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Molecular Medicine

, Volume 20, Issue 1, pp 138–146 | Cite as

The Role of HMGB1 in the Pathogenesis of Inflammatory and Autoimmune Diseases

  • Melinda Magna
  • David S. Pisetsky
Review Article

Abstract

High-mobility group box 1 (HMGB1) protein is a highly abundant protein that can promote the pathogenesis of inflammatory and autoimmune diseases once it is in an extracellular location. This translocation can occur with immune cell activation as well as cell death, with the conditions for release associated with the expression of different isoforms. These isoforms result from post-translational modifications, with the redox states of three cysteines at positions 23, 45 and 106 critical for activity. Depending on the redox states of these residues, HMGB1 can induce cytokine production via toll-like receptor 4 (TLR4) or promote chemotaxis by binding the chemokine CXCL12 for stimulation via CXCR4. Fully oxidized HMGB1 is inactive. During the course of inflammatory disease, HMGB1 can therefore play a dynamic role depending on its redox state. As a mechanism to generate alarmins, cell death is an important source of HMGB1, although each major cell death form (necrosis, apoptosis, pyroptosis and NETosis) can lead to different isoforms of HMGB1 and variable levels of association of HMGB1 with nucleosomes. The association of HMGB1 with nucleosomes may contribute to the pathogenesis of systemic lupus erythematosus by producing nuclear material whose immunological properties are enhanced by the presence of an alarmin. Since HMGB1 levels in blood or tissue are elevated in many inflammatory and autoimmune diseases, this molecule can serve as a unique biomarker as well as represent a target of novel therapies to block its various activities.

Notes

Acknowledgments

This work was supported by a VA Merit Review Grant, a grant from the Alliance for Lupus Research (ALR) and National Institutes of Health grant 5U19-AI056363.

