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Molecular Medicine

, Volume 20, Issue 1, pp 158–163 | Cite as

The Expression of HMGB1 on Microparticles Released during Cell Activation and Cell Death In Vitro and In Vivo

  • David S. Pisetsky
Review Article

Abstract

High mobility group box protein 1 (HMGB1) is a nonhistone nuclear protein that is a prototypic alarmin that can stimulate innate immunity and drive the pathogenesis of a wide range of inflammatory diseases. While HMGB1 can be released from both activated and dying cells, its biochemical and immunological properties differ depending on the release mechanism, resulting from redox changes and posttranslational modifications including acetylation. In addition to release of HMGB1, cell death is associated with the release of microparticles. Microparticles are small membrane-bound vesicles that contain cytoplasmic, nuclear and membrane components. Like HMGB1, microparticles display immunological activity and levels are elevated in diseases characterized by inflammation and vasculopathy. While studies have addressed the immunological effects of HMGB1 and microparticles independently, HMGB1, like other nuclear molecules, is a component of microparticles. Evidence for the physical association of HMGB1 comes from Western blot analysis of microparticles derived from RAW 264.7 macrophage cells stimulated by lipopolysaccharide (LPS) or induced to undergo apoptosis by treatment with etoposide or staurosporine in vitro. Analysis of microparticles in the blood of healthy volunteers receiving LPS shows the presence of HMGB1 as assessed by flow cytometry. Together, these findings indicate that HMGB1 can be a component of microparticles and may contribute to their activities. Furthermore, particle HMGB1 may represent a useful biomarker for in vivo events that may not be reflected by measurement of the total amount of HMGB1 in the blood.

