Advertisement

Molecular Medicine

, Volume 18, Issue 6, pp 930–937 | Cite as

HMGB1 Mediates Cognitive Impairment in Sepsis Survivors

  • Sangeeta S Chavan
  • Patricio T Huerta
  • Sergio Robbiati
  • S I Valdes-Ferrer
  • Mahendar Ochani
  • Meghan Dancho
  • Maya Frankfurt
  • Bruce T Volpe
  • Kevin J Tracey
  • Betty Diamond
Research Article

Abstract

Severe sepsis, a syndrome that complicates infection and injury, affects 750,000 annually in the United States. The acute mortality rate is approximately 30%, but, strikingly, sepsis survivors have a significant disability burden: up to 25% of survivors are cognitively and physically impaired. To investigate the mechanisms underlying persistent cognitive impairment in sepsis survivors, here we developed a murine model of severe sepsis survivors following cecal ligation and puncture (CLP) to study cognitive impairments. We observed that serum levels of high mobility group box 1 (HMGB1), a critical mediator of acute sepsis pathophysiology, are increased in sepsis survivors. Significantly, these levels remain elevated for at least 4 wks after CLP? Sepsis survivors develop significant, persistent impairments in learning and memory, and anatomic changes in the hippocampus associated with a loss of synaptic plasticity. Administration of neutralizing anti-HMGBl antibody to survivors, beginning 1 wk after onset of peritonitis, significantly improved memory impairments and brain pathology. Administration of recombinant HMGB1 to naíve mice recapitulated the memory impairments. Together, these findings indicate that elevated HMGB1 levels mediate cognitive decline in sepsis survivors, and suggest that it may be possible to prevent or reverse cognitive impairments in sepsis survivors by administration of anti-HMGB1 antibodies.

Notes

Acknowledgments

This study was supported by a grant from the National Institute of Health (NIGMS GM62508 to KJ Tracey). The authors would like to thank Thomas W Faust and Tomas S Huerta for help in the behavioral assessments, and Roseann Berlin for technical assistance.

