Skip to main content
SpringerLink
Log in

Upregulation of HMGB1 in wall of ruptured and unruptured human cerebral aneurysms: preliminary results

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

A growing body of evidence suggests that inflammation plays a crucial role in cerebral aneurysm initiation, progression, and rupture. High-mobility group box 1 (HMGB1) is a non-histone nuclear protein that can serve as an alarmin to drive the pathogenesis of inflammatory disease. The purpose of this study was to investigate the expression of HMGB1 in the wall of ruptured and unruptured human cerebral aneurysms. Human cerebral aneurysms (25 ruptured and 16 unruptured) were immunohistochemically stained for HMGB1. As controls, four specimens of the middle cerebral arteries obtained at autopsy were also immunostained. Immunofluorescence double staining was used to determine HMGB1 cellular distribution. HMGB1 was nearly undetectable in the controls. All aneurysm tissues stained positive for HMGB1 monoclonal antibody, and expression of HMGB1 was more abundant in ruptured aneurysm tissue than unruptured aneurysms (p < 0.05). Furthermore, the expression of HMGB1 had no correlation with aneurysm size and time resected after the rupture. HMGB1 nuclear immunoreactivity was co-localized with immunoreactivity of CD3 in T lymphocytes, CD20 in B lymphocytes, CD68 in macrophages, α-SMA in smooth muscle cells, and CD31 in endothelial cells. Cytoplasmic HMGB1 localization was also detected in macrophages and T lymphocytes. Taken together, HMGB1 is expressed in the wall of human cerebral aneurysms and is more abundant in ruptured aneurysms than in unruptured ones. These data indicate a possible role of HMGB1 in the pathophysiology of human cerebral aneurysms.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Agresti A, Lupo R, Bianchi ME, Muller S (2003) HMGB1 interacts differentially with members of the Rel family of transcription factors. Biochem Biophys Res Commun 302:421–426

    Article  CAS  PubMed  Google Scholar 

  2. Aoki T, Kataoka H, Nishimura M, Ishibashi R, Morishita R, Miyamoto S (2012) Regression of intracranial aneurysms by simultaneous inhibition of nuclear factor-kappaB and Ets with chimeric decoy oligodeoxynucleotide treatment. Neurosurgery 70:1534–1543. doi:10.1227/NEU.0b013e318246a390

    Article  PubMed  Google Scholar 

  3. Chalouhi N, Ali MS, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Koch WJ, Dumont AS (2012) Biology of intracranial aneurysms: role of inflammation. J Cereb Blood Flow Metab 32:1659–1676. doi:10.1038/jcbfm.2012.84

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. de Souza AW, Westra J, Limburg PC, Bijl M, Kallenberg CG (2012) HMGB1 in vascular diseases: its role in vascular inflammation and atherosclerosis. Autoimmun Rev 11:909–917. doi:10.1016/j.autrev.2012.03.007

    Article  PubMed  Google Scholar 

  5. Frosen J, Piippo A, Paetau A, Kangasniemi M, Niemela M, Hernesniemi J, Jaaskelainen J (2004) Remodeling of saccular cerebral artery aneurysm wall is associated with rupture—histological analysis of 24 unruptured and 42 ruptured cases. Stroke J Cereb Circ 35:2287–2293. doi:10.1161/01.Str.0000140636.30204.Da

    Article  Google Scholar 

  6. Frosen J, Tulamo R, Heikura T, Sammalkorpi S, Niemela M, Hernesniemi J, Levonen AL, Horkko S, Yla-Herttuala S (2013) Lipid accumulation, lipid oxidation, and low plasma levels of acquired antibodies against oxidized lipids associate with degeneration and rupture of the intracranial aneurysm wall. Acta Neuropathol Commun 1:71. doi:10.1186/2051-5960-1-71

    Article  PubMed Central  PubMed  Google Scholar 

  7. Hasan D, Chalouhi N, Jabbour P, Hashimoto T (2012) Macrophage imbalance (M1 vs. M2) and upregulation of mast cells in wall of ruptured human cerebral aneurysms: preliminary results. J Neuroinflam 9:222. doi:10.1186/1742-2094-9-222

