Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis

Abstract

Physiological anti-inflammatory mechanisms can potentially be exploited for the treatment of inflammatory disorders. Here we report that the neurotransmitter acetylcholine inhibits HMGB1 release from human macrophages by signaling through a nicotinic acetylcholine receptor. Nicotine, a selective cholinergic agonist, is more efficient than acetylcholine and inhibits HMGB1 release induced by either endotoxin or tumor necrosis factor-alpha (TNF-α). Nicotinic stimulation prevents activation of the NF-κB pathway and inhibits HMGB1 secretion through a specific 'nicotinic anti-inflammatory pathway' that requires the α7 nicotinic acetylcholine receptor (α7nAChR). In vivo, treatment with nicotine attenuates serum HMGB1 levels and improves survival in experimental models of sepsis, even when treatment is started after the onset of the disease. These results reveal acetylcholine as the first known physiological inhibitor of HMGB1 release from human macrophages and suggest that selective nicotinic agonists for the α7nAChR might have therapeutic potential for the treatment of sepsis.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Cholinergic agonists inhibit human macrophages.
Figure 2: Nicotinic stimulation specifically inhibits HMGB1 release.
Figure 3: Nicotinic treatment prevents lethal endotoxemia.
Figure 4: Nicotinic stimulation prevents the NF-κB pathway.
Figure 5: Nicotine improves survival in 'established' sepsis.
Figure 6: The 'nicotinic anti-inflammatory pathway.'

References

  1. Sands, K.E. et al. Epidemiology of sepsis syndrome in 8 academic medical centers. JAMA 278, 234–240 (1997).

    Article  CAS  Google Scholar 

  2. Angus, D.C. et al. Quality-adjusted survival in the first year after the acute respiratory distress syndrome. Am. J. Respir. Crit. Care Med. 163, 1389–1394 (2001).

    Article  CAS  Google Scholar 

  3. Marshall, J.C. Inflammation, coagulopathy, and the pathogenesis of multiple organ dysfunction syndrome. Crit. Care Med. 29, S99–S106 (2001).

    Article  CAS  Google Scholar 

  4. Friedman, G., Silva, E. & Vincent, J.L. Has the mortality of septic shock changed with time. Crit. Care Med. 26, 2078–2086 (1998).

    Article  CAS  Google Scholar 

  5. Czura, C.J. et al. HMGB1 in the immunology of sepsis (not septic shock) and arthritis. Adv. Immunol. 84, 181–200 (2004).

    Article  CAS  Google Scholar 

  6. Tracey, K.J. et al. Anti-cachectin/tnf monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 330, 662–664 (1987).

    Article  CAS  Google Scholar 

  7. Dinarello, CA. The interleukin-1 family: 10 years of discovery. FASEB J. 8, 1314–1325 (1994).

    Article  CAS  Google Scholar 

  8. Dinarello, C.A. Therapeutic strategies to reduce IL-1 activity in treating local and systemic inflammation. Curr. Opin. Pharmacol. 4, 378–385 (2004).

    Article  CAS  Google Scholar 

  9. Riedemann, N.C., Guo, R.F. & Ward, P.A. Novel strategies for the treatment of sepsis. Nat. Med. 9, 517–524 (2003).

    Article  CAS  Google Scholar 

  10. Scaffidi, P., Misteli, T. & Bianchi, M.E. Release of chromatin protein hmgb1 by necrotic cells triggers inflammation. Nature 418, 191–195 (2002).

    Article  CAS  Google Scholar 

  11. Abraham, E. et al. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Norasept ii study group. Lancet 351, 929–933 (1998).

    Article  CAS  Google Scholar 

  12. Abraham, E., et al. Lenercept (p55 tumor necrosis factor receptor fusion protein) in severe sepsis and early septic shock, A randomized, double-blind, placebo-controlled, multicenter phase iii trial with 1,342 patients. Crit. Care Med. 29, 503–510 (2001).

    Article  CAS  Google Scholar 

  13. Fisher, C.J. et al. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome. Results from a randomized, double-blind, placebo-controlled trial. Phase iii rhil-1ra sepsis syndrome study group. JAMA 271, 1836–1843 (1994).

    Article  Google Scholar 

  14. Eskandari, M.K. et al. Anti-tumor necrosis factor antibody therapy fails to prevent lethality after cecal ligation and puncture or endotoxemia. J. Immunol. 148, 2724–2730 (1992).

    CAS  Google Scholar 

  15. Wang, H. et al. Hmg-1 as a late mediator of endotoxin lethality in mice. Science 285, 248–251 (1999).

    Article  CAS  Google Scholar 

  16. Andersson, U., et al. High mobility group 1 protein (hmg-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med. 192, 565–570 (2000).

    Article  CAS  Google Scholar 

  17. Ulloa, L. et al. Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation. Proc. Natl. Acad. Sci. USA 99, 12351–12356 (2002).

    Article  CAS  Google Scholar 

  18. Bustin, M. At the crossroads of necrosis and apoptosis, signaling to multiple cellular targets by HMGB1. Sci STKE 151 (2002).

  19. Yang, H. et al. Reversing established sepsis with antagonists of endogenous high-mobility group box 1. Proc. Natl. Acad. Sci. USA 101, 296–301 (2004).

    Article  CAS  Google Scholar 

  20. Bonaldi, T. et al. (2003) Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J. 22, 5551–5560.

    Article  CAS  Google Scholar 

  21. Li, J. et al. Structural basis for the proinflammatory cytokine activity of high mobility group box 1. Mol. Med. 9, 37–45 (2003).