References

  1. 1.
    Andersson U, Tracey KJ. (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29:139–62.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Harris HE, Andersson U, Pisetsky DS. (2012) HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat. Rev. Rheumatol. 8:195–202.CrossRefPubMedGoogle Scholar
  3. 3.
    Yang H, Antoine DJ, Andersson U, Tracey KJ. (2013) The many faces of HMGB1: a molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J. Leukoc. Biol. 93:856–73.Google Scholar
  4. 4.
    Andersson U, Harris HE. (2010) The role of HMGB1 in the pathogenesis of rheumatic disease. Biochim. Biophys. Acta. 1799:141–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Wang H, et al. (1999) HMG-1 as a late mediator of endotoxin lethality in mice. Science. 285:248–51.CrossRefGoogle Scholar
  6. 6.
    Pullerits R, et al. (2003) High mobility group box chromosomal protein 1, a DNA binding cytokine, induces arthritis. Arthritis Rheum. 48:1693–700.CrossRefPubMedGoogle Scholar
  7. 7.
    Taniguchi N, et al. (2003) High mobility group box chromosomal protein 1 plays a role in the pathogenesis of rheumatoid arthritis as a novel cytokine. Arthritis Rheum. 48:971–81.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Kokkola R, et al. (2003) Successful treatment of collagen-induced arthritis in mice and rats by targeting extracellular high mobility group box chromosomal protein 1 activity. Arthritis Rheum. 48:2052–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Ulfgren AK, et al. (2004) Down-regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids. Arthritis Rheum. 50:1586–94.CrossRefPubMedGoogle Scholar
  10. 10.
    Popovic K, et al. (2005) Increased expression of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in skin lesions of patients with lupus erythematosus. Arthritis Rheum. 52:3639–45.CrossRefPubMedGoogle Scholar
  11. 11.
    Ek M, Popovic K, Harris HE, Nauclér CS, Wahren-Herlenius M. (2006) Increased extracellular levels of the novel proinflammatory cytokine high mobility group box chromosomal protein 1 in minor salivary glands of patients with Sjögren’s syndrome. Arthritis Rheum. 54:2289–94.CrossRefPubMedGoogle Scholar
  12. 12.
    Grundtman C, et al. (2010) Effects of HMGB1 on in vitro responses of isolated muscle fibers and functional aspects in skeletal muscles of idiopathic inflammatory myopathies. FASEB J. 24:570–8.CrossRefPubMedGoogle Scholar
  13. 13.
    Ahn JK, Cha HS, Bae EK, Lee J, Koh EM. (2011) Extracellular high-mobility group box 1 is increased in patients with Behcet’s disease with intestinal involvement. J. Korean Med. Sci. 26:697–700.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mitroulis I, et al. (2011) Neutrophil extracellular trap formation is associated with IL-1β and autophagy-related signaling in gout. PLoS One. 6:e29318.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Abdulahad DA, et al. (2012) Urine levels of HMGB1 in systemic lupus erythematosus patients with and without renal manifestations. Arthritis Res. Ther. 14:R184.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Maugeri N, et al. (2012) Circulating platelets as a source of the damage-associated molecular pattern HMGB1 in patients with systemic sclerosis. Autoimmunity. 45:584–7.CrossRefPubMedGoogle Scholar
  17. 17.
    Abdulahad DA, et al. (2013) High mobility group box 1 (HMGB1) in relation to cutaneous inflammation in systemic lupus erythematosus (SLE). Lupus. 22:597–606.CrossRefPubMedGoogle Scholar
  18. 18.
    Oktayoglu P, et al. (2013) Elevated serum levels of high mobility group box protein 1 (HMGB1) in patients with ankylosing spondylitis and its association with disease activity and quality of life. Rheumatol. Int. 33:1327–31.CrossRefPubMedGoogle Scholar
  19. 19.
    Schierbeck H, et al. (2013) HMGB1 levels are increased in patients with juvenile idiopathic arthritis, correlate with early onset of disease, and are independent of disease duration. J. Rheumatol. 40:1604–13.CrossRefPubMedGoogle Scholar
  20. 20.
    Cato L, Stott K, Watson M, Thomas JO. (2008) The interaction of HMGB1 and linker histones occurs through their acidic and basic tails. J. Mol. Biol. 384:1262–72.CrossRefPubMedGoogle Scholar
  21. 21.
    Štros M. (2010) HMGB proteins: interactions with DNA and chromatin. Biochim. Biophys. Acta. 1799:101–13.CrossRefPubMedGoogle Scholar
  22. 22.
    Thomas JO, Stott K. (2012) H1 and HMGB1: modulators of chromatin structure. Biochem. Soc. Trans. 40:341–346.CrossRefPubMedGoogle Scholar
  23. 23.
    Gardella S, et al. (2002) The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep. 3:995–1001.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Bonaldi T, et al. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22:5551–60.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Scaffidi P, Misteli T, Bianchi ME. (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418:191–5.CrossRefGoogle Scholar
  26. 26.
    Rovere-Querini P, et al. (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 5:825–30.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Galluzzi L, et al. (2012) Molecular definitions of cell death subroutines: recommendations of the Nomenclature Committee on Cell Death 2012. Cell Death Differ. 19:107–20.CrossRefGoogle Scholar
  28. 28.
    Hori O, et al. (1995) The receptor for advanced glycation end products (RAGE) is a cellular binding site for amphoterin. Mediation of neurite outgrowth and co-expression of rage and amphoterin in the developing nervous system. J. Biol. Chem. 270:25752–61.CrossRefPubMedGoogle Scholar
  29. 29.
    Park JS, et al. (2004) Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J. Biol. Chem. 279:7370–77.CrossRefPubMedGoogle Scholar
  30. 30.
    Park JS, et al. (2006) High mobility group box 1 protein interacts with multiple toll-like receptors. Am. J. Physiol. Cell Physiol. 290:C917–24.CrossRefGoogle Scholar
  31. 31.
    Dumitriu IE, Baruah P, Bianchi ME, Manfredi AA, Rovere-Querini P. (2005) Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells. Eur. J. Immunol. 35:2184–90.CrossRefPubMedGoogle Scholar
  32. 32.
    Ivanov S, et al. (2007) A novel role for HMGB1 in TLR9-mediated inflammatory responses to CpG-DNA. Blood. 110:1970–81.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Dintilhac A, Bernués J. (2002) HMGB1 interacts with many apparently unrelated proteins by recognizing short amino acid sequences. J. Biol. Chem. 277:7021–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Bianchi ME. (2009) HMGB1 loves company. J. Leukoc. Biol. 86:573–6.CrossRefPubMedGoogle Scholar
  35. 35.
