Published: 2016-02-18

High mobility group box 1 protein in the central nervous system

Department of Neurosurgery, Poznan University of Medical Science, Poland
Department of Neurosurgery, Poznan University of Medical Science, Poland
Department of Neurosurgery, Poznan University of Medical Science, Poland
Department of Neurosurgery, Poznan University of Medical Science, Poland
high mobility group box 1 amphoterine HMGB1 central nervous system stroke


High-mobility group box 1 protein (HMGB1) is a multifunctional protein originally identified as a nuclear transcription modifier. Two pathways are leading to HMGB1 release to the extracellular space i.e. active secretion triggered by noxious stimulation and passive leakage due to necrotic membrane damage. Binding with receptors for advanced glycation end products (RAGE) as well as Toll-like receptor 2 (TLR2) and TLR4 leads to nuclear factor ?B (NF-?B) activation and proinflammatory reaction in target cells. Secretion of cytokines, upregulation of adhesion molecules and chemoattraction are triggered by the extracellular HMGB1. Such ubiquitous and numerous protein plays a role in pathogenesis of many common diseases like sepsis, rheumatoid arthritis and pneumonia. Central nervous system (CNS) disorders are also mediated by HMGB1. Multiple studies highlight pivotal role of HMGB1 in acute pathologies of CNS like cerebral ischemia, aneurysmal subarachnoid hemorrhage as well as chronic degenerative disorders such as Alzheimer’s disease and multiple sclerosis. Wide range of HMGB1 antagonists are currently investigated as novel therapeutic agents in sepsis, colitis and stroke. This review article provides basic information about HMGB1 protein and its role in the pathogenesis of CNS diseases.


