TY - JOUR
T1 - Anovel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA
AU - Ivanov, Stanimir
AU - Dragoi, Ana Maria
AU - Wang, Xin
AU - Dallacosta, Corrado
AU - Louten, Jennifer
AU - Musco, Giovanna
AU - Sitia, Giovanni
AU - Yap, George S.
AU - Wan, Yinsheng
AU - Biron, Christine A.
AU - Bianchi, Marco E.
AU - Wang, Haichao
AU - Chu, Wen Ming
PY - 2007/9/15
Y1 - 2007/9/15
N2 - 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 TNFα secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFα, 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.
AB - 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 TNFα secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNFα, 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.
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U2 - 10.1182/blood-2006-09-044776
DO - 10.1182/blood-2006-09-044776
M3 - Article
C2 - 17548579
AN - SCOPUS:34250837518
VL - 110
SP - 1970
EP - 1981
JO - Blood
JF - Blood
SN - 0006-4971
IS - 6
ER -