Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis
Open accessAbstract
The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the α7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an α7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of α7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.
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Splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation fails to reduce levels further.
“Splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation fails to reduce levels further (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
The principal components for cytokine suppression by the vagus nerve converge in the spleen.
“Recent studies of the physiology, functional anatomy, and cellular molecular mechanisms of the cholinergic antiinflammatory pathway indicate that the principal components for cytokine suppression by the vagus nerve converge in the spleen (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there TNF crosses into the systemic circulation.
“The spleen is the major source of both hepatic and systemic TNF during endotoxemia; it releases newly synthesized TNF into the splenic vein, which drains into the liver, and from there, TNF crosses into the systemic circulation (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
Vagus nerve stimulation in wild-type mice inhibits TNF synthesis in spleen, liver, and blood but not in α7 nAChR subunit-knockout animals.
“Vagus nerve stimulation in WT mice inhibits TNF synthesis in spleen, liver, and blood but not in α7 nAChR subunit-knockout animals (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
Common celiac branch vagotomy abrogates the TNF-suppressing effects of vagus nerve stimulation in spleen and serum.
“The functional anatomic mechanism of vagus nerve-derived signals to spleen traverses the common celiac branch of the vagus nerve because common celiac branch vagotomy abrogates the TNF-suppressing effects of vagus nerve stimulation in spleen and serum.”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
The reduction in inflammation following vagus nerve stimulation in paw and air pouch models is likely attributable to downregulation of cytokine production by the reticuloendothelial system and redirection of leukocyte trafficking away from the periphery.
“As the vagus nerve does not signal directly to either the paw or the subcutaneous tissues, it is likely that the reduction in inflammation observed following vagus nerve stimulation in these models is attributable to the downregulation of cytokine production by the reticuloendothelial system and redirection of leukocyte trafficking away from the periphery (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
A major source of systemic TNF during lethal challenges is the spleen.
“And now it appears that a major source of systemic TNF during lethal challenges is the spleen, the source of Galen's black bile (28).”
From Physiology and immunology of the cholinergic antiinflammatory pathway (2007) · cites this paper as [28]
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- Authors
- Huston, J. M., Ochani, M., Rosas-Ballina, M., Liao, H., Ochani, K., Pavlov, V. A., Gallowitsch-Puerta, M., Ashok, M., Czura, C. J., Foxwell, B., Tracey, K. J., & Ulloa, L.
- Affiliations
- 1Laboratory of Biomedical Science
- Imperial College London (GB)
- Northwell Health (US)
- Venue
- The Journal of Experimental Medicine
- Publisher
- Rockefeller University Press
- Published
- 2006-06-19
- Volume
- 203
- Issue
- 7
- Pages
- 1623-1628
- ISSN
- 0022-1007 (ISSN-L)
- 1540-9538
- PMC
- PMC2118357
- OpenAlex
- W2154170498
- Cited by
- 683
- References
- 30
- Citations by year
- 2026: 25 · 2025: 22 · 2024: 37 · 2023: 32 · 2022: 50 · 2021: 51 · 2020: 37 · 2019: 44 · 2018: 33 · 2017: 40 · 2016: 29 · 2015: 31 · 2014: 36 · 2013: 25 · 2012: 39
- FWCI
- 18.41
- 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 (R01GM057226)
- National Center for Research Resources (M01RR018535)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Psychiatry and Mental health › Cancer, Stress, Anesthesia, and Immune Response
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- splenectomy, cholinergic anti-inflammatory pathway, vagus nerve stimulation, alpha7 nicotinic acetylcholine receptor, endotoxemia, polymicrobial sepsis, TNF-α, reticuloendothelial system, spleen, nicotine, inflammatory cytokines, neuroimmune regulation
- MeSH terms
- Acetylcholine, Animals, Female, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Rats, Inbred Lew, Splenectomy, Signal Transduction, Mice, Knockout, Sepsis, Endotoxemia, Mice, Rats
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