    Article  CAS  Google Scholar 

  22. Borovikova, L.V. et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405, 458–462 (2000).

    Article  CAS  Google Scholar 

  23. Bernik, T.R. et al. Pharmacological stimulation of the cholinergic antiinflammatory pathway. J. Exp. Med. 195, 781–788 (2002).

    Article  CAS  Google Scholar 

  24. Tracey, K.J. The inflammatory reflex. Nature 420, 853–859 (2002).

    Article  CAS  Google Scholar 

  25. Wang, H. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003).

    Article  CAS  Google Scholar 

  26. Rendon-Mitchell, B. et al. IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism. J. Immunol. 170, 3890–3897 (2003).

    Article  CAS  Google Scholar 

  27. Lee, J.C. et al. A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746 (1994).

    Article  CAS  Google Scholar 

  28. Derijard, B. et al. Independent human map-kinase signal transduction pathways defined by mek and mkk isoforms. Science 267, 682–685 (1995).

    Article  CAS  Google Scholar 

  29. Baeuerle, P.A. & Henkel, T. Function and activation of NF-κB in the immune system. Annu. Rev. Immunol. 12, 141–179 (1994).

    Article  CAS  Google Scholar 

  30. Li, Q. & Verma, I.M. NF-κB regulation in the immune system. Nat. Rev. Immunol. 2, 725–734 (2002).

    Article  CAS  Google Scholar 

  31. Wang, H., Czura, C. & Tracey, K.J. Lipid unites disparate syndromes of sepsis. Nat. Med. 10, 124–125 (2004).

    Article  CAS  Google Scholar 

  32. Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nat. Rev. Neurosci. 3, 102–114 (2002).

    Article  CAS  Google Scholar 

  33. Wess, J. Muscarinic acetylcholine receptor knockout mice, novel phenotypes and clinical implications. Annu. Rev. Pharmacol. Toxicol. 44, 423–450 (2004).

    Article  CAS  Google Scholar 

  34. Unwin, N. Acetylcholine receptor channel imaged in the open state. Nature 373, 37–43 (1995).

    Article  CAS  Google Scholar 

  35. Hogg, R.C., Raggenbass, M. & Bertrand, D. Nicotinic acetylcholine receptors, from structure to brain function. Rev. Physiol. Biochem. Pharmacol. 147, 1–46 (2003).

    Article  CAS  Google Scholar 

  36. Ando, Y. Transdermal nicotine for ulcerative colitis. Ann. Intern. Med. 127, 491–492 (1997).

    Article  CAS  Google Scholar 

  37. Guarini, S. et al. Efferent vagal fibre stimulation blunts nuclear factor-κB activation and protects against hypovolemic hemorrhagic shock. Circulation 107, 1189–1194 (2003).

    Article  Google Scholar 

  38. Ulloa, L. Batliwalla, F.M., Andersson, U., Gregersen, P.K. & Tracey, K.J. High mobility group box chromosomal protein 1 as a nuclear protein, cytokine, and potential therapeutic target in arthritis. Arthritis Rheum. 48, 876–881 (2003).

    Article  CAS  Google Scholar 

  39. Andersson, U. & Erlandsson-Harris, H. Hmgb1 is a potent trigger of arthritis. J. Intern. Med. 255, 344–350 (2004).

    Article  CAS  Google Scholar 

  40. Jick, H. & Walker, A.M. Cigarette smoking and ulcerative colitis. N. Engl. J. Med. 308, 261–263 (1983).

    Article  CAS  Google Scholar 

  41. Rampton, D.S. Smoking and ulcerative colitis. Lancet 1, 168 (1984).

    Article  CAS  Google Scholar 

  42. Martin, T.R. MIF mediation of sepsis. Nat. Med. 6, 140–141 (2000).

    Article  CAS  Google Scholar 

  43. Calandra, T. et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat. Med. 6, 164–170 (2000).

    Article  CAS  Google Scholar 

  44. Yan, J. et al. Therapeutic effects of lysophosphatidylcholine in experimental sepsis. Nat. Med. 10, 161–167 (2004).

    Article  CAS  Google Scholar 

  45. Ulloa, L., Diaz-Nido, J. & Avila, J. Depletion of casein kinase II by antisense oligonucleotide prevents neuritogenesis in neuroblastoma cells. EMBO J. 12, 1633–1640 (1993).

    Article  CAS  Google Scholar 

  46. Ulloa, L. et al. Inhibition of transforming growth factor-beta/SMAD signaling by the interferon-gamma/STAT pathway. Nature 397, 710–713 (1999).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors are grateful for the suggestions of J. Li, R. Wagner, P. Wang, L. Mantell, J. Peña and H. Yang. This research was supported by the Faculty Awards Program of the North Shore Research Institute, the North Shore-LIJ GCRC, NIGMS and DARPA.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Luis Ulloa.

Ethics declarations

Competing interests

The authors have pending patents related to the potential value of the α7 nicotinic acetylcholine receptor for the treatment of inflammatory disorders.

Supplementary information

Supplementary Fig. 1

Cycloheximide did not block entoxin-induced HMGB1 extracellular release from macrophages (PDF 49 kb)

Supplementary Fig. 2

Nicotinic inhibits the activation of the NF–κB signaling induced by peptidoglycan from S. aureus (PDF 60 kb)

Supplementary Table 1

Effect of nicotinic treatment during lethal endotoxemia (PDF 9 kb)

Supplementary Table 2

Effect of nicotinic treatment during peritonitis (PDF 9 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wang, H., Liao, H., Ochani, M. et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 10, 1216–1221 (2004). https://doi.org/10.1038/nm1124

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1124

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing