Neurotoxicity Research

, Volume 20, Issue 2, pp 159–169 | Cite as

Extracellular HMGB1 Released by NMDA Treatment Confers Neuronal Apoptosis via RAGE-p38 MAPK/ERK Signaling Pathway

  • Seung-Woo Kim
  • Chae-Moon Lim
  • Jung-Bin Kim
  • Joo-Hyun Shin
  • Sanghyun Lee
  • Minhyung Lee
  • Ja-Kyeong Lee
Article

Abstract

High mobility group box 1 (HMGB1) was originally identified as ubiquitously expressed nonhistone DNA-binding protein, but recently, it was found to act as an endogenous danger molecule, which signals danger and traumatic cell death. Previously, the authors showed that HMGB1 is massively released immediately after an ischemic insult and that it subsequently activates microglia and induces inflammation in the postischemic brain. Here, we showed the endogenous danger molecule-like function of HMGB1 in primary cortical cultures. HMGB1 was found to be accumulated in NMDA-treated primary cortical culture media, and media collected from these cultures were able to induce neuronal cell death when added to fresh primary cortical cultures. However, HMGB1-depleted NMDA-conditioned media produced by HMGB1 siRNA transfection or by preincubation with anti-HMGB1 antibody or with HMGB1 A box failed to induce neuronal cell death. Furthermore, siRNA-mediated HMGB1 knockdown substantially suppressed NMDA- or Zn2+-induced cell death. It was interesting to find that extracellular HMGB1-induced neuronal apoptosis, as evidenced by TUNEL staining and caspase 3 assay in combination with double immunofluorescence staining. A series of RAGE and HMGB1 co-immunoprecipitation experiments in the presence of SB203580 and PD98059 (p38 MAPK and ERK inhibitors, respectively) demonstrated that RAGE-p38 MAPK and RAGE-ERK pathway might underlie extracellular HMGB1-mediated neuronal apoptosis. These results together with our previous reports regarding microglial activation by extracellular HMGB1 indicate that HMGB1 functions as a novel danger signal, which aggravates brain damage via autocrine and paracrine manners.

