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Cited by 1,563Vagus Nerve Stimulation ResearchHeart Rate Variability and Autonomic ControlNeuropeptides and Animal Physiology

Physiology and immunology of the cholinergic antiinflammatory pathway

Open access
Tracey, Kevin J.·2007·Journal of Clinical Investigation
DOI 10.1172/jci30555PMC PMC1783813
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Abstract

Cytokine production by the immune system contributes importantly to both health and disease.The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death.The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway.Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases.Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes.Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.The germ is nothing; the terrain is everything. -Louis Pasteur (on his deathbed)Historical perspective of the cytokine theory of disease For more than 1,500 years, the predominant medical doctrine of disease causation was the humoral theory of disease.As posited by Galen (Claudius Galenus of Pergamum, 129-200 AD), this theory held that disease was caused by an imbalance in bodily humors.Produced by internal organs, the humors mediated healthful effects when their levels were properly regulated and balanced.This theory was not displaced until advances in microscopy and microbiology enabled Rudolf Virchow to formulate the theory of cellular pathology and Louis Pasteur the germ theory of disease.Research into the causes of illness turned outward as a growing body of investigation focused on exogenous rather than endogenous factors in disease causation.Pasteur's deathbed remark, however, belied the notion that germs could tell the whole story.It was a tacit acknowledgment to Claude Bernard, who advocated that health was due to equilibrium in the "milieu interieur" and maintained by "a continuous and delicate compensation, established as by the most sensitive of balances" (Lessons on the phenomena of life common to animals and vegetables).Common wisdom in the 1970s dictated that the immune response to pathogens or injury was uniformly for the good.Every facet of the immune response was believed to have a role (albeit some unknown) in eradicating invaders and neutralizing the potential for damage.Certainly, or so the reasoning went, the body would not use its own cells to make potentially toxic molecules in quantities large enough to injure tissues or even kill.The development of shock, tissue injury, circulatory collapse, hemorrhagic necrosis, multiple organ failure, and other physiological calamities associated with bacterial infection were attributed to the direct action of pathogenic toxins, not the host response.A few dared to challenge this view, notably Lewis Thomas, who wrote in his classic 1975 book The lives of a cell, "When we sense lipopolysaccharide, we are likely to turn on every defense at our disposal; we will bomb, defoliate, blockade, seal off, and destroy all the tissues in the area.All of this seems unnecessary, panicdriven . . .The self-disintegration of the whole animal that follows a systemic injection can be interpreted as a well-intentioned but lethal error.The mechanism is itself quite a good one, when used with precision and restraint (1)."Scientific advances would soon prove his statement to be unerringly prescient.Early investigators exploring physiological mechanisms of fever, weight loss, and acute phase responses to acute and chronic infection led the way in changing beliefs about disease pathogenesis.They gave evidence that proteins produced by macrophages and other immune cells, not pathogens, caused tissue damage and disease syndromes in experimental animals.Studies in the 1980s of these proteins, newly named cytokines (including, for example, IL-1, IL-6, and TNF), revealed that they possessed pleiotropic biological activities that were either beneficial or injurious.From this emerged the cytokine theory of disease, the concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease (Figure 1) (reviewed in ref. 2).Consider as one example the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock caused by infection with Gram-negative bacteria.TNF is produced during Gram-negative bacteria-induced acute septic shock (3).Administration of TNF to healthy mammals (including humans) reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of the disease (4), and gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock (5).Other pathophysiological activities ascribed to TNF were the capacity to cause fever and localized inflammation (4, 6).Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of

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Written from the paper’s full text.

TL;DR

This review synthesizes evidence that the vagus nerve, via its principal neurotransmitter acetylcholine acting on the α7 subunit of the nicotinic acetylcholine receptor (α7 nAChR), suppresses proinflammatory cytokine production through an "inflammatory reflex" termed the cholinergic antiinflammatory pathway. The author argues this neural circuit restrains cytokine-mediated tissue damage across experimental sepsis, endotoxemia, ischemia/reperfusion, hemorrhagic shock, arthritis, ileus, and pancreatitis, and proposes an "immunological homunculus" framework for CNS regulation of immunity.

