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

DOI PDF 15 Citations
  • Stanimir Ivanov
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Ana-Maria Dragoi
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Xin Wang
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Corrado Dallacosta
    San Raffaele Scientific Institute, Milano, Italy;
  • Jennifer Louten
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Giovanna Musco
    San Raffaele Scientific Institute, Milano, Italy;
  • Giovanni Sitia
    San Raffaele Scientific Institute, Milano, Italy;
  • George S. Yap
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Yinsheng Wan
    Department of Biology, Providence College, Providence, RI;
  • Christine A. Biron
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;
  • Marco E. Bianchi
    San Raffaele University, Faculty of Medicine, Milano, Italy;
  • Haichao Wang
    Department of Emergency Medicine, North Shore-Long Island Jewish Research Institute, Manhasset, NY
  • Wen-Ming Chu
    Department of Molecular Microbiology and Immunology, Brown University, Providence, RI;

Description

<jats:title>Abstract</jats:title><jats:p>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.</jats:p>

Journal

  • Blood

    Blood 110 (6), 1970-1981, 2007-09-15

    American Society of Hematology

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