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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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“The discovery of the central importance of the spleen (Huston et al., 2006) necessitated a modification of this plan, because of evidence that the rodent spleen receives little or no direct (cholinergic) innervation from the vagus, only noradrenergic fibers from the splenic sympathetic nerves (Bellinger et al.”
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Expression and Function of the Cholinergic System in Immune Cells
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Self-citationAnti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease
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BackgroundInfluentialSelf-citationCytokine Storm—Definition, Causes, and Implications
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“Splenectomy or VNS in rats with intact spleens resulted in identical suppression of the LPS-evoked increase in serum TNF-α (Huston et al., 2006).”
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The liver–brain–gut neural arc maintains the Treg cell niche in the gut
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α7-Cholinergic Receptor Mediates Vagal Induction of Splenic Norepinephrine
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Reflex control of inflammation by sympathetic nerves, not the vagus
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MethodAlpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases
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“Notably, after splenectomy the beneficial effects of vagus nerve stimulation were lost [71], but 2512 H.”
BackgroundManipulation of the inflammatory reflex as a therapeutic strategy
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“As discussed above, the a7nAChR has been identified as the extracellular target of the CAP through KO studies.(8,9,11) The intracellular effects of a7nAChR activation, however, are numerous and not mutually exclusive.”
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MethodNeuro-immune interactions via the cholinergic anti-inflammatory pathway
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“…inhibits pro-inflammatory cytokine production and systemic inflammation, thus identifying a non-classical immunoregulatory and anti-inflammatory function of the efferent vagus nerve (Borovikova et al., 2000; Wang et al., 2003; De Jonge et al., 2005; Huston et al., 2006; Ghia et al., 2006) (Fig.1).”
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“The brain’s response to intestinal inflammation is translated into action potentials in the efferent vagus nerve which function to inhibit the production of proinflammatory cytokines [238].”
BackgroundNerve Stimulation: Immunomodulation and Control of Inflammation
Ulloa, L., Quiróz-González, S., & Rosas, R. T. (2017) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2017.10.006 · Cited by 169
“However, these mechanisms appeared to be independent of neuronal modulation of the spleen because ST36 electrostimulation still inhibited systemic inflammation in splenectomized animals [2].”
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“Despite its recent identification, different investigators have already reported that electrical or pharmacological stimulation of the vagus nerve can restrain systemic inflammation in experimental ischemia and reperfusion (16–18), hemorrhage and resuscitation (18), pancreatitis (19), colitis (20), endotoxemia (15, 21…”
BackgroundMethodInfluentialSelf-citationThe Interplay between Autonomic Nervous System and Inflammation across Systemic Autoimmune Diseases
Bellocchi, C., Carandina, A., Montinaro, B., Targetti, E., Furlan, L., Rodrigues, G. D., Tobaldini, E., & Montano, N. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23052449 · Cited by 186
Olofsson, P. S., Katz, D. A., Rosas‐Ballina, M., Levine, Y. A., Ochani, M., Valdés‐Ferrer, S. I., Pavlov, V. A., Tracey, K. J., & Chavan, S. S. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00405 · Cited by 169
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Balancing the autonomic nervous system to reduce inflammation in rheumatoid arthritis
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“Previous studies have shown that vagal nerve stimulation has a major effect on circulating cytokines, specifically causing a dramatic decrease in TNFproduction from the spleen (12).”
BackgroundThe vagus nerve as a modulator of intestinal inflammation
van der Zanden, E. P., Boeckxstaens, G. E., & de Jonge, W. J. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2008.01252.x · Cited by 155
Nicotine in Inflammatory Diseases: Anti-Inflammatory and Pro-Inflammatory Effects
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“The existence of a functional relationship between vagus nerve, released ACh, and the reticuloendothelial system was confirmed by lesioning approaches [11].”
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Noninvasive ultrasound stimulation of the spleen to treat inflammatory arthritis
Zachs, D. P., Offutt, S. J., Graham, R. S., Kim, Y., Mueller, J., Auger, J. L., Schuldt, N. J., Kaiser, C. R. W., Heiller, A. P., Dutta, R., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08721-0 · Cited by 143
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“Similarly, an a7-nAChR-agonist attenuated systemic inflammation causing decreased TNF production [144, 145].”
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van Maanen, M. A., Vervoordeldonk, M. J., & Tak, P. P. (2009) · Nature Reviews Rheumatology · doi:10.1038/nrrheum.2009.31 · Cited by 140
“Recent data indicate that the spleen may have a role in exerting the anti-inflammatory effects of vagus nerve activity, as VNS fails to attenuate serum TNF level increases in splenectomized mice treated with endotoxin”
BackgroundIdentification of a brainstem locus that inhibits tumor necrosis factor
Kressel, A. M., Tsaava, T., Levine, Y. A., Chang, E. H., Addorisio, M. E., Chang, Q., Burbach, B. J., Carnevale, D., Lembo, G., Zador, A. M., et al. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2008213117 · Cited by 133
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“The net effect of vagus nerve–mediated signals within the spleen is the inhibition of cytokine release by red pulp and marginal zone macrophages, which together account for 90% of the TNF and IL-1 produced during acute endotoxemia (23, 29).”
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The Inflammatory Reflex and the Role of Complementary and Alternative Medical Therapies
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“and improving survival in mice challenged with lipopolysaccharide.”
Neuronal and Nonneuronal Cholinergic Structures in the Mouse Gastrointestinal Tract and Spleen
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“Notably, nicotine directly and dose-dependently reduces proinflammatory cytokines release from peritoneal and splenic macrophages (de Jonge et al., 2005; Huston et al., 2006; Wang et al., 2003).”
BackgroundThe Pathophysiology of Septic Shock
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“In addition, rendering these animals immune to vagal stimulation either by genetic manipulation or vagotomy led to an exaggerated proinflammatory cytokine response.(51) It is now understood that these cytokine-suppressive effects of vagal stimulation are mediated by the release of its neurotransmitter acetylcholine (A…”
Cholinergic System Dysfunction and Neurodegenerative Diseases: Cause or Effect?
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“ACh and nicotine inhibit TNF-a and NF- B production from lipopolysaccharide (LPS)-stimulated human macrophages and splenocytes [24,28].”
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“Following splenectomy, the cholinergic anti-inflammatory pathway is completely inhibited.(57,58) Although its direct association has yet to be established, impairment in this antiinflammatory pathway may play a role in the increased propensity for overwhelming post-splenectomy infection (OPSI).”
BackgroundNovel Insights for Systemic Inflammation in Sepsis and Hemorrhage
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“These findings suggested that intact vagal innervation via common celiac branches is required for vagus nerve regulation of splenic and systemic TNFa levels (Huston et al., 2006).”
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Boundaries and integration between microbiota, the nervous system, and immunity
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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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