Key findings

  • Vagus nerve stimulation significantly inhibits TNF release in animals receiving lethal endotoxin, and inhibits IL-1, IL-6, IL-8, and HMGB1 as well; the effect is absent in α7 nAChR–knockout animals and in vagotomized animals, indicating α7 nAChR–dependent signaling.
  • The spleen is identified as the principal source of systemic TNF during endotoxemia: splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation then fails to reduce them further; common celiac branch vagotomy abrogates the TNF-suppressing effects of stimulation in spleen and serum.
  • In cecal perforation sepsis, nicotine given 24 hours after onset of lethal peritonitis significantly reduced serum HMGB1, indicating the pathway can act after disease is established; in E. coli peritonitis, vagotomy increased inflammatory cell recruitment, cytokine levels, and liver damage, while nicotine restored balance.
  • In hemorrhagic shock, vagus nerve stimulation conferred protection against hypotension, prolonged survival, and decreased TNF; protective effects were reversed by the nicotinic antagonist chlorisondamine, and bilateral vagotomy ablated ACTH1-24's protective effects.
  • Signaling is proposed to proceed via decreased nuclear translocation of NF-κB and JAK2-mediated phosphorylation/activation of STAT3 recruited to α7 nAChR.

Methods

  • Narrative review article (Journal of Clinical Investigation), not primary research; it synthesizes the author's own laboratory work and the broader literature on the cholinergic antiinflammatory pathway.
  • Evidence base is predominantly preclinical animal models (rodent endotoxemia, cecal ligation/perforation sepsis, live E. coli peritonitis, hemorrhagic shock, aortic and splanchnic ischemia/reperfusion, myocardial ischemia/reperfusion, carrageenan paw edema and air pouch inflammation, experimental pancreatitis, surgery-induced ileus) plus cited clinical observations.
  • No new data, systematic search strategy, or meta-analysis is reported; the paper presents a mechanistic wiring diagram and a conceptual framework.

Limitations

  • Stated: the paper notes that clinical studies show decreased vagus nerve activity is associated with increased disease severity but "have not established a causal relationship," and that it remains possible severe disease itself suppresses vagus nerve activity; the final answer "shall await clinical studies of vagus nerve modulation in humans."
  • Stated: whether α7 nAChR downstream signaling in immunologically competent cells requires cofactors, ion channel activity, or other substrates is uncertain, and ongoing studies are needed.
  • Stated: whether compensation, sensitization, desensitization, or tolerance occurs in the pathway is unknown (e.g., after truncal vagotomy), and the role of α7 AChR on lymphocytes and microglia in autoimmune disease is described as "an unexplored possibility."
  • Evident from the text: the review is single-authored by a researcher whose laboratory generated much of the cited work, and the "immunological homunculus" is explicitly speculative ("I suspect," "it is plausible," "artistic rendition"), with no direct evidence presented for somatotopic CNS control of specific immune responses.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1172/jci30555

Cites

105 of 105 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 138 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease.

    “From this emerged the cytokine theory of disease, the concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease (Figure 1) (reviewed in ref. 2).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [2] Tracey, K.J. 2005.Fatal sequence: the killer within. Dana Press. Washington, DC, USA. 238 pp.

      Not checked in the free run.

  • Premisecitation

    Gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock.

    “gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock (5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Pfeffer, 1993, Cell. source

      Not checked in the free run.

  • Premisecitation

    Administration of TNF to healthy mammals, including humans, reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of septic shock.

    “Administration of TNF to healthy mammals (including humans) reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of the disease (4)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Tracey, 1986, Science. source

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  • Premisecitation

    TNF is produced during Gram-negative bacteria-induced acute septic shock.

    “TNF is produced during Gram-negative bacteria-induced acute septic shock (3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Tracey, 1987, Nature. source

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  • Interpretationcitation

    α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.