    Article  CAS  Google Scholar 

  8. Hasan D, Hashimoto T, Kung D, Macdonald RL, Winn HR, Heistad D (2012) Upregulation of cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1) in wall of ruptured human cerebral aneurysms: preliminary results. Stroke J Cereb Circ 43:1964–1967. doi:10.1161/STROKEAHA.112.655829

    Article  CAS  Google Scholar 

  9. Hu Y, Zhang Z, Torsney E, Afzal AR, Davison F, Metzler B, Xu Q (2004) Abundant progenitor cells in the adventitia contribute to atherosclerosis of vein grafts in ApoE-deficient mice. J Clin Invest 113:1258–1265. doi:10.1172/JCI19628

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Humphrey JD, Taylor CA (2008) Intracranial and abdominal aortic aneurysms: similarities, differences, and need for a new class of computational models. Annu Rev Biomed Eng 10:221–246. doi:10.1146/annurev.bioeng.10.061807.160439

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Kanellakis P, Agrotis A, Kyaw TS, Koulis C, Ahrens I, Mori S, Takahashi HK, Liu K, Peter K, Nishibori M, Bobik A (2011) High-mobility group box protein 1 neutralization reduces development of diet-induced atherosclerosis in apolipoprotein e-deficient mice. Arterioscler Thromb Vasc Biol 31:313–319. doi:10.1161/ATVBAHA.110.218669

    Article  CAS  PubMed  Google Scholar 

  12. Killer-Oberpfalzer M, Aichholzer M, Weis S, Richling B, Jones R, Virmani R, Cruise GM (2012) Histological analysis of clipped human intracranial aneurysms and parent arteries with short-term follow-up. Cardiovasc Pathol 21:299–306. doi:10.1016/j.carpath.2011.09.010

    Article  PubMed  Google Scholar 

  13. Kohno T, Anzai T, Kaneko H, Sugano Y, Shimizu H, Shimoda M, Miyasho T, Okamoto M, Yokota H, Yamada S, Yoshikawa T, Okada Y, Yozu R, Ogawa S, Fukuda K (2012) High-mobility group box 1 protein blockade suppresses development of abdominal aortic aneurysm. J Cardiol 59:299–306. doi:10.1016/j.jjcc.2012.01.007

    Article  PubMed  Google Scholar 

  14. Kurki MI, Hakkinen SK, Frosen J, Tulamo R, von und zu Fraunberg M, Wong G, Tromp G, Niemela M, Hernesniemi J, Jaaskelainen JE, Yla-Herttuala S (2011) Upregulated signaling pathways in ruptured human saccular intracranial aneurysm wall: an emerging regulative role of Toll-like receptor signaling and nuclear factor-kappaB, hypoxia-inducible factor-1A, and ETS transcription factors. Neurosurgery 68:1667–1675. doi:10.1227/NEU.0b013e318210f001

    Article  PubMed  Google Scholar 

  15. Lotze MT, Tracey KJ (2005) High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal. Nat Rev Immunol 5:331–342. doi:10.1038/nri1594

    Article  CAS  PubMed  Google Scholar 

  16. Molyneux AJ, Kerr RS, Birks J, Ramzi N, Yarnold J, Sneade M, Rischmiller J (2009) Risk of recurrent subarachnoid haemorrhage, death, or dependence and standardised mortality ratios after clipping or coiling of an intracranial aneurysm in the International Subarachnoid Aneurysm Trial (ISAT): long-term follow-up. Lancet Neurol 8:427–433. doi:10.1016/S1474-4422(09)70080-8

    Article  PubMed Central  PubMed  Google Scholar 

  17. Nakahara T, Tsuruta R, Kaneko T, Yamashita S, Fujita M, Kasaoka S, Hashiguchi T, Suzuki M, Maruyama I, Maekawa T (2009) High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage. Neurocrit Care 11:362–368. doi:10.1007/s12028-009-9276-y