Notes

Acknowledgments

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

References

  1. 1.
    Harris HE, Andersson U, Pisetsky DS. (2012) HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat. Rev. Rheumatol. 8:195–202.Google Scholar
  2. 2.
    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. 93:865–73.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Štros M. (2010) HMGB proteins: interactions with DNA and chromatin. Biochim. Biophys. Acta. 1799:101–13.CrossRefPubMedGoogle Scholar
  4. 4.
    Thomas JO, Stott K. (2012) H1 and HMGB1: modulators of chromatin structure. Biochem. Soc. Trans. 40:341–6.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.
    Andersson U, Tracey KJ. (2011) HMGB1 is a therapeutic target for sterile inflammation and infection. Annu. Rev. Immunol. 29:139–62.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    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
  8. 8.
    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
  9. 9.
    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
  10. 10.
    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
  11. 11.
    Scaffidi P, Misteli T, Bianchi ME. (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 418:191–5.CrossRefGoogle Scholar
  12. 12.
    Bonaldi T, et al. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22:5551–60.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Rovere-Querini P, et al. (2004) HMGB1 is an endogenous immune adjuvant released by necrotic cells. EMBO Rep. 5:825–30.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lu B, et al. (2014) JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc. Natl. Acad. Sci. U. S. A. 111:3068–73.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Miao EA, Rajan JV, Aderem A. (2011) Caspase-1-induced pyroptotic cell death. Immunol. Rev. 243:206–14.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lamkanfi M, et al. (2010) Inflammasome-dependent release of the alarmin HMGB1 in endotoxemia. J. Immunol. 185:4385–92.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Nyström S, et al. (2013) TLR activation regulates damage-associated molecular pattern isoforms released during pyroptosis. EMBO J. 32:86–99.CrossRefPubMedGoogle Scholar
  18. 18.
    Duprez L, et al. (2011) RIP kinase-dependent necrosis drives lethal systemic inflammatory response syndrome. Immunity. 35:908–18.CrossRefGoogle Scholar
  19. 19.
    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
  20. 20.
    Kaczmarek A, Vandenabeele P, Krysko DV. (2013) Necroptosis: the release of damage-associated molecular patterns and its physiological relevance. Immunity. 38:209–23.CrossRefGoogle Scholar
  21. 21.
    Linkermann A, Green DR. (2014) Necroptosis. N. Engl. J. Med. 370:455–65.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    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
  23. 23.
    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
  24. 24.
    Kazama H, Ricci J-E, Herndon HM, Hoppe G, Green DR. (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
  25. 25.
    Urbonaviciute V, et al. (2009) Oxidation of the alarmin high-mobility group box 1 protein (HMGB1) during apoptosis. Autoimmunity. 42:305–7.CrossRefPubMedGoogle Scholar
  26. 26.
    Ditsworth D, Zong WX, Thompson CB. (2007) Activation of poly(ADP)-ribose polymerase (PARP-1) induces release of the pro-inflammatory mediator HMGB1 from the nucleus. J. Biol. Chem. 282:17845–54.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Kennedy CL, Smith DJ, Lyras D, Chakravorty A, Rood JI. (2009) Programmed cellular necrosis mediated by the pore-forming α-Toxin from Clostridium septicum. PLoS Pathog. 5:e1000516.CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Morinaga Y, et al. (2010) Legionella pneumophilia induces cathepsin B-dependent necrotic cell death with releasing high mobility group box 1 in macrophages. Respir. Res. 11:158–66.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Lau A, et al. (2013) RIPK3-mediated necroptosis promotes donor kidney inflammatory injury and reduces allograft survival. Am. J. Transplant. 13:2805–18.CrossRefPubMedGoogle Scholar
  30. 30.
    Inoue H, Tani K. (2014) Multimodal immunogenic cancer cell death as a consequence of anticancer cytotoxic treatments. Cell Death Differ. 21:39–49.CrossRefPubMedGoogle Scholar
  31. 31.
    Jiang N, Reich CF 3rd, Pisetsky DS. (2003) Role of macrophages in the generation of circulating blood nucleosomes from dead and dying cells. Blood. 102:2243–50.CrossRefPubMedGoogle Scholar
  32. 32.
    György B, et al. (2011) Membrane vesicles, current state-of-the art: emerging role of extracellular vesicles. Cell. Mol. Life Sci. 68:2667–88.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Van der Pol E, Böing AN, Harrison P, Sturk A, Nieuwland R. (2012) Classification, functions, and clinical relevance of extracellular vesicles. Pharmacol. Rev. 64:676–705.CrossRefPubMedGoogle Scholar
  34. 34.
    Shifrin DA Jr., Becckler MD, Coffey RJ, Tyska MJ. (2013) Extracellular vesicles: communication, coercion, and conditioning. Mol. Biol. Cell. 24:1253–9.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Charras GT. (2008) A short history of blebbing. J. Microsc. 231:466–78.CrossRefPubMedGoogle Scholar
  36. 36.
    Charras GT, Coughlin M, Mitchison TJ, Mahadevan L. (2008) Life and times of a cellular bleb. Biophys. J. 94:1836–53.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Berda-Haddad Y, et al. (2011) Sterile inflammation of endothelial cell-derived apoptotic bodies is mediated by interleukin-1α. Proc. Natl. Acad. Sci. U. S. A. 108:20684–9.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Casciola-Rosen LA, Anhalt G, Rosen A. (1994) Autoantigens targeted in systemic lupus erythematosus are clustered in two populations of surface structures on apoptotic keratinocytes. J. Exp. Med. 179:1317–30.CrossRefPubMedGoogle Scholar
  39. 39.
    Schiller M, et al. (2008) Autoantigens are translocated into small apoptotic bodies during early stages of apoptosis. Cell Death Differ. 15:183–91.CrossRefPubMedGoogle Scholar
  40. 40.
    Orozco AF, Lewis DE. (2010) Flow cytometric analysis of circulating microparticles in plasma. Cytometry A. 77:502–14.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Pisetsky DS, Ullal AJ, Gauley J, Ning TC. (2012) Microparticles as mediators and biomarkers of rheumatic disease. Rheumatology (Oxford). 51:1737–46.CrossRefGoogle Scholar
  42. 42.
    Reich CF 3rd, Pisetsky DS. (2009) The content of DNA and RNA in microparticles released by Jurkat and HL-60 cells undergoing in vitro apoptosis. Exp. Cell Res. 315:760–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Ullal AJ, Pisetsky DS, Reich CF 3rd. (2010) Use of SYTO 13, a fluorescent dye binding nucleic acids, for the detection of microparticles in in vitro systems. Cytometry A. 77:294–301.PubMedPubMedCentralGoogle Scholar
  44. 44.
    Pisetsky DS. (2013) The translocation of nuclear molecules during inflammation and cell death. Antioxid. Redox Signal. 20:1117–25.CrossRefPubMedGoogle Scholar
  45. 45.
    Jiang W, Li J, Gallowitsch-Puerta M, Tracey KJ, Pisetsky DS. (2005) The effects of CpG DNA on HMGB1 release by murine macrophage cell lines. J. Leukoc. Biol. 78:930–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Jiang W, Pisetsky DS. (2006) The role of IFN-alpha and nitric oxide in the release of HMGB1 by RAW 264.7 cells stimulated with polyinosinic-polycytidylic acid or lipopolysaccharide. J. Immunol. 177:3337–43.CrossRefPubMedGoogle Scholar
  47. 47.
    Jiang W, Bell CW, Pisetsky DS. (2007) The relationship between apoptosis and high-mobility group protein 1 release from murine macrophages stimulated with lipopolysaccharide or polyinosinic-polycytidylic acid. J. Immunol. 178:6495–503.CrossRefPubMedGoogle Scholar
  48. 48.
    Gauley J, Pisetsky DS. (2010) The release of microparticles by RAW 264.7 macrophage cells stimulated with TLR ligands. J. Leukoc. Biol. 87:1115–23.CrossRefPubMedGoogle Scholar
  49. 49.
    Spencer DM, Gauley J, Pisetsky DS. (2014) The properties of microparticles from RAW 264.7 macrophage cells undergoing in vitro activation or apoptosis. Innate Immun. 20:239–48.CrossRefPubMedGoogle Scholar
  50. 50.
    Soop A, et al. (2013) Effect of lipopolysaccharide administration on the number, phenotype and content of nuclear molecules in blood microparticles of normal human subjects. Scand. J. Immunol. 78:205–13.CrossRefPubMedGoogle Scholar
  51. 51.
    Hallström L, Berghäll E, Frostell C, Sollevi A, Soop AL. (2011) Immunomodulation by a combination of nitric oxide and glucocorticoids in a human endotoxin model. Acta. Anaesthesiol. Scand. 55:20–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Rouhiainen A, Imai S, Rauvala H, Parkkinen J. (2000) Occurrence of amphoterin (HMG1) as an endogenous protein of human platelets that is exported to the cell surface upon platelet activation. Thromb. Haemost. 84:1087–94.CrossRefPubMedGoogle Scholar
  53. 53.
    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
  54. 54.
    Hreggvidsdottir HS, et al. (2009) The alarmin HMGB1 acts in synergy with endogenous and exogenous danger signals to promote inflammation. J. Leukoc. Biol. 86:655–62.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Leclerc P, et al. (2013) IL-1β/HMGB1 complexes promote the PGE2 biosynthesis pathway in synovial fibroblasts. Scand J. Immunol. 77:350–60.Google Scholar

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Authors and Affiliations

  • David S. Pisetsky
    • 1
    • 2
  1. 1.Duke University Medical CenterDurhamUSA
  2. 2.Medical Research ServiceDurham Veterans Administration Medical CenterDurhamUSA

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