The Cholinergic Anti‐Inflammatory Pathway Regulates the Host Response during Septic Peritonitis
Abstract
BACKGROUND: The nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of tumor necrosis factor- alpha by endotoxin-stimulated macrophages. This anti-inflammatory effect is mediated by an interaction between acetylcholine, the principal neurotransmitter of the vagus nerve, and cholinergic nicotinic acetylcholine receptors on macrophages. METHODS: We determined the role of this "cholinergic anti-inflammatory pathway" during septic peritonitis induced in mice by intraperitoneal injection of live Escherichia coli. Septic peritonitis was preceded by inhibition of the cholinergic anti-inflammatory pathway by unilateral cervical vagotomy, by stimulation of this pathway by pretreatment of mice with nicotine, or by a combination of both interventions. RESULTS: Initial cytokine release during septic peritonitis was enhanced after previous vagotomy and was decreased after nicotine pretreatment, independently of the integrity of the vagus nerve. Further study established that vagotomy before septic peritonitis resulted in an enhanced influx of neutrophils and a marked increase in proinflammatory cytokine levels and liver damage. Conversely, nicotine pretreatment strongly decreased cell influx, proinflammatory cytokine levels, and liver damage, whereas bacterial clearance and survival were impaired. DISCUSSION: These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.
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Administration of nicotine to animals with bacterial peritonitis restored cytokine balance, reduced influx of inflammatory cells, and attenuated liver tissue damage.
“Administration of nicotine to these animals restored the cytokine balance, reduced influx of inflammatory cells, and attenuated tissue damage in the liver (35).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [35]
In a bacterial peritonitis model, vagotomy causes a significant increase in inflammatory cells recruited to the peritoneum, higher cytokine levels, and more extensive liver tissue damage.
“In a model of bacterial peritonitis based upon intraperitoneal injection of live Escherichia coli, vagotomy caused a significant increase in the number of inflammatory cells recruited to the peritoneum, higher cytokine levels, and more extensive tissue damage in the liver (35).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [35]
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- Authors
- van Westerloo, D. J., Giebelen, I. A. J., Florquin, S., Daalhuisen, J., Bruno, M. J., de Vos, A. F., Tracey, K. J., & van der Poll, T.
- Affiliations
- University of Amsterdam (NL)
- Venue
- The Journal of Infectious Diseases
- Publisher
- Oxford University Press (OUP)
- Published
- 2005-06-15
- Volume
- 191
- Issue
- 12
- Pages
- 2138-2148
- ISSN
- 0022-1899 (ISSN-L)
- 1537-6613
- OpenAlex
- W2114821371
- Cited by
- 316
- References
- 34
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 12 · 2023: 5 · 2022: 16 · 2021: 11 · 2020: 10 · 2019: 13 · 2018: 12 · 2017: 14 · 2016: 12 · 2015: 17 · 2014: 17 · 2013: 20 · 2012: 14
- FWCI
- 13.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Infectious Diseases (publishedVersion)
- PubMed (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- cholinergic anti-inflammatory pathway, vagus nerve, septic peritonitis, Escherichia coli infection, vagotomy, nicotine, nicotinic acetylcholine receptors, macrophages, TNF-α, inflammatory cytokines, neutrophil influx, liver injury, innate immune response, bacterial clearance
- MeSH terms
- Animals, Escherichia coli Infections, Female, Mice, Inbred C57BL, Nicotine, Peritonitis, Receptors, Nicotinic, Vagotomy, Vagus Nerve, Neuroimmunomodulation, Cytokines, Sepsis, Mice
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