PubMed source DOI: 10.1182/blood-2006-09-044776 PMC Full Text View journal details
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