The DOI matches its Crossref record; 105 of the 107 references it cites were found in a registry or an index; none of the 138 sources its claims cite is checked for support yet.
Physiology and immunology of the cholinergic antiinflammatory pathway
Open accessAbstract
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
Overview
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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.
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In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [2] Tracey, K.J. 2005.Fatal sequence: the killer within. Dana Press. Washington, DC, USA. 238 pp.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“gene knockout or pharmacological blockade of TNF activity prevents the development of lethal septic shock (5).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [5] Pfeffer, 1993, Cell. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Administration of TNF to healthy mammals (including humans) reproduces the hemodynamic, metabolic, immunological, and pathological manifestations of the disease (4)”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [4] Tracey, 1986, Science. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIn the paper
“TNF is produced during Gram-negative bacteria-induced acute septic shock (3).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [3] Tracey, 1987, Nature. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Stimulation of vagus nerve signals was shown to significantly inhibit TNF release in animals receiving lethal amounts of endotoxin (18).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
- Not checked yetcites [18] Borovikova, 2000, Nature. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Recent results showing that intracerebroventricular administration of muscarine receptor agonists significantly decreases serum TNF levels during endotoxemia indicate that muscarinic brain networks also regulate the cytokine-controlling function of the vagus nerve.(34).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [34] Pavlov, 2006, Proc. Natl. Acad. Sci. U. S. A. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Treatment of these mice with nicotine, a potent α7 nAChR agonist, significantly reduced serum levels of HMGB1, a cytokine mediator of lethality in this model (27).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [27] Wang, 2004, Nat. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“Intracerebral administration of muscarine agonists also stimulates an increase in vagus nerve signaling to the heart as measured by increasing instantaneous heart rate variability”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [34] Pavlov, 2006, Proc. Natl. Acad. Sci. U. S. A. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIn the paper
“This indicates that vagus nerve-derived cholinergic signals provide tonic or continuous neurological modulation of cytokine synthesis, functioning as a governor on an engine that limits the magnitude of the immune response.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
- Not checked yetcites [26] Wang, 2003, Nature. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 31
- Probably not a substantial claim. 1
None of the sources cited for this claim have been checked yet.
In the paper
“Other pathophysiological activities ascribed to TNF were the capacity to cause fever and localized inflammation (4, 6).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Vagus nerve stimulation in WT mice inhibits TNF synthesis in spleen, liver, and blood but not in α7 nAChR subunit-knockout animals (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
- Not checked yetcites [17] Bernik, 2002, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“vagus nerve stimulation in α7 nAChR-knockout animals fails to suppress cytokine synthesis whereas it significantly inhibits cytokine release in wild-type littermates (26).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
- Not checked yetcites [26] Wang, 2003, Nature. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“When sufficient concentrations are achieved, proinflammatory cytokine levels are inhibited, the magnitude of the inflammatory response is dampened, and damage is prevented.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Antiinflammatory humoral mechanisms restrain cytokine production
What the sources say
- Not checked yetcites [10] Nathan, 2002, Nature. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the 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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Splenectomy significantly reduces TNF levels in liver and blood, and vagus nerve stimulation fails to reduce levels further (28).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 2
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“IL-10-deficient mice have increased susceptibility to both inflammatory bowel disease and adjuvant arthritis”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Antiinflammatory humoral mechanisms restrain cytokine production
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [35] van Westerloo, 2005, J. Infect. Dis. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Stimulation of the vagus nerve in mice with surgery-induced ileus significantly attenuated hypomotility and reduced cytokine production (22).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [22] de Jonge, 2005, Nat. Immunol. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [20] Altavilla, 2006, Shock. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [23] Borovikova, 2000, Auton. Neurosci. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Other studies indicate that cholinergic stimulation controls endothelial activation, leukocyte recruitment, coagulation, and fibrinolysis, which modulates the development of damage during sepsis (25,36).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Administration of GTS-21, an α7 nAChR receptor agonist, significantly decreased pancreati-tis severity and attenuated pulmonary inflammation (24).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Pancreatitis.
What the sources say
- Not checked yetcites [24] van Westerloo, 2006, Gastroenterology. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [19] Mioni, 2005, Crit. Care Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“A high-fat diet also activates increased efferent vagus nerve activity, which decreases TNF levels and confers significant protection against hemorrhagic shock (41).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Hemorrhagic shock.
