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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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Zhou, W., Song, M. Y., Wang, M. R., Jin, M. Q., Xie, P. M., & Zhang, P. L. (2022) · Advanced ultrasound in diagnosis and therapy · doi:10.37015/audt.2022.200034 · Cited by 2
Abdel-Aziz, N., & Saif‐Elnasr, M. (2024) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2024.2381759 · Cited by 2
“Nicotine and acetylcholine inhibit the production of NF-κB and cytokines via α7nAChR located in splenocytes and macrophages [55–58].”
Matsuo, S., Uni, R., Wu, C.-H., Nakamura, Y., Umene, R., Surattichaiyakul, B., Nangaku, M., Inagi, R., Nishino, T., & Inoue, T. (2025) · Scientific Reports · doi:10.1038/s41598-025-23583-x · Cited by 2
“2B), this finding is consistent with previous reports demonstrating that splenectomy suppresses TNF-α production 35 .”
Bakary, N. M. E., Thabet, N. M., Rashed, L., Azab, K. S., Helal, H., Maarouf, R. E., & Abdel-Rafei, M. K. (2025) · Immunopharmacology and Immunotoxicology · doi:10.1080/08923973.2025.2591423 · Cited by 2
“…by studies in which surgical removal of the spleen largely reduces the initial increases in plasma tNF-α level in response to systemic inflammation [33,34]. consequently, a blockade of tNF-α production in the spleen (as occurs with a central nervous system-driven increase in splenic nerve…”
Wu, Z. Y., Yao, B., & Yu, J. (2026) · Frontiers in Medicine · doi:10.3389/fmed.2026.1841517 · Cited by 2
“Implantable vagus nerve stimulation (VNS) has demonstrated clear anti-inflammatory eects in experimental models, including attenuation of tumor necrosis factor (TNF) release, reduction of systemic cytokine responses, and improved survival in preclinical models of sepsis (16, 33, 90).”
Ziaka, M. (2026) · Pathogens · doi:10.3390/pathogens15070659 · Cited by 2
The Postnatal Leptin Surge Supports Immune Cell Function in Rats
Hunsche, C., Hernández, O., Mela, V., Viveros, M., & la Fuente, M. D. (2021) · Immunological Investigations · doi:10.1080/08820139.2021.1940199 · Cited by 2
“We chose the spleen of these animals to carry out the study since this secondary lymphoid organ, which is the largest in both humans and rodents, is responsible for establishing effective innate and adaptive immune responses and regulating cytokine production (Cesta 2006; Huston et al. 2006; Nolte et al. 2002).”
BackgroundMethodHommes, T. J., Wiersinga, W. J., & van der Poll, T. (2009) · Springer eBooks · doi:10.1007/978-3-540-92276-6_4 · Cited by 2
Medicinal nicotine in COVID-19 acute respiratory distress syndrome, the new corticosteroid
Ahmad, F. (2022) · World Journal of Critical Care Medicine · doi:10.5492/wjccm.v11.i4.228 · Cited by 2
Jarczak, D., & Nierhaus, A. (2023) · Lessons from the ICU · doi:10.1007/978-3-031-17572-5_3 · Cited by 2
The innervated gut and critical illness
Larsson, J. W., Olofsson, P. S., & Sundman, E. (2025) · Current Opinion in Critical Care · doi:10.1097/mcc.0000000000001260 · Cited by 2
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Stress System Regulation of Chronic Low-grade Inflammation
Rohleder, N. (2012) · Advances in Neuroimmune Biology · doi:10.3233/nib-012904 · Cited by 2
“Consistent with this assumption, presence of the spleen was required for survival of in vivo models of sepsis [104].”
