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 disease. 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 responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' 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 alpha7 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 alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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Vagus nerve stimulation fails to suppress cytokine synthesis in α7 nAChR-knockout animals whereas it significantly inhibits cytokine release in wild-type littermates.
“vagus nerve stimulation in α7 nAChR-knockout animals fails to suppress cytokine synthesis whereas it significantly inhibits cytokine release in wild-type littermates (26).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [26]
Vagus nerve-derived cholinergic signals provide tonic or continuous neurological modulation of cytokine synthesis, functioning as a governor that limits the magnitude of the immune response.
“This indicates that vagus nerve-derived cholinergic signals provide tonic or continuous neurological modulation of cytokine synthesis, functioning as a governor on an engine that limits the magnitude of the immune response.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [26]
Macrophages and other cytokine-producing cells express acetylcholine receptors that transduce an intracellular signal inhibiting cytokine synthesis.
“Macrophages and other cytokine-producing cells express acetylcholine receptors (AChRs), which transduce an intracellular signal that inhibits cytokine synthesis (26,27).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [26]
The α7 subunit of the nicotinic AChR is the best characterized cholinergic receptor that suppresses cytokines.
“The best characterized of these cholinergic receptors that suppress cytokines is the α7 subunit of the nicotinic AChR (α7 nAChR).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [26]
Mice deficient in either the α7 nAChR subunit or vagus nerve activity have exaggerated TNF levels when exposed to endotoxin.
“Mice exposed to endotoxin realize an unbalanced, excessive cytokine response characterized by exaggerated TNF levels if they are deficient in either the α7 nAChR subunit (as a result of genetic knockout) or vagus nerve activity (as a result of vagotomy) (18,26).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [26]
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- Authors
- Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., Al-Abed, Y., Czura, C. J., & Tracey, K. J.
- Corresponding author
- Tracey, Kevin J.
- ORCID
- Venue
- Nature
- Published
- 2002-12-22
- Volume
- 421
- Issue
- 6921
- Pages
- 384-388
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2073295417
- Cited by
- 3,228
- References
- 26
- Citations by year
- 2026: 142 · 2025: 128 · 2024: 181 · 2023: 141 · 2022: 180 · 2021: 203 · 2020: 181 · 2019: 169 · 2018: 154 · 2017: 164 · 2016: 146 · 2015: 142 · 2014: 160 · 2013: 133 · 2012: 127
- FWCI
- 36.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- cholinergic anti-inflammatory pathway, vagus nerve, acetylcholine, inflammation regulation, innate immune response, cytokine production
- MeSH terms
- Acetylcholine, Aging, Animals, Bungarotoxins, Cells, Cultured, Electric Stimulation, Female, Humans, Inflammation, Male, Mice, Inbred C57BL, Nicotine, Receptors, Nicotinic, RNA, Messenger, Tumor Necrosis Factor-alpha, Vagus Nerve, Macrophages, Peritoneal, Mice, Knockout, Endotoxemia, Protein Subunits, Mice, alpha7 Nicotinic Acetylcholine Receptor
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