What the sources say
- Not checked yetcites [41] Luyer, 2005, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [20] Altavilla, 2006, Shock. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 4
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > A wiring diagram as a template for the immunological homunculus
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [22] de Jonge, 2005, Nat. Immunol. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
In the paper
“Vagus nerve stimulation of rats during lethal hemorrhagic shock conferred significant protection against the development of hypotension, prolonged survival, and decreased TNF production (21).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Hemorrhagic shock.
What the sources say
- Not checked yetcites [21] Guarini, 2003, Circulation. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Administration of nicotine to these animals restored the cytokine balance, reduced influx of inflammatory cells, and attenuated tissue damage in the liver (35).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Sepsis.
What the sources say
- Not checked yetcites [35] van Westerloo, 2005, J. Infect. Dis. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the 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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [28] Huston, 2006, J. Exp. Med. source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“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.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
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.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“The vagus nerve was reported to have important anti-inflammatory activities in acute inflammation due to inhibition of TNF [107].”
From Interaction of the endocrine system with inflammation: a function of energy and volume regulation (2014) · cites this paper as [107]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Acupuncture fact-sheet citation points to a brain-injury study
MinorThe 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.
“The NIH fact sheet on acupuncture notes that "preclinical studies have documented acupuncture's effects, but they have not been able to fully explain how acupuncture works within the framework of the Western system of medicine" (64).”
“64. Biswas, A.K., Scott, W.A., Sommerauer, J.F., and Luckett, P.M. 2000. Heart rate variability after acute traumatic brain injury in children. Crit. Care Med. 28:3907-3912.”
Citations
Cites
2 retracted
Mioni, C., Bazzani, C., Giuliani, D., Altavilla, D., Leone, S., Ferrari, A., Minutoli, L., Bitto, A., Marini, H., Zaffe, D., et al. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000186762.05301.13 · Cited by 148
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Items 101–200 of 996
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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“1 3 4 5 6 7 Q1 8 9 Q2 10 11 12 13 14 1 6 17 18 19 20 21 22 23 24 25 26 27 2 8 43 44 45 Q4 46 47 48 49 50 51 52 53 54 55 56 57 58 Q3 Brain, Behavior, and Immunity xxx (2014) xxx–xxx Contents lists available at ScienceDirect Brain, Behavior, and Immunity journal homepage: www.elsevier .com/locate /ybrbi Heart rate varia…”
BackgroundInfluentialUnderstanding immunity requires more than immunology
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Self-citationNeuroendocrine and Immune Contributors to Fatigue
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Pharmacologic cholinesterase inhibition improves survival in experimental sepsis*
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“It can be speculated that the central muscarinic network influences the vagal cholinergic anti-inflammatory response (7).”
BackgroundHeart Rate Characteristics: Physiomarkers for Detection of Late-Onset Neonatal Sepsis
Fairchild, K. D., & O’Shea, T. M. (2010) · Clinics in Perinatology · doi:10.1016/j.clp.2010.06.002 · Cited by 160
“The effect, termed the cholinergic antiinflammatory response, results from acetylcholine binding to nicotinic acetylcholine receptors on tissue macrophages, resulting in decreased activation of the transcription factor nuclear factor kB and decreased release of tumor necrosis factor a, IL1b, and other cytokines.(14,15…”
Ackland, G. L., Yao, S. T., Rudiger, A., Dyson, A., Stidwill, R. P., Poputnikov, D. M., Singer, M., & Gourine, A. V. (2010) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181c03dfa · Cited by 155
“1-AR antagonists preserve sympathovagal balance and may therefore enhance vagal (parasympathetic) anti-inflammatory effects (10).”
BackgroundWang, J., Song, Y., Zheng, C., & Leng, S. X. (2018) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2018/1972714 · Cited by 158
“The phytochemicals may be an optimal therapeutic option to counteract pathogenesis of neurodegenerative diseases, mainly through four approaches (Figure 2): (1) reducing systemic inflammation by scavenging free radicals, NOS, and proinflammatory cytokines in the periphery to ease brain inflammation via the BBB; (2) re…”
BackgroundInfluentialPathogenesis of Sjögren's syndrome
Nikolov, N. P., & Illei, G. G. (2009) · Current Opinion in Rheumatology · doi:10.1097/bor.0b013e32832eba21 · Cited by 153
The possible association between COVID-19 and postural tachycardia syndrome
Goldstein, D. S. (2020) · Heart Rhythm · doi:10.1016/j.hrthm.2020.12.007 · Cited by 153
“A cholinergic anti-inflammatory pathway involves cytokine-induced increases in vagal afferent traffic and vagal efferent inhibitory effects on inflammasomal cytokine release.(3) Vagal stimulation inhibits the production of the cytokine tumor necrosis factor a, probably via the 2 main neurotransmitters of the ANS, acet…”
Wager‐Smith, K., & Markou, A. (2010) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2010.09.010 · Cited by 153
“VNS is effective against a wide variety of conditions with inflammatory features, such as endotoxemia (Borovikova et al. 2000), experimental sepsis, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes (Tracey 2007) (for review).”
