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Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation

Nature volume 421, pages 384–388 (2003)Cite this article

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.

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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.

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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.

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Authors and Affiliations

  1. Laboratory of Biomedical Science, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, New York, 11030, USA

    Hong Wang, Man Yu, Mahendar Ochani, Carol Ann Amella, Mahira Tanovic, Seenu Susarla, Jian Hua Li, Haichao Wang, Huan Yang, Luis Ulloa, Christopher J. Czura & Kevin J. Tracey

  2. Laboratory of Medicinal Chemistry, North Shore Long Island Jewish Research Institute, 350 Community Drive, Manhasset, New York, 11030, USA

    Yousef Al-Abed

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Correspondence to Kevin J. Tracey.

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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

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