    “Nonetheless, together the present results indicate that α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] de Jonge, 2005, Nat. Immunol. source

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    • cites [27] Wang, 2004, Nat. Med. source

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  • May combine two claims. 31
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Premisecitation

    TNF has the capacity to cause fever and localized inflammation.

    “Other pathophysiological activities ascribed to TNF were the capacity to cause fever and localized inflammation (4, 6).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [4] Tracey, 1986, Science. source

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    • cites [6] Dinarello, 1986, J. Exp. Med. source

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  • May combine two claims.

    Premisecitation

    TNF is a necessary and sufficient mediator of lethal septic shock caused by infection with Gram-negative bacteria.

    “Consider as one example the case of TNF, a cytokine implicated as a necessary and sufficient mediator of lethal septic shock caused by infection with Gram-negative bacteria.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Tracey, 1987, Nature. source

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    • cites [4] Tracey, 1986, Science. source

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    • cites [5] Pfeffer, 1993, Cell. source

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  • May combine two claims.

    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Huston, 2006, J. Exp. Med. source

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    Premisecitation

    Intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS.

    “an accidental discovery revealed that intracerebral administration of a molecule that inhibited TNF production also increased efferent vagus nerve activity and inhibited inflammation outside the CNS (17).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Bernik, 2002, J. Exp. Med. source

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    Premisecitation

    Vagus nerve stimulation fails to suppress cytokine synthesis in α7 nAChR-knockout animals whereas it significantly inhibits cytokine release in wild-type littermates.

    “vagus nerve stimulation in α7 nAChR-knockout animals fails to suppress cytokine synthesis whereas it significantly inhibits cytokine release in wild-type littermates (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Wang, 2003, Nature. source

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    Premisecitation

    When sufficient concentrations of endogenous antiinflammatory mediators are achieved, proinflammatory cytokine levels are inhibited, the inflammatory response is dampened, and damage is prevented.

    “When sufficient concentrations are achieved, proinflammatory cytokine levels are inhibited, the magnitude of the inflammatory response is dampened, and damage is prevented.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Nathan, 2002, Nature. source

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    Premisecitation

    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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Huston, 2006, J. Exp. Med. source

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    Premisecitation

    Vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, ischemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis.

    “Subsequent work established that vagus nerve signaling inhibits cytokine activities and improves disease endpoints in experimental models of sepsis, ischemia/reperfusion, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis (17)(18)(19)(20)(21)(22)(23)(24)(25).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Bernik, 2002, J. Exp. Med. source

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    • cites [18] Borovikova, 2000, Nature. source

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    • cites [19] Mioni, 2005, Crit. Care Med. source

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  • May combine two claims.

    Premisereasoning

    The vagus nerve is a primitive extension of the CNS to visceral organs, including spleen and liver, which are major sources of damaging cytokines.

    “this cranial nerve, which meanders through the thorax and abdomen and has been termed the single most important nerve in the body, is a primitive extension of the CNS to the visceral organs, including organs of the reticuloendothelial system, such as the spleen and liver, that are major sources of damaging cytokines.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    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).”
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    • cites [28] Huston, 2006, J. Exp. Med. source

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  • May combine two claims.

    Premisecitation

    Ligand-receptor interaction on cytokine-expressing cells culminates in decreased nuclear translocation of NF-κB and activation of STAT3 via phosphorylation by JAK2 recruited to the α7 nAChR.

    “Ligand-receptor interaction on cytokine-expressing cells culminates in decreased nuclear translocation of NF-κB as well as activation of the transcription factor STAT3 via phosphorylation by JAK2, which is recruited to the α7 nAChR (Figure 3) (22,27).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [22] de Jonge, 2005, Nat. Immunol. source

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    • cites [27] Wang, 2004, Nat. Med. source

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  • May combine two claims.

    Interpretationcitation

    Clinical successes using drugs that specifically inhibit TNF in inflammatory bowel disease or rheumatoid arthritis directly implicate a pathogenic role of TNF in other diseases and validate the cytokine theory of disease in humans.