BackgroundSystemic Biomarkers of Accelerated Aging in Schizophrenia: A Critical Review and Future Directions
Nguyen, T. T., Eyler, L. T., & Jeste, D. V. (2017) · Schizophrenia Bulletin · doi:10.1093/schbul/sbx069 · Cited by 156
Mechanisms of CCK signaling from gut to brain
Raybould, H. E. (2007) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2007.09.006 · Cited by 151
Behavioural fever is a synergic signal amplifying the innate immune response
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The vagus nerve as a modulator of intestinal inflammation
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“From the pioneering work of Tracey 13 it is postulated that the cholinergic anti-inflammatory resulting in a vagus efferent firing subsequently leading to an attenuation of cytokine release from macrophages via nAChR α7.”
Immunomodulation after ischemic stroke: potential mechanisms and implications for therapy
Samary, C. S., Pelosi, P. P., Silva, P. L., & Rocco, P. R. M. (2016) · Critical Care · doi:10.1186/s13054-016-1573-1 · Cited by 148
“The main function of the vagus nerve is to regulate the parasympathetic nervous system (PNS), which is also involved in the control of inflammation [45].”
BackgroundEpidemiology of Stress and Asthma: From Constricting Communities and Fragile Families to Epigenetics
Wright, R. J. (2010) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2010.09.011 · Cited by 146
Autonomic Modulation for Cardiovascular Disease
Hadaya, J. E., & Ardell, J. L. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.617459 · Cited by 158
“On a molecular level, vagal nerve stimulation has been associated with reduced pro-inflammatory cytokine release and improved nitric oxide signaling (Tracey, 2007; Ruble et al., 2010; Calvillo et al., 2011; Sabbah, 2011).”
BackgroundDelayed Treatment of Delirium Increases Mortality Rate in Intensive Care Unit Patients
Heymann, A., Radtke, F. M., Schiemann, A., Luetz, A., MacGuill, M., Wernecke, K.-D., & Spies, C. (2010) · Journal of International Medical Research · doi:10.1177/147323001003800503 · Cited by 141
Etiology and Treatment of Pain and Psychosocial Issues in Patients With Inflammatory Bowel Diseases
Regueiro, M., Greer, J. B., & Szigethy, E. (2017) · Gastroenterology · doi:10.1053/j.gastro.2016.10.036 · Cited by 142
Vagus Nerve Stimulation at the Interface of Brain–Gut InteractionsPreprint
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“These neutrophils exert a crucial role in the pathophysiology of I/R injury by the release of proteases and oxygen-derived radicals, amplifying renal injury [7–9].”
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Exercise, inflammation, and fatigue in cancer survivors
LaVoy, E. C. P., Fagundes, C. P., & Dantzer, R. (2026) · PubMed · doi:10.22029/eir.2016.1710 · Cited by 138
Neuroprotective actions of melanocortins: a therapeutic opportunity
Catania, A. (2008) · Trends in Neurosciences · doi:10.1016/j.tins.2008.04.002 · Cited by 137
The Inflammatory Reflex and the Role of Complementary and Alternative Medical Therapies
Oke, S. L., & Tracey, K. J. (2009) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1393.013 · Cited by 139
Self-citationNew Concepts of Microbial Translocation in the Neonatal Intestine: Mechanisms and Prevention
Sherman, M. P. (2010) · Clinics in Perinatology · doi:10.1016/j.clp.2010.05.006 · Cited by 139
The extended autonomic system, dyshomeostasis, and COVID-19
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Mascia, L., Sakr, Y. L., Pasero, D., Payen, D. M., Reinhart, K., Vincent, J., & Sepsis Occurrence in Acutely Ill Patients (SOAP) Investigators (2008) · Intensive Care Medicine · doi:10.1007/s00134-007-0974-7 · Cited by 135
“pathway” [20].”
Multiple roles for nicotine in Parkinson's disease
Quik, M., Huang, L. Z., Parameswaran, N., Bordia, T., Campos, C., & Perez, X. A. (2009) · Biochemical Pharmacology · doi:10.1016/j.bcp.2009.05.003 · Cited by 137
“Activation of these intracellular messengers may modulate immune responsiveness to enhance neuronal function/integrity [76,77].”