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  1. Guldbrandsen A, Vethe H, Farag Y, Oveland E, Garberg H, Berle M, et al. In-depth characterization of the cerebrospinal fluid proteome displayed through the CSF Proteome Resource (CSF-PR). Mol Cell Proteomics. 2014 Jul 18;13(11):3152–3163.
  2. Comings DE, Harris DC. Nuclear proteins. II. Similarity of nonhistone proteins in nuclear sap and chromatin, and essential absence of contractile proteins from mouse liver nuclei. J Cell Biol. 1976 Aug;70(2 pt 1):440–452.
  3. Hock R, Furusawa T, Ueda T, Bustin M. HMG chromosomal proteins in development and disease. Trends Cell Biol. 2007 Feb;17(2):72–79.
  4. Calogero S, Grassi F, Aguzzi A, Voigtländer T, Ferrier P, Ferrari S, et al. The lack of chromosomal protein Hmg1 does not disrupt cell growth but causes lethal hypoglycaemia in newborn mice. Nat Genet. 1999 Jul;22(3):276–280.
  5. Bianchi ME. HMGB1 loves company. J Leukoc Biol. 2009 Sep;86(3):573–576.
  6. Wang H, Bloom O, Zhang M, Vishnubhakat JM, Ombrellino M, Che J, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999 Jul 9;285(5425):248–251.
  7. Andersson U, Tracey KJ. HMGB1 is a therapeutic target for sterile inflammation and infection. Annu Rev Immunol. 2011 Jan;29:139–162.
  8. Goodwin GH, Sanders C, Johns EW. A new group of chromatin-associated proteins with a high content of acidic and basic amino acids. Eur J Biochem. 1973 Sep 21;38(1):14–19.
  9. Johns E, Goodwin C, Walker J, Sanders C. Chromosomal proteins related to histones. Ciba Found Symp. 1975;28:95–112.
  10. Janko C, Filipović M, Munoz LE, Schorn C, Schett G, Ivanović-Burmazović I, et al. Redox modulation of HMGB1-related signaling. Antioxid Redox Signal. 2014 Mar 1;20(7):1075–1085.
  11. Ferrari S, Finelli P, Rocchi M, Bianchi ME. The active gene that encodes human high mobility group 1 protein (HMG1) contains introns and maps to chromosome 13. Genomics. 1996 Jul;35(2):367–371.
  12. Bustin M. Revised nomenclature for high mobility group (HMG) chromosomal proteins. Trends Biochem Sci. 2001 Mar;26(3):152–153.
  13. Merenmies J, Pihlaskari R, Laitinen J, Wartiovaara J, Rauvala H. 30-kDa heparin-binding protein of brain (amphoterin) involved in neurite outgrowth. Amino acid sequence and localization in the filopodia of the advancing plasma membrane. J Biol Chem. 1991 Sep 5;266(25):16722–16729.
  14. Yang H, Lundbäck P, Ottosson L, Erlandsson-Harris H, Venereau E, Bianchi ME, et al. Redox modification of cysteine residues regulates the cytokine activity of high mobility group box-1 (HMGB1). Mol Med. 2012 Jan;18(8):250–259.
  15. Yang H, Antoine DJ, Andersson U, Tracey KJ. The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol. 2013 Jun;93(6):865–873.
  16. Lotze MT, Tracey KJ. High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol. 2005 Apr;5(4):331–342.
  17. Bonaldi T, Talamo F, Scaffidi P, Ferrera D, Porto A, Bachi A, et al. Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 2003 Oct 15;22(20):5551–5560.
  18. Seong S-Y, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004 Jun;4(6):469–478.
  19. Wang H, Yang H, Tracey KJ. Extracellular role of HMGB1 in inflammation and sepsis. J Intern Med. 2004 Mar;255(3):320–331.
  20. Malarkey CS, Churchill MEA. The high mobility group box: the ultimate utility player of a cell. Trends Biochem Sci. 2012;37(12):553–562.
  21. Ulloa L, Messmer D. High-mobility group box 1 (HMGB1) protein: friend and foe. Cytokine Growth Factor Rev. 2006 Jun;17(3):189–201.
  22. Ramasamy R, Yan SF, Herold K, Clynes R, Schmidt AM. Receptor for advanced glycation end products: fundamental roles in the inflammatory response: winding the way to the pathogenesis of endothelial dysfunction and atherosclerosis. Ann N Y Acad Sci. 2008 Apr;1126:7–13.
  23. Musumeci D, Roviello GN, Montesarchio D. An overview on HMGB1 inhibitors as potential therapeutic agents in HMGB1-related pathologies. Pharmacol Ther. Elsevier Inc.; 2014 Mar;141(3):347–357.
  24. Yang H, Wang H, Czura CJ, Tracey KJ. The cytokine activity of HMGB1. J Leukoc Biol. 2005 Jul;78(1):1–8.
  25. Thomas JO, Stott K. H1 and HMGB1: modulators of chromatin structure. Biochem Soc Trans. 2012 Apr;40(2): 341–346.
  26. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002 Jul;418(6894):191–195.
  27. Yang Q, Wang J-Z, Li J-C, Zhou Y, Zhong Q, Lu F-L, et al. High-mobility group protein box-1 and its relevance to cerebral ischemia. J Cereb blood flow Metab. Nature Publishing Group; 2010 Feb;30(2):243–254.
  28. Agnello D, Wang H, Yang H, Tracey KJ, Ghezzi P. HMGB-1, a DNA-binding protein with cytokine activity, induces brain TNF and IL-6 production, and mediates anorexia and taste aversion. Cytokine. 2002 May 21;18(4):231–236.
  29. O’Connor KA, Hansen MK, Rachal Pugh C, Deak MM, Biedenkapp JC, Milligan ED, et al. Further characterization of high mobility group box 1 (HMGB1) as a proinflammatory cytokine: central nervous system effects. Cytokine. 2003 Dec 21;24(6):254–265.
