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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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In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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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“Early work performed by the Tracey group and others used constant voltage stimulation to show TNF modulation in rodents, often in the range of 1–5 V (Borovikova et al. 2000; Huston et al. 2006; Rosas-Ballina et al. 2008, 2011; Vida et al. 2011).”
BackgroundMethodEffect of major abdominal surgery on the host immune response to infection
Buttenschoen, K., Fathimani, K., & Buttenschoen, D. C. (2010) · Current Opinion in Infectious Diseases · doi:10.1097/qco.0b013e32833939cb · Cited by 21
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Potential of α7 nicotinic acetylcholine receptor PET imaging in atherosclerosis.
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Neural Control of Gastrointestinal Function
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“The formation of TNF-α in the spleen is reduced by stimulation of the vagus nerve and enhanced by vagotomy (Huston et al., 2006).”
BackgroundTracey, K. J. (2014) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a016360 · Cited by 21
“By following the track of the vagus nerve from the brain stem, down the neck, across the thorax, and into the abdomen, and either dividing the nerve in some cases, or electrically stimulating it along its course in others, we discovered that the point of convergence of the vagus nerve signals to regulate serum TNF dur…”
BackgroundSelf-citationNeuroimmune communication of the cholinergic system in gut inflammation and autoimmunity
Halder, N., Yadav, S., & Lal, G. (2024) · Autoimmunity Reviews · doi:10.1016/j.autrev.2024.103678 · Cited by 21
Noninvasive Vagus Nerve Electrical Stimulation for Immune Modulation in Sepsis Therapy
Mac, C., Nguyen, G. L. T., Nguyên, D. T., Huang, S.-M., Peng, H., Chang, Y., Lo, S., Chiang, H. K., Yang, Y.-Z., Song, H., et al. (2025) · Journal of the American Chemical Society · doi:10.1021/jacs.4c16367 · Cited by 20
Bagaitkar, J., Zeller, I., Renaud, D. E., & Scott, D. A. (2012) · Tobacco Induced Diseases · doi:10.1186/1617-9625-10-18 · Cited by 20
“Nicotine, a major component of cigarette smoke, is also a potent α7nAChR agonist [5,6].”
BackgroundClinical approach to autonomic dysfunction
Wells, R. M., & Tonkin, A. (2016) · Internal Medicine Journal · doi:10.1111/imj.13216 · Cited by 20
Peripheral neurons: Master regulators of skin and mucosal immune response
Basso, L., Serhan, N., Tauber, M., & Gaudenzio, N. (2019) · European Journal of Immunology · doi:10.1002/eji.201848027 · Cited by 25
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“Extensive earlier investigations have reported that spleen, the main source of circulating pro-inflammatory cytokines, is the target organ of the vagus nerve for controlling pro-inflammatory cytokine production (Huston et al. 2006; Rosas-Ballina et al. 2008).”
BackgroundInhibition of acute lung inflammation by a neuroimmune circuit induced by vagal nerve stimulation
Murray, K. M., Cremin, M., Tay, E. X. Y., Sanchez, K., Schreiber, S., Lloyd, E., Brust‐Mascher, I., Leigh, W. A., Ashfaq, J., Gareau, M. G., et al. (2025) · Science Advances · doi:10.1126/sciadv.adw7080 · Cited by 24
“The electrical stimulation of vagal efferent neurons to induce CAIP reduced LPS-induced TNF production in the spleen but not the lung ( 23 ).”
Choque, P. N. B., Vieira, R. P., Ulloa, L., Grabulosa, C. C., Irigoyen, M. C., Angelis, K. D., de Oliveira, A. P. L., Tracey, K. J., Pavlov, V. A., & Consolim‐Colombo, F. M. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.624895 · Cited by 19
“…while VNS, which activates the inflammatory reflex and its efferent cholinergic arm, results in suppression of proinflammatory cytokine levels, this approach does not have an effect of IL-10 levels (Borovikova et al., 2000; Huston et al., 2006; Rosas-Ballina et al., 2011; Olofsson et al., 2017).”
BackgroundSelf-citationWireless optoelectronic devices for vagus nerve stimulation in mice
Donahue, M. J., Ejneby, M. S., Jakešová, M., Caravaca, A. S., Andersson, G., Sahalianov, I. Y., Đerek, V., Hult, H., Olofsson, P. S., & Głowacki, E. D. (2022) · Journal of Neural Engineering · doi:10.1088/1741-2552/aca1e3 · Cited by 20
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Collateral benefits of studying the vagus nerve in bioelectronic medicine
Pavlov, V. A. (2019) · Bioelectronic Medicine · doi:10.1186/s42234-019-0021-3 · Cited by 19
Self-citationInflammation, Immunity and the Autonomic Nervous System
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“ACh transmits inflammatory signaling through the vagus nerve, which not only affects immune responses in the spleen but also alleviates inflammation by inhibiting macrophage cytokine synthesis [231–233].”
Non-Neuronal Acetylcholine: The Missing Link Between Sepsis, Cancer, and Delirium?
Sfera, A., Cummings, M., & Osorio, C. P. (2015) · Frontiers in Medicine · doi:10.3389/fmed.2015.00056 · Cited by 18
“A non-neuronal cholinergic system was also described in the CNS comprised astrocytes, microglia, and endothelial cells (27).”
BackgroundInfluentialEffects of Nicotine and Vagus Nerve in Severe Acute Pancreatitis–Associated Lung Injury in Rats
Ma, P., Yu, K., Yu, J., Wang, W., Ding, Y., Chen, C., Chen, X., Zhao, K., Zuo, T., He, X., et al. (2015) · Pancreas · doi:10.1097/mpa.0000000000000575 · Cited by 18
“However, electrical vagus nerve stimulation failed to inhibit serum TNF levels in splenectomized rats during endotoxemia, indicating that the cholinergic anti-inflammatory pathway is closely related to the spleen.(33) In caerulein-induced pancreatitis, inhibition of the cholinergic anti-inflammatory pathway by vagotom…”
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The roles of the nerve-immune axis in modulating bone regeneration
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“by controlling the level of blood cells (functionality and subtypes of neutrophils and other leucocytes, red blood cells, and platelets) [55,56], which requires NF-κB-mediated regulation [57].”
BackgroundBrinkman, D. J., Simon, T., ten Hove, A. S., Zafeiropoulou, K., Welting, O., van Hamersveld, P. H. P., Willemze, R. A., Yim, A. Y. F. L., Verseijden, C., Hakvoort, T. B. M., et al. (2022) · Journal of Neuroinflammation · doi:10.1186/s12974-022-02504-z · Cited by 17
“It has been shown that the anti-inflammatory effect of VNS in experimental endotoxemia rests on innervation of the spleen through the splenic nerve bundle [10, 11].”
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“Evidence for a beneficial effect of VNS in Crohn’s disease comes from studies of patients with moderate-to-severe disease who manifested clinical, biological, and endoscopic improvement after six months of VNS, and a reduction in inflammation of colonic tissues [47].”
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Treatment of chronic inflammatory diseases with implantable medical devices*
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Metadata
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › 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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