Zhao, M. F., He, X., Bi, X., Yu, X., Wier, W. G., & Zang, W. (2013) · Basic Research in Cardiology · doi:10.1007/s00395-013-0345-1 · Cited by 134
“of the efferent arm results in prevention of excessive inflammation and modulation of cytokine production [24, 48, 49].”
BackgroundContinuous Hemodiafiltration with PMMA Hemofilter in the Treatment of Patients with Septic Shock
Nakada, T., Oda, S., Matsuda, K., Sadahiro, T., Nakamura, M., Abe, R., & Hirasawa, H. (2008) · Molecular Medicine · doi:10.2119/2007-00108.nakada · Cited by 134
‘Multimorbidity’ as the manifestation of network disturbances
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“Emerging evidence indicates that disease is a consequence of interactions between multiple physiological networks – in particular, those that regulate gene networks [4] including the activities of the autonomic nervous system [5], the hypothalamic-pituitaryadrenal axis (HPA) [6,7] and the bioenergetics within the mito…”
BackgroundElectrical stimulation of cranial nerves in cognition and disease
Adair, D., Truong, D. Q., Esmaeilpour, Z., Gebodh, N., Borges, H., Ho, L., Bremner, J. D., Badran, B. W., Napadow, V., Clark, V. P., et al. (2020) · Brain stimulation · doi:10.1016/j.brs.2020.02.019 · Cited by 136
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“VNS is also effective in a number of inflammatory states such as severe arthritis and ischaemia (Tracey, 2007).”
Central sympatholytics prolong survival in experimental sepsis
Hofer, S., Steppan, J., Wagner, T., Funke, B., Lichtenstern, C., Martin, E., Graf, B. M., Bierhaus, A., & Weigand, M. A. (2009) · Critical Care · doi:10.1186/cc7709 · Cited by 130
“Recent studies, however, have suggested that there seems to be a connection between the central muscarinic network and the vagal cholinergic response [26], influencing each other.”
BackgroundThe Pathophysiology of Septic Shock
Nduka, O. O., & Parrillo, J. E. (2009) · Critical Care Clinics · doi:10.1016/j.ccc.2009.08.002 · Cited by 134
“7), with an immunosensing afferent arm (cytokine stimulation of vagal afferents) and an efferent immunosuppressing arm (the cholinergic anti-inflammatory pathway).(54) Recent studies suggest that the spleen plays a significant role as an effector organ for this pathway.”
BackgroundAnti-Inflammatory Effects of Acupuncture Stimulation via the Vagus Nerve
Lim, H.-D., Kim, M., Lee, C. Y., & Namgung, U. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151882 · Cited by 139
“This ‘cholinergic anti-inflammatory reflex’ appears to control several inflammatory diseases such as rheumatoid arthritis, diabetes, and obesity [7,22].”
BackgroundCholinergic Neural Signals to the Spleen Down-Regulate Leukocyte Trafficking via CD11b
Huston, J. M., Rosas‐Ballina, M., Xue, X., Dowling, O., Ochani, K., Ochani, M., Yeboah, M. M., Chatterjee, P. K., Tracey, K. J., & Metz, C. N. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0802684 · Cited by 134
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“For example, local inflammatory reactions such as arthritis in the paw may be suppressed by vagal nerve stimulation (Tracey, 2007).”
BackgroundThomsen, M. S., & Mikkelsen, J. D. (2012) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2012.07.006 · Cited by 127
“…vagal nerve-mediated reduction of TNF-α release from peripheral macrophages, the so-called cholinergic anti-inflammatory pathway (Wang et al., 2003; Tracey, 2007), inviting the possibility that peripheral immune cells invading the brain in response to an insult is the basis of the protective…”
BackgroundAnti-inflammatory effects of nicotine in obesity and ulcerative colitis
Lakhan, S. E., & Kirchgessner, A. L. (2011) · Journal of Translational Medicine · doi:10.1186/1479-5876-9-129 · Cited by 133
“In addition, it has been strongly implicated as a mediator of sepsis and studies of sepsis have shown elevated circulating levels of this cytokine [26].”
BackgroundJiang, Y., Li, L., Liu, B., Zhang, Y., Chen, Q., & Li, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0102342 · Cited by 128
“This is the so-called ‘‘cholinergic anti-inflammatory pathway,’’ and it represents a physiological mechanism whereby the brain can interact with the innate immune system to control inflammatory response [28].”