    “Clinical successes in the 1990s using drugs that specifically inhibit TNF for patients with inflammatory bowel disease or rheumatoid arthritis directly implicated a pathogenic role of this cytokine in other diseases (7-9) and validated in humans the fundamental premise of the cytokine theory of disease.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [7] Elliott, 1994, Lancet. source

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    • cites [8] Dinarello, 2004, Curr. Opin. Pharmacol. source

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    • cites [9] Targan, 1997, N. Engl. J. Med. source

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    Premisecitation

    IL-10-deficient mice have increased susceptibility to both inflammatory bowel disease and adjuvant arthritis.

    “IL-10-deficient mice have increased susceptibility to both inflammatory bowel disease and adjuvant arthritis”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [11] Davidson, 1996, J. Exp. Med. source

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    • cites [12] Johansson, 2001, J. Immunol. source

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    • cites [13] Sternberg, 1989, Proc. Natl. Acad. Sci. U. S. A. source

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    Premisecitation

    In a bacterial peritonitis model, vagotomy causes a significant increase in inflammatory cells recruited to the peritoneum, higher cytokine levels, and more extensive liver tissue damage.

    “In a model of bacterial peritonitis based upon intraperitoneal injection of live Escherichia coli, vagotomy caused a significant increase in the number of inflammatory cells recruited to the peritoneum, higher cytokine levels, and more extensive tissue damage in the liver (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] van Westerloo, 2005, J. Infect. Dis. source

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  • May combine two claims.

    Premisecitation

    Stimulation of the vagus nerve in mice with surgery-induced ileus significantly attenuates hypomotility and reduces cytokine production.

    “Stimulation of the vagus nerve in mice with surgery-induced ileus significantly attenuated hypomotility and reduced cytokine production (22).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] de Jonge, 2005, Nat. Immunol. source

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  • May combine two claims.

    Premisecitation

    Vagus nerve stimulation confers protection against shock after splanchnic artery reperfusion injury and inhibits production of TNF and other cytokines.

    “In another model, vagus nerve stimulation conferred significant protection against the development of shock after splanchnic artery reperfusion injury and inhibited the production of TNF and other cytokines (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Altavilla, 2006, Shock. source

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    Premisecitation

    Vagus nerve stimulation in carrageenan-induced paw swelling significantly attenuates edema formation and inhibits local production of cytokines in the zone of inflammation.

    “Stimulation of the vagus nerve in animals subjected to carrageenan-induced paw swelling significantly attenuated the development of edema formation and inhibited the local production of cytokines in the zone of inflammation (23).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Borovikova, 2000, Auton. Neurosci. source

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    Premisecitation

    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).”
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    • cites [25] Saeed, 2005, J. Exp. Med. source

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    • cites [36] van Westerloo, 2006, J. Thromb. Haemost. source

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  • May combine two claims.

    Premisecitation

    Administration of GTS-21 significantly decreases pancreatitis severity and attenuates pulmonary inflammation.

    “Administration of GTS-21, an α7 nAChR receptor agonist, significantly decreased pancreati-tis severity and attenuated pulmonary inflammation (24).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] van Westerloo, 2006, Gastroenterology. source

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    Premisecitation

    Stimulation of the vagus nerve during myocardial ischemia/reperfusion in rats significantly reduces accumulation of free radicals and the incidence of severe arrhythmias and lethality.

    “Stimulation of the vagus nerve during myocardial ischemia/reperfusion in rats significantly reduced the accumulation of free radicals and reduced the incidence of severe arrhythmias and lethality (19).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Mioni, 2005, Crit. Care Med. source

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  • May combine two claims.

    Premisecitation

    A high-fat diet activates increased efferent vagus nerve activity, decreases TNF levels, and confers protection against hemorrhagic shock.

    “A high-fat diet also activates increased efferent vagus nerve activity, which decreases TNF levels and confers significant protection against hemorrhagic shock (41).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [41] Luyer, 2005, J. Exp. Med. source

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  • May combine two claims.

