Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation
Open accessAbstract
Endothelial cell activation plays a critical role in regulating leukocyte recruitment during inflammation and infection. Based on recent studies showing that acetylcholine and other cholinergic mediators suppress the production of proinflammatory cytokines via the α7 nicotinic acetylcholine receptor (α7 nAChR) expressed by macrophages and our observations that human microvascular endothelial cells express the α7 nAChR, we examined the effect of cholinergic stimulation on endothelial cell activation in vitro and in vivo. Using the Shwartzman reaction, we observed that nicotine (2 mg/kg) and the novel cholinergic agent CAP55 (12 mg/kg) inhibit endothelial cell adhesion molecule expression. Using endothelial cell cultures, we observed the direct inhibitory effects of acetylcholine and cholinergic agents on tumor necrosis factor (TNF)-induced endothelial cell activation. Mecamylamine, an nAChR antagonist, reversed the inhibition of endothelial cell activation by both cholinergic agonists, confirming the antiinflammatory role of the nAChR cholinergic pathway. In vitro mechanistic studies revealed that nicotine blocked TNF-induced nuclear factor–κB nuclear entry in an inhibitor κB (IκB)α- and IκBε-dependent manner. Finally, with the carrageenan air pouch model, both vagus nerve stimulation and cholinergic agonists significantly blocked leukocyte migration in vivo. These findings identify the endothelium, a key regulator of leukocyte trafficking during inflammation, as a target of anti-inflammatory cholinergic mediators.
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Vagus nerve stimulation in a subcutaneous carrageenan air pouch model significantly inhibits recruitment of polymorphonuclear leukocytes to the inflammatory zone.
“Vagus nerve stimulation of mice in a model of subcutaneous inflammation caused by injecting carrageenan into an air pouch significantly inhibited the recruitment of polymorphonuclear leukocytes to the inflammatory zone (25).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [25]
Cholinergic stimulation controls endothelial activation, leukocyte recruitment, coagulation, and fibrinolysis, which modulates the development of damage during sepsis.
“Other studies indicate that cholinergic stimulation controls endothelial activation, leukocyte recruitment, coagulation, and fibrinolysis, which modulates the development of damage during sepsis (25,36).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [25]
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- Authors
- Saeed, R. W., Varma, S., Peng-Nemeroff, T., Sherry, B., Balakhaneh, D., Huston, J., Tracey, K. J., Al-Abed, Y., & Metz, C. N.
- Affiliations
- Northwell Health (US)
- 1Laboratory of Medicinal Biochemistry, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
- 2Laboratory of Chemokine Biology, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
- 3Laboratory of Medicinal Chemistry, Institute for Medical Research at North Shore–LIJ, Manhasset, NY 11030
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2005-04-04
- Volume
- 201
- Issue
- 7
- Pages
- 1113-1123
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2213139
- OpenAlex
- W2151660617
- Cited by
- 489
- References
- 48
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 18 · 2023: 13 · 2022: 18 · 2021: 19 · 2020: 17 · 2019: 19 · 2018: 21 · 2017: 23 · 2016: 27 · 2015: 38 · 2014: 25 · 2013: 27 · 2012: 25
- FWCI
- 16.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Experimental Medicine (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Funders
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- National Institute of General Medical Sciences
- National Institute of Allergy and Infectious Diseases
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nicotinic Acetylcholine Receptors Study
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- cholinergic anti-inflammatory pathway, endothelial activation, alpha7 nicotinic acetylcholine receptor, acetylcholine, nicotine, leukocyte recruitment, leukocyte migration, IκBα, IκBε, vagus nerve stimulation, Shwartzman reaction, microvascular endothelial cells, inflammation
- MeSH terms
- Acetylcholine, Animals, Carrageenan, Cell Migration Inhibition, Enzyme-Linked Immunosorbent Assay, Female, Flow Cytometry, Humans, Inflammation, Leukocytes, Mecamylamine, Mice, Inbred BALB C, Nicotine, Phagocytes, Receptors, Nicotinic, Shwartzman Phenomenon, Tumor Necrosis Factor-alpha, Vagus Nerve, Blotting, Western, Cell Adhesion Molecules, DNA Primers, Cholinergic Agents, Nicotinic Antagonists, Reverse Transcriptase Polymerase Chain Reaction, Endothelial Cells, Mice, alpha7 Nicotinic Acetylcholine Receptor
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