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Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE

Nature Immunology volume 8, pages 487–496 (2007)Cite this article

A Corrigendum to this article was published on 01 July 2007

This article has been updated

Abstract

Increased concentrations of DNA-containing immune complexes in the serum are associated with systemic autoimmune diseases such as lupus. Stimulation of Toll-like receptor 9 (TLR9) by DNA is important in the activation of plasmacytoid dendritic cells and B cells. Here we show that HMGB1, a nuclear DNA-binding protein released from necrotic cells, was an essential component of DNA-containing immune complexes that stimulated cytokine production through a TLR9–MyD88 pathway involving the multivalent receptor RAGE. Moreover, binding of HMGB1 to class A CpG oligodeoxynucleotides considerably augmented cytokine production by means of TLR9 and RAGE. Our data demonstrate a mechanism by which HMGB1 and RAGE activate plasmacytoid dendritic cells and B cells in response to DNA and contribute to autoimmune pathogenesis.

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Figure 1: HMGB1 binds to CpG-A DNA and augments cytokine production by pDCs.
Figure 2: HMGB1 B-box augments IFN-α production induced by immunostimulatory CpG-A.
Figure 3: CpG-A but not CpG-B augments the binding of HMGB1 to RAGE.
Figure 4: RAGE-TLR9–dependent IFN-α production induced by HMGB1–CpG-A.
Figure 5: HMGB1 is present in DNA-containing immune complexes: inhibition of binding by RAGE-Fc.
Figure 6: Inhibition of AM-14 B cell proliferation induced by DNA-containing immune complexes by RAGE-Fc and A box antagonist.
Figure 7: The HMGB1-CpG-A complex recruits RAGE, MyD88 and TLR9.
Figure 8: HMGB1 and RAGE mediate the induction of genes encoding type I interferons mediated by DNA-containing immune complexes present in sera from people with lupus.

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  • 24 May 2007

    In the version of this article initially published, the legends for Figures 3c and 5b fail to indicate that portions of these are the same experiments as in Figures 3b and 5a, respectively. The correct legends state “Binding with or without CpG-A is from the same experiment as in b” (for Fig. 3c) and “Data for PL2-3 in the presence of supernatant alone (bold lines) as detected by anti-IgG2a (left, a,b) and by anti-HMGB1 (right, a,b) are from the same experiment” (for Fig. 5b). Also, error bars are missing from Figure 3c. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank M. McCarthy and J. Suzich for comments on the manuscript; J.-C. Finet for trytophan intrinsic fluorescence measurements; and L. Xu for technical assistance. TLR9- and MyD88-deficient mice were from S. Akira (Research Institute for Microbial Diseases); HMGB1-deficient MEFs were from M. Bianchi (San Raffaele University). Supported by Deutsche Forschungsgemeinschaft (DFG/SFB 405 to P.P.N.), the Alliance for Lupus Research and the National Institutes of Health (AI0677497-01).

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Authors and Affiliations

  1. Research Department, Inflammation and Autoimmune Group, MedImmune, Gaithersburg, 20878, Maryland, USA

    Jane Tian, Su-Yau Mao, Bo Chen, Kannaki Senthil, Herren Wu, Stacey Drabic, Ling Ling An, Laurent Audoly, Peter A Kiener & Anthony J Coyle

  2. Department of Microbiology, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Ana Maria Avalos & Ann Marshak-Rothstein

  3. Department of Medicine, University of Massachusetts Medical School, Worcester, 01605, Massachusetts, USA

    Peggy Parroche, Douglas Golenbock, Cherilyn Sirois, Katherine A Fitzgerald & Eicke Latz

  4. Rheumatology Research and Autoimmunity and Inflammation Program, Hospital for Special Surgery, New York, 10021, New York, USA

    Jing Hua & Mary K Crow

  5. Critical Therapeutics, Lexington, 02421, Massachusetts, USA

    Greg La Rosa

  6. Department of Medicine, University of Heidelberg, Heidelberg, D-69115, Germany

    Angelika Bierhaus & Peter Naworth

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Contributions

J.T. and S.-Y.M. carried out binding assays; A.M.A. and A.M.R., the B cell assays; B.C., immunoblots; H.W., L.L.A., L.A., K.S. and G.L.R., antibody generation and protein purification; E.L., P.P., S.D., D.G., C.S. and K.A.F., AlphaScreen assays and confocal microscopy; P.N. and A.B., generation of RAGE mice; and M.K.C. and J.H., lupus serum experiments. A.J.C. and P.A.K. conceived the experiments and wrote the paper.

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Correspondence to Anthony J Coyle.

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Competing interests

J.T., S.-Y.M., B.C., K.S., H.W., S.D., L.A., P.A.K. and A.J.C. are employees of MedImmune, developing therapeutic monoclonal antibodies to HMGB1. G.L.R. is an employee of Critical Therapeutics.

Supplementary information

Supplementary Table 1

DNA and peptide sequence. (PDF 51 kb)

Supplementary Methods (PDF 82 kb)

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Tian, J., Avalos, A., Mao, SY. et al. Toll-like receptor 9–dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8, 487–496 (2007). https://doi.org/10.1038/ni1457

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