BackgroundTanaka, S., Abe, C., Abbott, S. B. G., Zheng, S., Yamaoka, Y., Lipsey, J. E., Skrypnyk, N. I., Yao, J., Inoue, T., Nash, W., et al. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2021758118 · Cited by 129
“Activation of any one of these outflows could potentially explain the protective effect of vagal afferent stimulation against AKI (9, 33, 34).”
BackgroundInfluentialDifferential down-regulation of HLA-DR on monocyte subpopulations during systemic inflammation
Kim, O. Y., Monsel, A., Bertrand, M., et al. (2010) · Critical Care · doi:10.1186/cc8959 · Cited by 127
“None of the tested neuromediators, despite their known effects on immune cells [47-51] affected the expression of HLA-DR on monocyte subpopulations.”
BackgroundNicotine Exerts an Anti-inflammatory Effect in a Murine Model of Acute Lung Injury
Mabley, J. G., Gordon, S., & Pacher, P. (2010) · Inflammation · doi:10.1007/s10753-010-9228-x · Cited by 126
“The cholinergic anti-inflammatory pathway has been identified as a major neuromodulator of immune cell function [9] with stimulation of the vagus nerve protecting against endotoxic shock by directly affect-”
BackgroundCurrent concepts in neuromuscular transmission
Fagerlund, M. J., & Eriksson, L. I. (2009) · British Journal of Anaesthesia · doi:10.1093/bja/aep150 · Cited by 133
After the bomb drops: A new look at radiation-induced multiple organ dysfunction syndrome (MODS)
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The embodied mind: A review on functional genomic and neurological correlates of mind-body therapies
Muehsam, D. J., Lutgendorf, S. K., Mills, P. J., Rickhi, B., Chevalier, G., Bat, N., Chopra, D., & Gurfein, B. T. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.12.027 · Cited by 133
“Depressed vagus nerve ctivity is associated with increased morbidity and mortality in sepis, rheumatoid arthritis, lupus, sarcoidosis, inflammatory bowel iseases, trauma (Tracey, 2007) and stress (Porges, 1995).”
BackgroundInteraction of the endocrine system with inflammation: a function of energy and volume regulation
Straub, R. H. (2014) · Arthritis Research & Therapy · doi:10.1186/ar4484 · Cited by 121
“Growth hormone given to healthy volunteers slightly but significantly increased serum TNF and serum IL-6 [118].”
BackgroundInfluentialKosek, E., Altawil, R., Kadetoff, D., Finn, A., Westman, M., Maître, E. L., Andersson, M., Jensen‐Urstad, M., & Lampa, J. (2015) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2015.02.002 · Cited by 120
Systemic inflammation in traumatic spinal cord injury
Bloom, O., Herman, P. E., & Spungen, A. M. (2019) · Experimental Neurology · doi:10.1016/j.expneurol.2019.113143 · Cited by 123
“…past fifty years, it has become increasingly clear that many of the clinical hallmarks of inflammation are in fact due to biological effects of cytokines and other factors derived from immune cells, rather than from invading microorganisms, leading to the cytokine theory of disease (Tracey, 2007).”
InfluentialHeart rate variability biofeedback in chronic disease management: A systematic review
Fournié, C., Chouchou, F., Dalleau, G., Caderby, T., Cabrera, Q., & Verkindt, C. (2021) · Complementary Therapies in Medicine · doi:10.1016/j.ctim.2021.102750 · Cited by 130
Mental Stress and Its Effects on Vascular Health
Sara, J. D. S., Toya, T., Ahmad, A., Clark, M. M., Gilliam, W. P., Lerman, L. O., & Lerman, A. (2022) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2022.02.004 · Cited by 141
“Therefore, MSinduced withdrawal of parasympathetic nervous activity leads to enhanced release of proinflammatory cytokines, underpinned by an important difference between MS and physical (exercise)erelated stress, where in the latter there is increased parasympathetic nerve discharge.(128) Conversely, catecholamines b…”
BackgroundA Critical Role for Human Caspase-4 in Endotoxin Sensitivity
Kajiwara, Y., Schiff, T., Voloudakis, G., Sosa, M. A. G., Elder, G. A., Bozdagi, O., & Buxbaum, J. D. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1303424 · Cited by 119
“toimmunity, such as rheumatoid arthritis (20, 21).”