References

  1. 1.
    Iwashyna TJ, Ely EW, Smith DM and Langa KM. (2010) Long-term cognitive impairment and functional disability among survivors of severe sepsis. JAMA. 304:1787–94.CrossRefGoogle Scholar
  2. 2.
    Perl TM, Dvorak L, Hwang T and Wenzel RP. (1995) Long-term survival and function after suspected gram-negative sepsis. JAMA. 274:338–45.CrossRefGoogle Scholar
  3. 3.
    Quartin AA, Schein RM, Kett DH and Peduzzi PN. (1997) Magnitude and duration of the effect of sepsis on survival. Department of Veterans Affairs Systemic Sepsis Cooperative Studies Group. JAMA. 277:1058–63.CrossRefGoogle Scholar
  4. 4.
    Boomer JS, et al. (2011) Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA. 306:2594–605.CrossRefGoogle Scholar
  5. 5.
    Angus DC. (2010) The lingering consequences of sepsis: a hidden public health disaster? JAMA. 304:1833–4.CrossRefGoogle Scholar
  6. 6.
    Nathan C and Ding A. (2010) Nonresolving inflammation. Cell. 140:871–82.CrossRefGoogle Scholar
  7. 7.
    Xiao W, et al. (2011) A genomic storm in critically injured humans. J. Exp. Med. 208:2581–90.CrossRefGoogle Scholar
  8. 8.
    Angus DC, et al. (2007) Circulating high-mobility group box 1 (HMGB1) concentrations are elevated in both uncomplicated pneumonia and pneumonia with severe sepsis. Crit. Care Med. 35:1061–7.CrossRefGoogle Scholar
  9. 9.
    Stellwagen D and Malenka RC. (2006) Synaptic scaling mediated by glial TNF-alpha. Nature. 440:1054–9.CrossRefGoogle Scholar
  10. 10.
    Viviani B, et al. (2003) Interleukin-1beta enhances NMDA receptor-mediated intracellular calcium increase through activation of the Src family of kinases. J. Neurosci. 23:8692–700.CrossRefGoogle Scholar
  11. 11.
    Yoshida T, et al. (2012) Interleukin-1 receptor accessory protein organizes neuronal synaptogenesis as a cell adhesion molecule. J. Neurosci. 32:2588–600.CrossRefGoogle Scholar
  12. 12.
    Terrando N, et al. (2010) Tumor necrosis factor-alpha triggers a cytokine cascade yielding postoperative cognitive decline. Proc. Natl. Acad. Sci. U. S. A. 107:20518–22.CrossRefGoogle Scholar
  13. 13.
    Terrando N, et al. (2010) The impact of IL-1 modulation on the development of lipopolysaccharide-induced cognitive dysfunction. Crit Care. 14:R88.CrossRefGoogle Scholar
  14. 14.
    Goldstein RS, et al. (2006) Elevated high-mobility group box 1 levels in patients with cerebral and myocardial ischemia. Shock. 25:571–4.CrossRefGoogle Scholar
  15. 15.
    Yang H, et al. (2004) Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl. Acad. Sci. U. S. A. 101:296–301.CrossRefGoogle Scholar
  16. 16.
    Li J, et al. (2004) Recombinant HMGB1 with cytokine-stimulating activity. J. Immunol. Methods. 289:211–23.CrossRefGoogle Scholar
  17. 17.
    Chang EH, Rigotti A and Huerta PT. (2009) Age-related influence of the HDL receptor SR-BI on synaptic plasticity and cognition. Neurobiol. Aging. 30:407–19.CrossRefGoogle Scholar
  18. 18.
    Irwin S. (1968) Comprehensive observational assessment: Ia. A systematic, quantitative procedure for assessing the behavioral and physiologic state of the mouse. Psychopharmacologia. 1:222–57.CrossRefGoogle Scholar
  19. 19.
    Rogers DC, et al. (1997) Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome. 8:711–3.CrossRefGoogle Scholar
  20. 20.
    Contet C, Rawlins JN and Deacon RM. (2001) Acomparison of 129S2/SvHsd and C57BL/ 6JOlaHsd mice on a test battery assessing sensorimotor, affective and cognitive behaviours: implications for the study of genetically modified mice. Behav. Brain Res. 124:33–46.CrossRefGoogle Scholar
  21. 21.
    Deacon RM and Rawlins JN. (2002) Learning impairments of hippocampal-lesioned mice in a paddling pool. Behav. Neurosci. 116:472–8.CrossRefGoogle Scholar
  22. 22.
    DeGiorgio LA, et al. (2001) A subset of lupus anti-DNA antibodies cross-reacts with the NR2 glutamate receptor in systemic lupus erythematosus. Nat. Med. 7:1189–93.CrossRefGoogle Scholar
  23. 23.
    Eilam-Stock T, Serrano P, Frankfurt M and Luine V. (2012) Bisphenol-A impairs memory and reduces dendritic spine density in adult male rats. Behav. Neurosci. 126:175–85.CrossRefGoogle Scholar
  24. 24.
    Wang H, et al. (2001) HMGB1 as a late mediator of lethal systemic inflammation. Am. J. Respir. Crit. Care Med. 164:1768–73.CrossRefGoogle Scholar
  25. 25.
    Ulloa L. (2011) The anti-inflammatory potential of selective cholinergic agonists. Shock. 36:97–8.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2012

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • Sangeeta S Chavan
    • 1
  • Patricio T Huerta
    • 2
  • Sergio Robbiati
    • 2
  • S I Valdes-Ferrer
    • 1
  • Mahendar Ochani
    • 1
  • Meghan Dancho
    • 1
  • Maya Frankfurt
    • 3
  • Bruce T Volpe
    • 4
  • Kevin J Tracey
    • 1
  • Betty Diamond
    • 5
  1. 1.Laboratorie of Biomedical ScienceThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Laboratorie of Immune and Neural NetworksThe Feinstein Institute for Medical ResearchManhassetUSA
  3. 3.Department of Science EducationHofstra North Shore-LIJ School of MedicineHempsteadUSA
  4. 4.Laboratorie of Functional NeuroanatomyThe Feinstein Institute for Medical ResearchManhassetUSA
  5. 5.Center for Autoimmune and Musculoskeletal DiseasesThe Feinstein Institute for Medical ResearchManhassetUSA

Personalised recommendations