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.

  • Letter
  • Published:

Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation

Abstract

Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease1,2,3,4. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses5,6,7. This physiological mechanism, termed the ‘cholinergic anti-inflammatory pathway’5 has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor α7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in α7-deficient mice. Thus, the nicotinic acetylcholine receptor α7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.

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

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: α-Bungarotoxin-binding nicotinic receptors are clustered on the surface of macrophages.
Figure 2: Messenger RNA and protein expression of nicotinic acetylcholine receptor α7 subunit in primary human macrophages.
Figure 3: Antisense oligonucleotides to the α7 subunit inhibit the effect of nicotine on TNF release.
Figure 4: Increased cytokine production in α7-subunit-deficient mice during endotoxaemia.
Figure 5: Vagus nerve stimulation does not inhibit TNF production in α7-subunit-deficient mice.

Similar content being viewed by others

References

  1. Tracey, K. J. et al. Shock and tissue injury induced by recombinant human cachectin. Science 234, 470–474 (1986)

    Article  ADS  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Tracey, K. J. & Cerami, A. Tumor necrosis factor: a pleiotropic cytokine and therapeutic target. Annu. Rev. Med. 45, 491–503 (1994)

    Article  CAS  PubMed  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Bernik, T. R. et al. Pharmacological stimulation of the cholinergic anti-inflammatory pathway. J. Exp. Med. 195, 781–788 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  ADS  CAS  PubMed  Google Scholar 

  8. Lindstrom, J. M. in Hand Book of Receptors and Channels: Ligand- and Voltage-Gated Ion Channels (ed. North, A.) 153–175 (CRC Press, Boca Raton, Florida, 1995)

    Google Scholar 

  9. Leonard, S. & Bertrand, D. Neuronal nicotinic receptors: from structure to function. Nicotine Tob. Res. 3, 203–223 (2001)

    Article  CAS  PubMed  Google Scholar 

  10. Le Novere, N. & Changeux, J.-P. Molecular evolution of the nicotinic acetylcholine receptor: an example of multigene family in excitable cells. J. Mol. Evol. 40, 155–172 (1995)

    Article  ADS  CAS  PubMed  Google Scholar 

  11. Marubio, L. M. & Changeux, J.-P. Nicotinic acetylcholine receptor knockout mice as animal models for studying receptor function. Eur. J. Pharmacol. 393, 113–121 (2000)

    Article  CAS  PubMed  Google Scholar 

  12. Steinlein, O. New functions for nicotine acetylcholine receptors? Behav. Brain Res. 95, 31–35 (1998)

    Article  CAS  PubMed  Google Scholar 

  13. Lin, W. et al. Distinct roles of nerve and muscle in postsynaptic differentiation of the neuromuscular synapse. Nature 410, 1057–1064 (2001)

    Article  ADS  CAS  PubMed  Google Scholar 

  14. Feng, G., Steinbach, J. H. & Sanes, J. R. Rapsyn clusters neuronal acetylcholine receptors but is inessential for formation of an interneuronal cholinergic synapse. J. Neurosci. 18, 4166–4176 (1998)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Shoop, R. D., Yamada, N. & Berg, D. K. Cytoskeletal links of neuronal acetylcholine receptors containing α7 subunits. J. Neurosci. 20, 4021–4029 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Peng, X. et al. Human α7 acetylcholine receptor: cloning of the α7 subunit from the SH-SY5Y cell line and determination of pharmacological properties of native receptors and functional α7 homomers expressed in Xenopus oocytes. Mol. Pharmacol. 45, 546–554 (1994)

    CAS  PubMed  Google Scholar 

  17. Drisdel, R. C. & Green, W. N. Neuronal α-bungarotoxin receptors are α7 subunit homomers. J. Neurosci. 20, 133–139 (2000)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Seguela, P. et al. Molecular cloning, functional properties, and distribution of rat brain α7: a nicotinic cation channel highly permeable to calcium. J. Neurosci. 13, 596–604 (1993)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Gault, J. et al. Genomic organization and partial duplication of the human α7 neuronal nicotinic acetylcholine receptor gene (CHRNA7). Genomics 52, 173–185 (1998)

    Article  CAS  PubMed  Google Scholar 

  20. Bianchi, M. et al. An inhibitor of macrophage arginine transport and nitric oxide production (CNI-1493) prevents acute inflammation and endotoxin lethality. Mol. Med. 1, 254–266 (1995)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kumins, N. H., Hunt, J., Gamelli, R. L. & Filkins, J. P. Partial hepatectomy reduces the endotoxin-induced peak circulating level of tumour necrosis factor in rats. Shock 5, 385–388 (1996)

    Article  CAS  PubMed  Google Scholar 

  22. Orr-Urtreger, A. et al. Mice deficient in the α7 neuronal nicotinic acetylcholine receptor lack α-bungarotoxin binding sites and hippocampal fast nicotinic currents. J. Neurosci. 17, 9165–9171 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Franceschini, D. et al. Altered baroreflex responses in α7 deficient mice. Behav. Brain Res. 113, 3–10 (2000)

    Article  CAS  PubMed  Google Scholar 

  24. Vijayaraghavan, S. et al. Nicotinic receptors that bind α-bungarotoxin on neurons raise intracellular free Ca2+. Neuron 8, 353–362 (1992)

    Article  CAS  PubMed  Google Scholar 

  25. Shoop, R. D. et al. Synaptically driven calcium transients via nicotinic receptors on somatic spines. J. Neurosci. 21, 771–781 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cohen, P. S. et al. The critical role of p38 MAP kinase in T cell HIV-1 replication. Mol. Med. 3, 339–346 (1997)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. 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  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This work was supported in part by the National Institutes of Health, the National Institute of General Medical Sciences, and the Defense Advanced Research Projects Agency.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kevin J. Tracey.

Ethics declarations

Competing interests

The authors have patents pending.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, H., Yu, M., Ochani, M. et al. Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature 421, 384–388 (2003). https://doi.org/10.1038/nature01339

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01339

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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