Keywords

HMGB1 NMDA-conditioned media Apoptosis Primary cortical culture RAGE 

References

  1. Abraham E, Arcaroli J, Carmody A, Wang H, Tracey KJ (2000) HMG-1 as a mediator of acute lung inflammation. J Immunol 165:2950–2954PubMedGoogle Scholar
  2. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P (2002) HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine 18:231–236PubMedCrossRefGoogle Scholar
  3. Arancio O, Zhang HP, Chen X, Lin C, Trinchese F, Puzzo D, Liu S, Hegde A, Yan SF, Stern A, Luddy JS, Lue LF, Walker DG, Roher A, Buttini M, Mucke L, Li W, Schmidt AM, Kindy M, Hyslop PA, Stern DM, Du Yan SS (2004) RAGE potentiates Abetainduced perturbation of neuronal function in transgenic mice. EMBO J 23:4096–4105PubMedCrossRefGoogle Scholar
  4. Bianchi ME (2007) DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol 81:1–5PubMedCrossRefGoogle Scholar
  5. Bianchi ME, Manfredi AA (2007) High-mobility group box 1 (HMGB1) protein at the crossroads between innate and adaptive immunity. Immunol Rev 220:35–46PubMedCrossRefGoogle Scholar
  6. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, Rubartelli A, Agresti A, Bianchi ME (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22:5551–5560PubMedCrossRefGoogle Scholar
  7. Bustin M (1999) Regulation of DNA-dependent activities by the functional motifs of the high-mobility-group chromosomal proteins. Mol Cell Biol 19:5237–5246PubMedGoogle Scholar
  8. Faraco G, Fossati S, Bianchi ME, Patrone M, Pedrazzi M, Sparatore B, Moroni F, Chiarugi A (2007) High mobility group box 1 protein is released by neural cells upon different stresses and worsens ischemic neurodegeneration in vitro and in vivo. J Neurochem 103:590–603PubMedCrossRefGoogle Scholar
  9. Graham SH, Chen J (2001) Programmed cell death in cerebral ischemia. J Cereb Blood Flow Metab 21:99–109PubMedCrossRefGoogle Scholar
  10. Hayakawa K, Arai K, Lo EH (2010) Role of ERK map kinase and CRM1 in IL-1betastimulated release of HMGB1 from cortical astrocytes. Glia 58:1007–1015PubMedGoogle Scholar
  11. Hori O, Brett J, Slattery T, Cao R, Zhang J, Chen JX, Nagashima M, Lundh ER, Vijay S, Nitecki D (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 270:25752–25761PubMedCrossRefGoogle Scholar
  12. Ivanov S, Dragoi AM, Wang X, Dallacosta C, Louten J, Musco G, Sitia G, Yap GS, Wan Y, Biron CA, Bianchi ME, Wang H, Chu WM (2007) A novel role for HMGB1 in TLR9-mediated inflammatory response to CpG-DNA. Blood 110:1970–1981PubMedCrossRefGoogle Scholar
  13. Kim JB, Piao CS, Lee KW, Han PL, Ahn JI, Lee YS, Lee JK (2004) Delayed genomic responses to transient middle cerebral artery occlusion in the rat. J Neurochem 89:1271–1282PubMedCrossRefGoogle Scholar
  14. Kim JB, Sig Choi J, Yu YM, Nam K, Piao CS, Kim SW, Lee MH, Han PL, Park JS, Lee JK (2006) HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci 26:6413–6421PubMedCrossRefGoogle Scholar
  15. Kim JB, Lim CM, Yu YM, Lee JK (2008a) Induction and subcellular localization of high-mobility group box-1 (HMGB1) in the postischemic rat brain. J Neurosci Res 86:1125–1131PubMedCrossRefGoogle Scholar
  16. Kim K, Han JS, Kim HA, Lee M (2008b) Expression, purification and characterization of TAT-high mobility group box-1A peptide as a carrier of nucleic acids. Biotechnol Lett 30:1331–1337PubMedCrossRefGoogle Scholar
  17. Li J, Qu X, Schmidt AM (1998) Sp1-binding elements in the promoter of RAGE are essential for amphoterin-mediated gene expression in cultured neuroblastoma cells. J Biol Chem 273:30870–30878PubMedCrossRefGoogle Scholar
  18. Monteiro FA, Sousa MM, Cardoso I, do Amaral JB, Guimarães A, Saraiva MJ (2006) Activation of ERK1/2 MAP kinases in familial amyloidotic polyneuropathy. J Neurochem 97:151–161PubMedCrossRefGoogle Scholar
  19. Passalacqua M, Patrone M, Picotti GB, Del Rio M, Sparatore B, Melloni E, Pontremoli S (1998) Stimulated astrocytes release high-mobility group 1 protein, an inducer of LAN-5 neuroblastoma cell differentiation. Neuroscience 82:1021–1028PubMedCrossRefGoogle Scholar
  20. Pedrazzi M, Raiteri L, Bonanno G, Patrone M, Ledda S, Passalacqua M, Milanese M, Melloni E, Raiteri M, Pontremoli S, Sparatore B (2006) Stimulation of excitatory amino acid release from adult mouse brain glia subcellular particles by high mobility group box 1 protein. J Neurochem 99:827–838PubMedCrossRefGoogle Scholar
  21. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, Salomone S, Moskowitz MA (2008) Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab 28:927–938PubMedCrossRefGoogle Scholar
  22. Scaffidi P, Misteli T, Bianchi ME (2002) Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418:191–195PubMedCrossRefGoogle Scholar
  23. Sha Y, Zmijewski J, Xu Z, Abraham E (2008) HMGB1 develops enhanced proinflammatory activity by binding to cytokines. J Immunol 180:2531–2537PubMedGoogle Scholar
  24. Tian J, Avalos AM, Mao SY, Chen B, Senthil K, Wu H, Parroche P, Drabic S, Golenbock D, Sirois C, Hua J, An LL, Audoly L, La Rosa G, Bierhaus A, Naworth P, Marshak-Rothstein A, Crow MK, Fitzgerald KA, Latz E, Kiener PA, Coyle AJ (2007) Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 an RAGE. Nat Immunol 8:487–496PubMedCrossRefGoogle Scholar
  25. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, Frazier A, Yang H, Ivanova S, Borovikova L, Manogue KR, Faist E, Abraham E, Andersson J, Andersson U, Molina PE, Abumrad NN, Sama A, Tracey KJ (1999a) HMG-1 as a late mediator of endotoxin lethality in mice. Science 285:248–251PubMedCrossRefGoogle Scholar
  26. Wang H, Vishnubhakat JM, Bloom O, Zhang M, Ombrellino M, Sama A, Tracey KJ (1999b) Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes. Surgery 126:389–392PubMedCrossRefGoogle Scholar
  27. Weise J, Engelhorn T, Dorfler A, Aker S, Bahr M, Hufnagel (2005) Expression time course and spatial distribution of activated caspase-3 after experimental status epilepticus: contribution of delayed neuronal cell death to seizure-induced neuronal injury. Neurobiol Dis 18:582–590PubMedCrossRefGoogle Scholar
  28. Yan SD, Chen X, Fu J, Chen M, Zhu H, Roher A, Slattery T, Zhao L, Nagashima M, Morser J, Migheli A, Nawroth P, Stern D, Schmidt AM (1996) RAGE and amyloid-β peptide neurotoxicity in Alzheimer’s disease. Nature 382:685–691PubMedCrossRefGoogle Scholar
  29. Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, Susarla SM, Ulloa L, Wang H, DiRaimo R, Czura CJ, Wang H, Roth J, Warren HS, Fink MP, Fenton MJ, Andersson U, Tracey KJ (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc Natl Acad Sci USA 101:296–301PubMedCrossRefGoogle Scholar
  30. Youn JH, Oh YJ, Kim ES, Choi JE, Shin JS (2008) High mobility group box 1 protein binding to lipopolysaccharide facilitates transfer of lipopolysaccharide to CD14 and enhances lipopolysaccharide-mediated TNF-alpha production in human monocytes. J Immunol 180:5067–5074PubMedGoogle Scholar
  31. Zhai DX, Kong QF, Xu WS, Bai SS, Peng HS, Zhao K, Li GZ, Wang DD, Sun B, Wang JH, Wang GY, Li HL (2008) RAGE expression is up-regulated in human cerebral ischemia and pMCAO rats. Neurosci Lett 445:117–121PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Seung-Woo Kim
    • 1
  • Chae-Moon Lim
    • 1
  • Jung-Bin Kim
    • 1
  • Joo-Hyun Shin
    • 1
  • Sanghyun Lee
    • 2
  • Minhyung Lee
    • 2
  • Ja-Kyeong Lee
    • 1
  1. 1.Department of Anatomy and Center for Advanced Medical Education (BK21 Project)Inha University School of MedicineInchonRepublic of Korea
  2. 2.Department of Bioengineering, College of EngineeringHanyang UniversitySeoulKorea

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