The neuroscience of sadness: A multidisciplinary synthesis and collaborative review
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“…system (Deuchars et al., 2018; Porges, 2011), hypothalamic-pituitary-adrenal (HPA) axis (Porges, 2011), inflammatory pathways (Kolcun et al., 2017; Tracey, 2007, 2002), metabolism including glucose regulation (Berthoud, 2008; Dienel, 2019; Malbert et al., 2017; Pavlov and Tracey, 2012), brain-gut…”
Satapathy, S. K., Ochani, M., Dancho, M. E., Hudson, L., Rosas‐Ballina, M., Valdés‐Ferrer, S. I., Olofsson, P. S., Harris, Y., Roth, J., Chavan, S. S., et al. (2011) · Molecular Medicine · doi:10.2119/molmed.2011.00083 · Cited by 119
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“Host control of inflammation involves a complex interaction between the neuroendocrine and the immune system [3,4].”
BackgroundResultSystemic inflammation induces axon injury during brain inflammation
Moreno, B., Jukes, J., Vergara‐Irigaray, N., Errea, O., Villoslada, P., Perry, V. H., & Newman, T. A. (2011) · Annals of Neurology · doi:10.1002/ana.22550 · Cited by 121
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Ultrasound Modulates the Splenic Neuroimmune Axis in Attenuating AKI
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“…function such that vagal impairment leads to dysregulation of immune system triggering downstream artherosclerotic processes as described by Tracey and colleagues (Huston and Tracey, 2010; Tracey, 2002, 2007; Tracey and Pavlov, 2012), as well as adverse effects of the disease process itself on HRV.”
BackgroundPartecke, L. I., Käding, A., Trung, D. N., Diedrich, S., Sendler, M., Weiß, F. U., Kühn, J., Mayerle, J. V., Beyer, K., von Bernstorff, W., et al. (2017) · Oncotarget · doi:10.18632/oncotarget.15019 · Cited by 117
Role of Vagus Nerve Stimulation in the Treatment of Chronic Pain
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“Increasing experimental evidence suggested that VNS might modulate the immune response and systemic in fl ammation through the CAP [117 – 120].”
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“In light of studies suggesting that the vagus nerve modulates the production of proinflammatory cytokines, including TNF-α [52], we also controlled for heart rate, which is a proxy measure of parasympathetic outflow to the heart [53].”
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Phillips, M. D., Flynn, M. G., McFarlin, B. K., Stewart, L. K., & Timmerman, K. L. (2010) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0b013e3181b11ab7 · Cited by 116
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Procaccini, C., Pucino, V., Rosa, V. D., Marone, G., & Matarese, G. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00143 · Cited by 116
Pathogen-induced heart rate changes associated with cholinergic nervous system activation
Fairchild, K. D., Srinivasan, V., Moorman, J. R., Gaykema, R. P. A., & Goehler, L. E. (2010) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00487.2010 · Cited by 108
“If vagal efferent signaling to macrophages and to the heart are coupled, the cholinergic anti-inflammatory response would be associated with slowing of the heart rate via ACh binding to muscarinic cholinergic receptors on cardiac pacemaker cells (30).”
BackgroundCaloric restriction may reverse age‐related autonomic decline in humans
Stein, P. K., Soare, A., Meyer, T. E., Cangemi, R., Holloszy, J. O., & Fontana, L. (2012) · Aging Cell · doi:10.1111/j.1474-9726.2012.00825.x · Cited by 108
“In contrast, activation of the parasympathetic nervous system, through stimulation of the efferent vagus nerve, decreases systemic inflammation in several experimental models of acute systemic inflammation (Tracey, 2007).”
BackgroundCerritelli, F., Frasch, M. G., Antonelli, M. C., Viglione, C., Vecchi, S., Chiera, M., & Manzotti, A. (2021) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.721605 · Cited by 108
“Moreover, considering the role of the vagus nerve in the CAP, which involves immune cells such as macrophages (Borovikova et al., 2000; Tracey, 2007; Fairchild et al., 2010; Frasch et al., 2016), and the sex-related neurodevelopment impact of microglial functions (Hanamsagar and Bilbo, 2016), the different characteris…”
BackgroundTargeting α-7 Nicotinic Acetylcholine Receptor in the Enteric Nervous System
Costantini, T. W., Krzyżaniak, M., Cheadle, G. A., Putnam, J. G., Hageny, A., Lopez, N., Eliceiri, B. P., Bansal, V., & Coimbra, R. S. M. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.04.005 · Cited by 112
Smoking and COVID-19: Adding Fuel to the Flame
Kashyap, V. K., Dhasmana, A., Massey, A. E., Kotnala, S., Zafar, N., Jaggi, M., Yallapu, M. M., & Chauhan, S. C. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21186581 · Cited by 108
Olivieri, F., Biscetti, L., Pimpini, L., Pelliccioni, G., Sabbatinelli, J., & Giunta, S. (2024) · Ageing Research Reviews · doi:10.1016/j.arr.2024.102521 · Cited by 132
“ANS imbalance, characterized by sympathetic overdrive and reduced parasympathetic activity, is closely linked to a pro-inflammatory state (Giunta et al., 2024a; Pongratz and Straub, 2014; Tracey, 2007).”