    Premisecitation

    Vagus nerve stimulation protects against leukocyte accumulation in the ileum and lung and reduces the severity of tissue damage; these effects are reversed by nicotinic receptor antagonists.

    “Vagus nerve stimulation conferred protection against leukocyte accumulation in the ileum and lung and reduced the severity of tissue damage; the protective effects were reversed by administration of nicotinic receptor antagonists (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Altavilla, 2006, Shock. source

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    Premisecitation

    Sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure are linked clinically to decreased vagus nerve activity.

    “Sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure are linked clinically to decreased vagus nerve activity (50)(51)(52)(53)(54).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [50] Lanza, 1998, Am. J. Cardiol. source

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    • cites [51] Soejima, 2000, Jpn. Circ. J. source

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    • cites [52] Bilchick, 2002, Am. J. Cardiol. source

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  • May combine two claims.

    Premisecitation

    Intracerebral administration of CNI-1493 increases vagus nerve activity and confers protection against ischemia/reperfusion-mediated damage.

    “Intracerebral administration of CNI-1493, a tetravalent guanylhydrazone that stimulates muscarinic brain networks, increased vagus nerve activity and conferred significant protection against ischemia/ reperfusion-mediated damage (17,44).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Bernik, 2002, J. Exp. Med. source

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    • cites [44] Bernik, 2002, J. Vasc. Surg. source

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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    The wiring diagram maps the concept that the brain can anatomically and functionally coordinate cytokine responses through neural networks analogous to other complex and essential physiological systems.

    “The wiring diagram for the cholinergic antiinflammatory pathway (Figure 2) maps the concept that the brain can anatomically and functionally coordinate cytokine responses through neural networks that are analogous to other complex and essential physiological systems.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Administration of nicotine achieves similar beneficial effects in ileus, activating phosphorylation of STAT3 and its binding to and transactivation of DNA-response elements.

    “Similar beneficial effects were achieved by administration of nicotine, which activated phosphorylation of STAT3 and its binding to and transactivation of its corresponding DNA-response elements.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] de Jonge, 2005, Nat. Immunol. source

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  • May combine two claims.

    Premisecitation

    Vagus nerve stimulation of rats during lethal hemorrhagic shock confers protection against hypotension, prolonged survival, and decreased TNF production.

    “Vagus nerve stimulation of rats during lethal hemorrhagic shock conferred significant protection against the development of hypotension, prolonged survival, and decreased TNF production (21).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Guarini, 2003, Circulation. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of nicotine to animals with bacterial peritonitis restored cytokine balance, reduced influx of inflammatory cells, and attenuated liver tissue damage.

    “Administration of nicotine to these animals restored the cytokine balance, reduced influx of inflammatory cells, and attenuated tissue damage in the liver (35).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [35] van Westerloo, 2005, J. Infect. Dis. source

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  • May combine two claims.

    Interpretationcitation

    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).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [28] Huston, 2006, J. Exp. Med. source

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    Premisecitation

    Exercise confers protection against cardiovascular disease and type 2 diabetes.

    “Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis (84)(85)(86)(87)(88)(89)(90).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [84] Jae, 2006, Metabolism. source

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    • cites [85] Goldhammer, 2005, Int. J. Cardiol. source

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    • cites [86] Obisesan, 2004, Arterioscler. Thromb. Vasc. Biol. source

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  • May combine two claims.

    Premisereasoning

    Weight loss and exercise are each associated with increasing vagus nerve activity.

    “Since weight loss and exercise are each associated with increasing vagus nerve activity, one can consider whether enhanced activity in the cholinergic antiinflammatory pathway might decrease cytokine production and reduce the damage and metabolic derangements mediated by chronic, low-grade systemic inflammation that is characteristic of the metabolic syndrome.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Behavioral modification, meditation, hypnosis, biofeedback, and cognitive and relaxation therapies can stimulate vagus nerve activity.

