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 Blood, 15 September 2007, Vol. 110, No. 6, pp. 1970-1981.
Prepublished online as a Blood First Edition Paper on June 4, 2007; DOI 10.1182/blood-2006-09-044776.

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IMMUNOBIOLOGY

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

Stanimir Ivanov1, Ana-Maria Dragoi1, Xin Wang1, Corrado Dallacosta2, Jennifer Louten1, Giovanna Musco2, Giovanni Sitia2, George S. Yap1, Yinsheng Wan3, Christine A. Biron1, Marco E. Bianchi4, Haichao Wang5, and Wen-Ming Chu1

1 Department of Molecular Microbiology and Immunology, Brown University, Providence, RI; 2 San Raffaele Scientific Institute, Milano, Italy; 3 Department of Biology, Providence College, Providence, RI; 4 San Raffaele University, Faculty of Medicine, Milano, Italy; 5 Department of Emergency Medicine, North Shore-Long Island Jewish Research Institute, Manhasset, NY

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 TNF{alpha} secretion. Loss of HMGB1 leads to a defect in the IL-6, IL-12, TNF{alpha}, 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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