BackgroundAerobic exercise attenuates inducible TNF production in humans
Sloan, R. P., Shapiro, P. A., DeMeersman, R. E., McKinley, P. S., Tracey, K. J., Slavov, I., Fang, Y., & Flood, P. D. (2007) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00147.2007 · Cited by 109
“Stimulation of vagus nerve activity in animals decreases levels of TNF during endotoxemia, sepsis, and ischemia (19, 20).”
BackgroundSelf-citationKiank, C., Taché, Y., & Larauche, M. H. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.08.006 · Cited by 107
Programming of respiratory health in childhood
Wright, R. J., & Brunst, K. J. (2013) · Current Opinion in Pediatrics · doi:10.1097/mop.0b013e32835e78cc · Cited by 108
Pharmacological Regulation of Neuropathic Pain Driven by Inflammatory Macrophages
Kiguchi, N., Kobayashi, D., Saika, F., Matsuzaki, S., & Kishioka, S. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18112296 · Cited by 106
“Consistent with this, nicotine treatment improves a variety of intractable inflammatory diseases in rodents [146,156,157,159,160].”
BackgroundMorelli, A., Sanfilippo, F., Arnemann, P. H., et al. (2018) · Critical Care Medicine · doi:10.1097/ccm.0000000000003520 · Cited by 103
Transcutaneous Cervical Vagus Nerve Stimulation Ameliorates Acute Ischemic Injury in Rats
Ay, İ., Nasser, R., Simon, B. J., & Ay, H. (2015) · Brain stimulation · doi:10.1016/j.brs.2015.11.008 · Cited by 103
“A well-known effect of cVNS in the periphery is inhibition of innate immune responses to tissue injury; cVNS exerts a powerful anti-inflammatory effect via activation of α7 nicotinic acetylcholine receptors (α7nAChRs) on peripheral macrophages in experimental models of sepsis, hemorrhagic shock, myocardial ischemia, a…”
BackgroundFavorable Neurocognitive Outcome with Low Tidal Volume Ventilation after Cardiac Arrest
Beitler, J. R., Ghafouri, T. B., Jinadasa, S. P., Mueller, A., Hsu, L., Anderson, R. J., Joshua, J., Tyagi, S. K., Malhotra, A., Sell, R., et al. (2017) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201609-1771oc · Cited by 105
“Insults ranging from acute myocardial infarction (44, 45) to sepsis (46, 47) have been shown to increase intracerebral proinflammatory cytokine levels and associated neuronal injury.”
BackgroundAruldass, A. R., Kitzbichler, M. G., Morgan, S. E., Lim, S. I., Lynall, M.-E., Turner, L., Vértes, P. E., Cavanagh, J., Cowen, P. J., Pariante, C. M., et al. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.08.226 · Cited by 103
The cholinergic anti-inflammatory pathway in humans: State-of-the-art review and future directions
Alen, N. V. (2022) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2022.104622 · Cited by 112
CNS Leptin Action Modulates Immune Response and Survival in Sepsis
Tschöp, J., Nogueiras, R., Lockie, S. H., Kasten, K. R., Castañeda, T. R., Huber, N., Guanciale, K., Pérez–Tilve, D., Habegger, K. M., Ottaway, N., et al. (2010) · Journal of Neuroscience · doi:10.1523/jneurosci.4875-09.2010 · Cited by 98
“The concept of a specific and functionally relevant CNS control of peripheral immune defense, as implied by the present results, is consistent with a series of observations reported by Tracey (2007).”
BackgroundResultInfluentialCheyuo, C., Wu, R., Zhou, M., Jacob, A., Coppa, G. F., & Wang, P. (2010) · Shock · doi:10.1097/shk.0b013e3181f48a37 · Cited by 97
“The binding of ghrelin to its receptor at the DVC activates the cholinergic anti-inflammatory pathway, which was recently described by Tracey (10).”
BackgroundInflammation and cardiorespiratory control: the role of the vagus nerve.