    Article  CAS  PubMed  Google Scholar 

  18. Siow RC, Churchman AT (2007) Adventitial growth factor signalling and vascular remodelling: potential of perivascular gene transfer from the outside-in. Cardiovasc Res 75:659–668. doi:10.1016/j.cardiores.2007.06.007

    Article  CAS  PubMed  Google Scholar 

  19. Starke RM, Chalouhi N, Jabbour PM, Tjoumakaris SI, Gonzalez LF, Rosenwasser RH, Wada K, Shimada K, Hasan DM, Greig NH, Owens GK, Dumont AS (2014) Critical role of TNF-alpha in cerebral aneurysm formation and progression to rupture. J Neuroinflam 11:77. doi:10.1186/1742-2094-11-77

    Article  Google Scholar 

  20. Sun Q, Wu W, Hu YC, Li H, Zhang D, Li S, Li W, Li WD, Ma B, Zhu JH, Zhou ML, Hang CH (2014) Early release of high-mobility group box 1 (HMGB1) from neurons in experimental subarachnoid hemorrhage in vivo and in vitro. J Neuroinflam 11:106. doi:10.1186/1742-2094-11-106

    Article  Google Scholar 

  21. Tsung A, Tohme S, Billiar TR (2014) High-mobility group box-1 in sterile inflammation. J Intern Med 276:425–443. doi:10.1111/joim.12276

    Article  CAS  PubMed  Google Scholar 

  22. Wardlaw JM, White PM (2000) The detection and management of unruptured intracranial aneurysms. Brain 123:205–221. doi:10.1093/brain/123.2.205

    Article  PubMed  Google Scholar 

  23. Wiebers DO, Whisnant JP, Huston J 3rd, Meissner I, Brown RD Jr, Piepgras DG, Forbes GS, Thielen K, Nichols D, O’Fallon WM, Peacock J, Jaeger L, Kassell NF, Kongable-Beckman GL, Torner JC (2003) Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet 362:103–110

    Article  PubMed  Google Scholar 

  24. Zhang D, Hu Y, Sun Q, Zhao J, Cong Z, Liu H, Zhou M, Li K, Hang C (2013) Inhibition of transforming growth factor beta-activated kinase 1 confers neuroprotection after traumatic brain injury in rats. Neuroscience 238:209–217. doi:10.1016/j.neuroscience.2013.02.022

    Article  CAS  PubMed  Google Scholar 

  25. Zhu XD, Chen JS, Zhou F, Liu QC, Chen G, Zhang JM (2012) Relationship between plasma high mobility group box-1 protein levels and clinical outcomes of aneurysmal subarachnoid hemorrhage. J Neuroinflam 9:194. doi:10.1186/1742-2094-9-194

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This study was supported by the National Natural Science Foundation, China (No. 81371294), and the Natural Science Foundation of Jiangsu Province (No. BK20141375).

Author information

Author notes

    Authors and Affiliations

    1. Department of Neurosurgery, Jinling Hospital, School of Medicine, Nanjing University, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, People’s Republic of China

      Dingding Zhang, Wei Wu, Huiying Yan, Tianwei Jiang, Zhuang Yu, Hua Li & Chunhua Hang

    2. Department of Neurosurgery, School of Medicine, Southern Medical University (Guangzhou), Jinling Hospital, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, People’s Republic of China

      Ming Liu & Chunhua Hang

    Authors
    1. Dingding Zhang
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Wei Wu
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Huiying Yan
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Tianwei Jiang
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Ming Liu
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Zhuang Yu
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Hua Li
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Chunhua Hang
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Chunhua Hang.

    Ethics declarations

    Conflict of interest

    All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

    Additional information

    D. Zhang and W. Wu contributed equally.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (TIFF 1027 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Zhang, D., Wu, W., Yan, H. et al. Upregulation of HMGB1 in wall of ruptured and unruptured human cerebral aneurysms: preliminary results. Neurol Sci 37, 219–226 (2016). https://doi.org/10.1007/s10072-015-2391-y

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s10072-015-2391-y

    Keywords

    Search

    Navigation