    “Behavioral modification, meditation, hypnosis, biofeedback, and cognitive and relaxation therapies, which have been advocated for treatment of inflammation, can stimulate vagus nerve activity (69)(70)(71)(72)(73)(74)(75).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [69] Nolan, 2005, Am. Heart J. source

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    • cites [70] Palomba, 1982, J. Psychosom. Res. source

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    • cites [71] Cowan, 1990, J. Electrocardiol. source

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  • The paper relies on this without support.

    Complex behavior originating in higher brain centers can directly influence outflow through the vagus nerve.

    “Abundant evidence points to the concept that complex behavior originating in higher brain centers can directly influence outflow through the vagus nerve.”

  • The paper relies on this without support.

    Deficiencies in the cholinergic antiinflammatory pathway lead to exaggerated cytokine responses and worsened morbidity.

    “The available evidence today may favor the former interpretation because deficiencies in the cholinergic antiinflammatory pathway lead to exaggerated cytokine responses and worsened morbidity.”

  • The paper relies on this without support.

    Nicotine inhibits cytokine production via an α7 nAChR-dependent mechanism.

    “current understanding that nicotine inhibits cytokine production via an α7 nAChR-dependent mechanism makes it plausible to consider whether this pathway is activated in the subset of patients that derive benefit from nicotine.”

  • The paper relies on this without support.

    Alzheimer disease and other brain degenerative disorders are characterized by cholinergic deficiency and decreased vagus nerve activity.

    “Alzheimer disease and other brain degenerative disorders are characterized by cholinergic deficiency and decreased vagus nerve activity.”

  • The paper relies on this without support.

    The CNS is organized somatotopically, such that specific neural networks regulate or coordinate particular actions in the periphery.

    “The CNS is organized somatotopically, such that specific neural networks regulate or coordinate particular actions in the periphery.”
5 of 5

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  • Acupuncture fact-sheet citation points to a brain-injury study

    Minor

    The text attributes a statement about acupuncture to an NIH fact sheet cited as reference 64, but reference 64 is a study of heart-rate variability after traumatic brain injury.

1 of 1

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Research works printed but not linked: 6

  1. Zingarelli, 1994, Am. J. Physiol., 266, H1512
  2. Balanescu, 2004, Med. Sci. Monit., 10, CR307
  3. Laversuch, 1997, J. Rheumatol., 24, 1540
  4. Shi, 1995, Zhongguo Zhong. Xi. Yi. Jie. He. Za Zhi., 15, 536
  5. Papadopoulos, 2005, Clin. Exp. Rheumatol., 23, 861
  6. Holguin, 2005, Chest., 127, 1102

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Authors
Tracey, K. J.
Affiliations
Feinstein Institute for Medical Research (US)
Corresponding author
Tracey, Kevin J.
ORCID
Tracey, Kevin J.
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2007-02-01
Volume
117
Issue
2
Pages
289-296
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci30555
PMC
PMC1783813
OpenAlex
W2002797282
Semantic Scholar
76a50e9232b81d22a72d6631b636a0d756df76b8
Cited by
1,563
References
107
Citations by year
2026: 73 · 2025: 58 · 2024: 76 · 2023: 58 · 2022: 72 · 2021: 89 · 2020: 92 · 2019: 76 · 2018: 79 · 2017: 87 · 2016: 78 · 2015: 78 · 2014: 88 · 2013: 87 · 2012: 89
FWCI
8.72
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • Defense Advanced Research Projects Agency
  • Advanced Research Projects Agency
  • National Institute of General Medical Sciences
Topics
  • Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
cholinergic anti-inflammatory pathway, vagus nerve, cytokine production, neuroimmune regulation, sepsis, endotoxemia, ischemia-reperfusion injury, hemorrhagic shock, arthritis, humoral theory, terrain theory, cholinergic agonists, neuroprotection, tissue damage, multiple organ failure
MeSH terms
Animals, Brain, Cholinergic Fibers, Humans, Inflammation, Models, Biological, Cytokines, History, 20th Century, History, 21st Century, History, Ancient

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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