BackgroundSomething’s happening here; what it is ain’t exactly clear*
Sloan, R. P. (2012) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2012.02546.x · Cited by 2
Vagotomy, Inflammation, and the Injured Patient
Jurkovich, G. J. (2011) · Archives of Surgery · doi:10.1001/archsurg.2011.238 · Cited by 2
Splenectomy and splenic dysfunction
Opal, S. M. (2010) · Elsevier eBooks · doi:10.1016/b978-0-323-04579-7.00082-4 · Cited by 2
VNS for the Treatment of Inflammatory Disorders of the Gastrointestinal Tract
Bonaz, B. L., Sinniger, V., Sonia Pellissier, A., & Clarençon, D. (2017) · Springer eBooks · doi:10.1007/978-3-319-28612-9_9 · Cited by 3
Zhang, A. Y., Marsh, K. M., Rastogi, R., Wu, D., Charles, E. J., Kron, I. L., Sawyer, R. G., & Yang, Z. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22189828 · Cited by 2
Alexandrova, E. A., Валерьевна, П. Е., Вадимовна, Б. И., Yulin, V. S., Suslov, A. G., Михайлович, Б. К., & Fomin, S. V. (2022) · Meditsinskiy sovet = Medical Council · doi:10.21518/2079-701x-2022-16-2-76-84 · Cited by 5
Neural Regulation of the Immune Response
Forsythe, P., & Bienenstock, J. (2009) · Springer eBooks · doi:10.1007/978-4-431-88315-9_29 · Cited by 2
Lv, Y., Liu, Q., Zhao, M., Jin, Y., & Lu, J.-Y. (2014) · Europe PMC (PubMed Central) · Cited by 2
Cytokines (Tumor Necrosis Factor, Interleukins) and Prostaglandins
Alstergren, P. J. (2009) · Wiley eBooks · doi:10.1002/9780470522226.ch17 · Cited by 2
Barraud, D., & Gibot, S. (2007) · Revue Francophone des Laboratoires · doi:10.1016/s1773-035x(07)80059-1 · Cited by 2
Ask, T. F., & Sütterlin, S. (2022) · bioRxiv · doi:10.1101/2022.02.17.480574 · Cited by 2
“Vagal (Huston et al., 2006; Wang H et al., 2003) and sympathetic (Madden et al., 1995; Vizi et al., 1998) inputs to the spleen have opposing effects on inflammatory marker expression.”
BackgroundEpithelial Ca 2+ waves triggered by enteric neurons heal the gutPreprint
Petsakou, A., Liu, Y., Liu, Y., Comjean, A., Hu, Y., & Perrimon, N. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.08.14.553227 · Cited by 2
Molecular Temporomandibular Joint Pain Biomarkers
Alstergren, P. J. (2017) · Springer eBooks · doi:10.1007/978-3-662-53994-1_7 · Cited by 1
Funayama, T., Nozu, T., Ishioh, M., Igarashi, S., Tanaka, H., Sumi, C., Saito, T., Toki, Y., Hatayama, M., Yamamoto, M., et al. (2024) · Neurogastroenterology & Motility · doi:10.1111/nmo.14949 · Cited by 1
“7 6 We therefore made a hypothesis that the spleen is involved in the brain neuropeptides-induced improvement of intestinal barrier function.”
Nash, W., & Okusa, M. D. (2025) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2025.151674 · Cited by 1
Marsh, K. M., Rabinovich, E. P., Rastogi, R., Zhang, A. Y., Sawyer, R. G., & Yang, Z. (2025) · Surgical Infections · doi:10.1177/10962964251394205 · Cited by 1
Stránský, D., Barabas, M., Šíma, M., & Slanař, O. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1831913 · Cited by 1
“Interestingly, the spleen is primarily innervated by sympathetic fibers, it can still be influenced by vagally mediated anti-inflammatory reflexes (Martelli et al., 2014; Huston et al., 2006).”
Mei, S., Fu, G., Gao, R., & Li, W. (2026) · Frontiers in Human Neuroscience · doi:10.3389/fnhum.2026.1837913 · Cited by 1
“Evidence from invasive VNS and animal studies suggests that splenic pathways may contribute to vagally mediated anti-inflammatory effects (Huston et al., 2006; Huston et al., 2009; Gigliotti et al., 2013; Ji et al., 2014), but the translational relevance of this mechanism to taVNS in DoC remains…”
The Neuroendocrine Axis: The Nervous System and Inflammation
Weismüller, K., Weigand, M. A., & Hofer, S. (2012) · Springer eBooks · doi:10.1007/978-3-642-25716-2_2 · Cited by 1
“It has been shown that the spleen is essential for inflammation control by the vagal nerve [36].”
Background
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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