  30. Faraco G, Fossati S, Bianchi ME, Patrone M, Pedrazzi M, Sparatore B, et al. 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. 2007 Oct;103(2):590–603.
  31. Zhou P, Li Y, Li W, Han T, Yang S, Yao Y, et al. [Changes in serum high mobility group box-1 protein and high-sensitivity C-reactive protein in patients with acute cerebral infarction and their clinical significance]. Zhongguo Wei Zhong Bing Ji Jiu Yi Xue. 2012 May;24(5):265–268.
  32. Kim J-B, Sig Choi J, Yu Y-M, Nam K, Piao C-S, Kim S-W, et al. HMGB1, a novel cytokine-like mediator linking acute neuronal death and delayed neuroinflammation in the postischemic brain. J Neurosci. 2006 Jun 14;26(24): 6413–6421.
  33. Bonanno G, Raiteri L, Milanese M, Zappettini S, Melloni E, Pedrazzi M, et al. The high-mobility group box 1 cytokine induces transporter-mediated release of glutamate from glial subcellular particles (gliosomes) prepared from in situ-matured astrocytes. Int Rev Neurobiol. 2007 Jan;82:73–93.
  34. Moskowitz MA, Lo EH, Iadecola C. The Science of Stroke: Mechanisms in Search of Treatments. Neuron. 2010;67(2):181–198.
  35. Hayakawa K, Qiu J, Lo EH. Biphasic actions of HMGB1 signaling in inflammation and recovery after stroke. Ann N Y Acad Sci. 2010 Oct;1207:50–57.
  36. Qiu J, Xu J, Zheng Y, Wei Y, Zhu X, Lo EH, et al. High-mobility group box 1 promotes metalloproteinase-9 upregulation through Toll-like receptor 4 after cerebral ischemia. Stroke. 2010 Sep;41(9):2077–2082.
  37. Kim J-B, Lim C-M, Yu Y-M, Lee J-K. Induction and subcellular localization of high-mobility group box-1 (HMGB1) in the postischemic rat brain. J Neurosci Res. 2008 Apr;86(5):1125–1131.
  38. Qiu J, Nishimura M, Wang Y, Sims JR, Qiu S, Savitz SI, et al. Early release of HMGB-1 from neurons after the onset of brain ischemia. J Cereb Blood Flow Metab. 2008 May;28(5):927–938.
  39. Fiuza C, Bustin M, Talwar S, Tropea M, Gerstenberger E, Shelhamer JH, et al. Inflammation-promoting activity of HMGB1 on human microvascular endothelial cells. Blood. 2003 Apr 1;101(7):2652–2660.
  40. Dumitriu IE, Baruah P, Manfredi AA, Bianchi ME, Rovere-Querini P. HMGB1: guiding immunity from within. Trends Immunol. 2005 Jul;26(7):381–387.
  41. Höhne C, Wenzel M, Angele B, Hammerschmidt S, Häcker H, Klein M, et al. High mobility group box 1 prolongs inflammation and worsens disease in pneumococcal meningitis. Brain. 2013 Jun;136(Pt 6):1746–1759.
  42. Zhu X-D, Chen J-S, Zhou F, Liu Q-C, Chen G, Zhang J-M. Relationship between plasma high mobility group box-1 protein levels and clinical outcomes of aneurysmal subarachnoid hemorrhage. J Neuroinflammation. 2012 Jan;9:194.
  43. Nakahara T, Tsuruta R, Kaneko T, Yamashita S, Fujita M, Kasaoka S, et al. High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage. Neurocrit Care. 2009 Dec;11(3):362–368.
  44. Asano T, Ichiki K, Koizumi S, Kaizu K, Hatori T, Mashiko K, et al. High mobility group box 1 in cerebrospinal fluid from several neurological diseases at early time points. Int J Neurosci. 2011 Aug;121(8):480–484.
  45. Ostberg T, Wähämaa H, Palmblad K, Ito N, Stridh P, Shoshan M, et al. Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis. Arthritis Res Ther. 2008 Jan;10(1):R1.
  46. Zhu S, Li W, Ward MF, Sama AE, Wang H. High mobility group box 1 protein as a potential drug target for infection- and injury-elicited inflammation. Inflamm Allergy Drug Targets. 2010 Mar;9(1):60–72.
  47. Gentile LF, Moldawer LL. HMGB1 as a therapeutic target for sepsis: it’s all in the timing! Expert Opin Ther Targets. Informa UK, Ltd. London; 2014 Jan.
  48. Wang H, Ward MF, Sama AE. Novel HMGB1-inhibiting therapeutic agents for experimental sepsis. Shock. 2009 Oct;32(4):348–357.
  49. Davé SH, Tilstra JS, Matsuoka K, Li F, DeMarco RA, Beer-Stolz D, et al. Ethyl pyruvate decreases HMGB1 release and ameliorates murine colitis. J Leukoc Biol. 2009 Sep;86(3):633–643.
  50. Kim I-D, Shin J-H, Lee H-K, Jin Y-C, Lee J-K. Intranasal delivery of HMGB1-binding heptamer peptide confers a robust neuroprotection in the postischemic brain. Neurosci Lett. Elsevier Ireland Ltd; 2012 Sep;525(2):179–183.
  51. Wang L, Zhang X, Liu L, Yang R, Cui L, Li M. Atorvastatin protects rat brains against permanent focal ischemia and downregulates HMGB1, HMGB1 receptors (RAGE and TLR4), NF-kappaB expression. Neurosci Lett. 2010 Mar 8;471(3):152–156.
  52. Okuma Y, Liu K, Wake H, Zhang J, Maruo T, Date I, et al. Anti-high mobility group box-1 antibody therapy for traumatic brain injury. Ann Neurol. 2012 Sep;72(3): 373–384.
  53. Uzawa A, Mori M, Taniguchi J, Masuda S, Muto M, Kuwabara S. Anti-high mobility group box 1 monoclonal antibody ameliorates experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2013 Apr;172(1):37–43.

How to Cite

Wąsik N, Jankowski R, Sokół B, Shahid H. High mobility group box 1 protein in the central nervous system. JMS [Internet]. 2016Feb.18 [cited 2020Aug.5];83(4):336-41. Available from: