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

Stanimir Ivanov, Ana Maria Dragoi, Xin Wang, Corrado Dallacosta, Jennifer Louten, Giovanna Musco, Giovanni Sitia, George S. Yap, Yinsheng Wan, Christine A. Biron, Marco E. Bianchi, Haichao Wang, Wen Ming Chu

Research output: Contribution to journalArticlepeer-review

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 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.

Original languageEnglish
Pages (from-to)1970-1981
Number of pages12
JournalBlood
Volume110
Issue number6
DOIs
Publication statusPublished - Sep 15 2007

ASJC Scopus subject areas

  • Hematology

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