Thayer, J. F., Loerbroks, A., & Sternberg, E. M. (2011) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2011.05.016 · Cited by 97
Chang, E. H., Chavan, S. S., & Pavlov, V. A. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00263 · Cited by 98
“However, different forms of nonresolved, exacerbated, or chronic inflammation cause secondary tissue injury and mediate pathogenesis in sepsis, IBD, rheumatoid arthritis, and many other diseases (Firestein, 2003; Tracey, 2007; Chavan and Tracey, 2017).”
BackgroundShiga, H., Hirasawa, H., Nishida, O., Oda, S., Nakamura, M., Mashiko, K., Matsuda, K., Kitamura, N., Kikuchi, Y., & Fuke, N. (2014) · Blood Purification · doi:10.1159/000369377 · Cited by 98
Sedation improves early outcome in severely septic Sprague Dawley rats
Qiao, H., Sanders, R. D., Ma, D., Xin-min, W., & Maze, M. (2009) · Critical Care · doi:10.1186/cc8012 · Cited by 98
“How dexmedetomidine induces its anti-inflammatory effect is currently unclear though it may be related to its central sympatholytic effects [23,30] and relative stimulation of the cholinergic anti-inflammatory pathway [16,17].”
BackgroundModulation of experimental arthritis by vagal sensory and central brain stimulation
Bassi, G. S., Dias, D. P. M., Franchin, M., Talbot, J., dos Reis, D. G., Menezes, G. B., Castania, J. A., Garcia‐Cairasco, N., Resstel, L. B. M., Salgado, H. C., et al. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.04.003 · Cited by 99
Sturmberg, J. P., Picard, M. A., Aron, D. C., Bennett, J. M., Bircher, J., DeHaven, M. J., Gijzel, S. M. W., Heng, H. H., Marcum, J. A., Martin, C. M., et al. (2019) · Frontiers in Medicine · doi:10.3389/fmed.2019.00059 · Cited by 110
“Rather, diseases emerge as a consequence of interactions among multiple physiological networks—in particular those that regulate gene networks (27, 50), activities of the autonomic nervous system (51) and the hypothalamic-pituitary-adrenal axis (HPA) (52, 53), as well as the bioenergetics within mitochondria in concer…”
BackgroundDetrimental consequences of brain injury on peripheral cells
Catania, A. P., Lonati, C., Sordi, A., & Gatti, S. (2009) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2009.04.006 · Cited by 98
“Stimulation of the vagus nerve prevented harmful effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes (Tracey, 2007).”
BackgroundGenuis, S. J. (2010) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2010.08.047 · Cited by 95
“…as well as cell-to-cell signaling, it is possible that various stimuli may trigger a host of varied cytokines or a ‘cytokine storm’ which may result in dysregulated cell signaling, biochemical disruption and inflammation with resulting clinical manifestations (Tracey, 2007; Czura and Tracey, 2005).”
BackgroundIdentification and treatment of symptoms associated with inflammation in medically ill patients
Dantzer, R., Capuron, L., Irwin, M. R., Miller, A. H., Ollat, H., Perry, V. H., Rousey, S., & Yirmiya, R. (2007) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2007.10.008 · Cited by 97
“Another strategy that applies to inflammatory processes both at the periphery and in the brain is to dampen cytokine production by enhancing cholinergic neurotransmission (Pollak et al., 2005; Tracey, 2007).”
Reiki Is Better Than Placebo and Has Broad Potential as a Complementary Health Therapy
McManus, D. E. (2017) · Journal of Evidence-Based Complementary & Alternative Medicine · doi:10.1177/2156587217728644 · Cited by 96
Forebrain Cholinergic Dysfunction and Systemic and Brain Inflammation in Murine Sepsis Survivors
Zaghloul, N., Addorisio, M. E., Silverman, H. A., Patel, H. L., Valdés-Ferrer, S. I., Ayasolla, K. R., Lehner, K. R., Olofsson, P. S., Nasim, M., Metz, C. N., et al. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01673 · Cited by 89
“Cortex areas and the hippocampus innervated by cholinergic pathways interact, directly or through multisynaptic pathways, with the dorsal vagal complex, the brainstem integrative center of the inflammatory reflex, a vagus nerve-based powerful regulator of peripheral immune responses and inflammation (17, 52, 59, 60).”
BackgroundSelf-citation
Metadata
- 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
- Published
- 2007-02-01
- Volume
- 117
- Issue
- 2
- Pages
- 289-296
- ISSN
- 0021-9738 (ISSN-L)
- 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
- bronze
- doi.org
- 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
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