Back to Search
Start Over
A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA.
- Source :
-
Blood [Blood] 2007 Sep 15; Vol. 110 (6), pp. 1970-81. Date of Electronic Publication: 2007 Jun 04. - Publication Year :
- 2007
-
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.
- Subjects :
- Animals
Calnexin metabolism
Cell Nucleus metabolism
CpG Islands
Endoplasmic Reticulum drug effects
Endoplasmic Reticulum metabolism
Enzyme-Linked Immunosorbent Assay
Extracellular Matrix metabolism
Flow Cytometry
Golgi Apparatus drug effects
Golgi Apparatus metabolism
HMGB1 Protein genetics
Immunoblotting
Immunoprecipitation
Lysosomes metabolism
Macrophages cytology
Macrophages drug effects
Macrophages metabolism
Mannose-Binding Lectins metabolism
Membrane Proteins metabolism
Mice
Mice, Knockout
Nitric Oxide Synthase Type II metabolism
Secretory Vesicles drug effects
Secretory Vesicles metabolism
Toll-Like Receptor 9 genetics
HMGB1 Protein physiology
Interleukin-12 metabolism
Interleukin-6 metabolism
Oligodeoxyribonucleotides pharmacology
Toll-Like Receptor 9 physiology
Tumor Necrosis Factor-alpha metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 0006-4971
- Volume :
- 110
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 17548579
- Full Text :
- https://doi.org/10.1182/blood-2006-09-044776