    Wähämaa H, et al. (2011) High mobility group box protein 1 in complex with lipopolysaccharide or IL-1 promotes an increased inflammatory phenotype in synovial fibroblasts. Arthritis Res. Ther. 13:R136.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Hreggvidsdóttir HS, et al. (2012) High mobility group box protein 1 (HMGB1)-partner molecule complexes enhance cytokine production by signaling through the partner molecule receptor. Mol. Med. 18:224–30.CrossRefPubMedGoogle Scholar
  37. 37.
    Leclerc P, et al. (2013) IL-1β/HMGB1 complexes promote the PGE2 biosynthesis pathway in synovial fibroblasts. Scand. J. Immunol. 77:350–60.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Venereau E, et al. (2012) Mutually exclusive redox forms of HMGB1 promote cell recruitment or proinflammatory cytokine release. J. Exp. Med. 209:1519–28.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Yang H, et al. (2012) Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol. Med. 18:250–9.CrossRefGoogle Scholar
  40. 40.
    Venereau E, Schiraldi M, Uguccioni M, Bianchi ME. (2013) HMGB1 and leukocyte migration during trauma and sterile inflammation. Mol. Immunol. 55:76–82.CrossRefPubMedGoogle Scholar
  41. 41.
    Valdés-Ferrer SI, et al. (2013) HMGB1 mediates splenomegaly and expansion of splenic CD11b+ Ly-6C (high) inflammatory monocytes in murine sepsis survivors. J. Intern. Med. 274:381–90.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Beyer C, et al. (2012) The extracellular release of DNA and HMGB1 from Jurkat T cells during in vitro necrotic cell death. Innate Immun. 18:727–37.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Nagata S, Hanayama R, Kawane K. (2010) Autoimmunity and the clearance of dead cells. Cell. 140:619–30.CrossRefPubMedGoogle Scholar
  44. 44.
    Kruse K, et al. (2010) Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis. 15:1098–113.CrossRefGoogle Scholar
  45. 45.
    Pisetsky DS. (2014) The translocation of nuclear molecules during inflammation and cell death. Antioxid. Redox Signal. 20:1117–25.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Bell CW, Jiang W, Reich CF 3rd, Pisetsky DS. (2006) The extracellular release of HMGB1 during apoptotic cell death. Am. J. Physiol. Cell Physiol. 291:C1318–25.CrossRefPubMedGoogle Scholar
  47. 47.
    Kazama H, et al. (2008) Induction of immunological tolerance by apoptotic cells requires caspase-dependent oxidation of high-mobility group box-1 protein. Immunity. 29:21–32.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Thorburn J, et al. (2009) Autophagy regulates selective HMGB1 release in tumor cells that are destined to die. Cell Death Differ. 16:175–83.CrossRefGoogle Scholar
  49. 49.
    Tang D, et al. (2010) HMGB1 release and redox regulates autophagy and apoptosis in cancer cells. Oncogene. 29:5299–310.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Urbonaviciute V, et al. (2009) Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis. Autoimmunity. 42:305–7.CrossRefPubMedGoogle Scholar
  51. 51.
    Miao EA, Rajan JV, Aderem A. (2011) Caspase-1-induced pyroptotic cell death. Immunol. Rev. 243:206–14.CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Nyström S, et al. (2013) TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis. EMBO J. 32:86–99.CrossRefPubMedGoogle Scholar
  53. 53.
    Lamkanfi M, et al. (2010) Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185:4385–92.CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Brinkmann V, Zychlinsky A. (2012) Neutrophil extracellular traps: is immunity the second function of chromatin? J. Cell Biol. 198:773–83.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Kessenbrock K, et al. (2009) Netting neutrophils in autoimmune small-vessel vasculitis. Nat. Med. 15:623–5.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Garcia-Romo GS, et al. (2011) Netting neutrophils are major inducers of Type I IFN production in pediatric systemic lupus erythematosus. Sci. Transl. Med. 3:73ra20.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Yipp BG, et al. (2012) Infection-induced NETosis is a dynamic process involving neutrophil multitasking in vivo. Nat. Med. 18:1386–93.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Xu J, et al. (2009) Extracellular histones are major mediators of death in sepsis. Nat. Med. 15:1318–21.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Pisetsky DS. (2012) The origin and properties of extracellular DNA: from PAMP to DAMP. Clin. Immunol. 144:32–40.CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Tian J, et al. (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol. 8:487–96.CrossRefGoogle Scholar
  61. 61.
    Urbonaviciute V, et al. (2008) Induction of inflammatory and immune responses by HMGB1-nucleosome complexes: implications for the pathogenesis of SLE. J. Exp. Med. 205:3007–18.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Wen Z, et al. (2013) Autoantibody induction by DNA-containing immune complexes requires HMGB1 with the TLR2/microRNA-155 pathway. J. Immunol. 190:5411–22.CrossRefPubMedGoogle Scholar
  63. 63.
    Sun W, et al. (2013) Immune complexes activate human endothelium involving the cell-signaling HMGB1-RAGE axis in the pathogenesis of lupus vasculitis. Lab. Invest. 93:626–38.CrossRefPubMedGoogle Scholar
  64. 64.
    Wang Q, et al. (2013) Pyroptotic cells externalize eat-me and release find-me signals and are efficiently engulfed by macrophages. Int. Immunol. 25:363–72.CrossRefPubMedGoogle Scholar
  65. 65.
    Antoine DJ, et al. (2012) Molecular forms of HMGB1 and keratin-18 as mechanistic biomarkers for mode of cell death and prognosis during clinical acetaminophen hepatotoxicity. J. Heptaol. 56:1070–9.CrossRefGoogle Scholar
  66. 66.
    Harrill AH, et al. (2012) The effects of heparins on the liver: application of mechanistic serum biomarkers in a randomized study in healthy volunteers. Clin. Pharmacol. Ther. 92:214–20.CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Musumeci D, Roviello GN, Montesarchio D. (2013) An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol. Ther. 141:347–57.CrossRefPubMedGoogle Scholar
  68. 68.
    Zhou Y, et al. (2013) Protective effects of necrostatin-1 against concanavalin A-induced acute hepatic injury in mice. Mediators Inflamm. 2013:706156.PubMedPubMedCentralGoogle Scholar
  69. 69.
    Peter ME. (2008) ROS eliminate danger. Immunity. 29:1–2.CrossRefPubMedGoogle Scholar
  70. 70.
    Nathan C, Ding A. (2010) Nonresolving inflammation. Cell. 140:871–82.CrossRefGoogle Scholar

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Authors and Affiliations

  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Medical Research ServiceDurham Veterans Administration Medical CenterDurhamUSA

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