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
AI snapshot
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
Cites
Statistics
Verification
Claims the paper makes
0 of 138 cited sources checked · 0 supported · 0 flagged
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
RetractedWu, X., Gao, J., Yan, J., Owyang, C., & Li, Y. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00791.2003 · Cited by 53
RetractedVagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W., & Tracey, K. J. (2000) · Nature · doi:10.1038/35013070 · Cited by 4,211
Self-citationTracey, K. J. (2002) · Nature · doi:10.1038/nature01321 · Cited by 3,728
Self-citationNicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation
Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., et al. (2003) · Nature · doi:10.1038/nature01339 · Cited by 3,228
Self-citationTargan, S. R., Hanauer, S. B., van Deventer, S. J. H., Mayer, L., Present, D. H., Braakman, T., DeWoody, K. L., Schaible, T. F., & Rutgeerts, P. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199710093371502 · Cited by 3,135
The anti-inflammatory effect of exercise
Petersen, A. M. W., & Pedersen, B. K. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00164.2004 · Cited by 3,100 · cited 1×
“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 (84–90).”
Gralton, B. (2008) · Art monthly Australia · Cited by 3,001
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738
Shock and Tissue Injury Induced by Recombinant Human Cachectin
Tracey, K. J., Beutler, B., Lowry, S. F., Merryweather, J., Wolpe, S., Milsark, I. W., Hariri, R. J., Fahey, T. J., Zentella, A., Albert, J. D., et al. (1986) · Science · doi:10.1126/science.3764421 · Cited by 2,549
Self-citation
Flagged first, then by citations
2 of the 107 references couldn’t be matched to a known paper.
Research works printed but not linked: 6
- Zingarelli, 1994, Am. J. Physiol., 266, H1512
- Balanescu, 2004, Med. Sci. Monit., 10, CR307
- Laversuch, 1997, J. Rheumatol., 24, 1540
- Shi, 1995, Zhongguo Zhong. Xi. Yi. Jie. He. Za Zhi., 15, 536
- Papadopoulos, 2005, Clin. Exp. Rheumatol., 23, 861
- Holguin, 2005, Chest., 127, 1102
Cited by
Sorted by citations
Items 401–500 of 996
Liu, X., Mei, Z., Qian, J., Zeng, Y., & Wang, M. (2013) · PubMed Central · doi:10.3969/j.issn.1673-5374.2013.34.004 · Cited by 59
“Therefore, future studies aim to refine and enhance the development of puerarin and CAP for highly targeted therapeutic approaches.”
InfluentialZhou, Z., Li, B., Dong, Z., Liu, F., Zhang, Y., Yu, Y., Shang, F., Wu, L., Wang, X., & Jin, Y. J. (2013) · PLoS ONE · doi:10.1371/journal.pone.0083102 · Cited by 49
“a7 nAChR plays a critical role in regulating the process of immunoregulation and inflammatory reaction in our body [35] throughwhich its specific agonist nicotine increases the expression of Ach to perform the anti-inflammatory function [36].”
BackgroundImpact of Dietary Fatty Acids on Cardiac Arrhythmogenesis
Rennison, J. H., & Wagoner, D. R. V. (2009) · Circulation Arrhythmia and Electrophysiology · doi:10.1161/circep.109.880773 · Cited by 50
Elia, A., & Fossati, S. (2023) · Frontiers in Physiology · doi:10.3389/fphys.2023.1060666 · Cited by 55
“Lastly, vagal neuromodulation improves cardiac ANS tone attenuating heart failure progression through the reduction of proinflammatory cytokine expression and both NE and AT- II circulating levels (Tracey, 2007; Zhang et al., 2009).”
BackgroundParoxysmal Sympathetic Hyperactivity in Pediatric Rehabilitation
Pozzi, M., Conti, V., Locatelli, F., et al. (2014) · Journal of Head Trauma Rehabilitation · doi:10.1097/htr.0000000000000084 · Cited by 48
Regulation of memory – From the adrenal medulla to liver to astrocytes to neurons
Gold, P. E. (2014) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2013.12.012 · Cited by 52
Cedillo, J. L., Arnalich, F., Martín-Sánchez, C., Quesada, A., Blanco, J. J. R., Maldifassi, M. C., Atienza, G., Renart, J., Fernández‐Capitán, C., Rio, F. G., et al. (2014) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiu425 · Cited by 48
“tensively reported in animal models of sepsis and other systemic inflammatory diseases [9–11], confirmation of this finding in humans has been impossible because no known marker accurately reflected the activity of the antiinflammatory pathway.”
BackgroundYuan, P., & Taché, Y. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00121.2017 · Cited by 50
“Of importance was the 82 identification of a vagus nerve-based inflammatory reflex in which the efferent arm 83 encompasses the cholinergic anti-inflammatory properties of the vagus (4, 52).”
BackgroundCalming the Nervous Heart: Autonomic Therapies in Heart Failure
Hanna, P., Shivkumar, K., & Ardell, J. L. (2018) · Cardiac failure review · doi:10.15420/cfr.2018.20.2 · Cited by 50
Chin, E., Lim, W. M., Ma, D., Rosales, F. J., & Goh, E. L. K. (2018) · Molecular Neurobiology · doi:10.1007/s12035-018-1345-9 · Cited by 48
de Oliveira, F. R., Fantucci, M. Z., Adriano, L., Valim, V., Cunha, T. M., Louzada‐Júnior, P., & Rocha, E. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19123953 · Cited by 54
“Third, the central nervous system (CNS), mostly autonomic nervous system dysfunction, can induce or perpetuate an unbalanced inflammatory response in the target-innervated organs of autoimmune diseases [3,34].”
BackgroundKohoutová, M., Horák, J., Jarkovská, D., Martínková, V., Tégl, V., Nalos, L., Vištějnová, L., Beneš, J., Švíglerová, J., Kuncová, J., et al. (2019) · Critical Care Medicine · doi:10.1097/ccm.0000000000003714 · Cited by 49
Wilson, M. A., Liberzon, I., Lindsey, M. L., Lokshina, Y., Risbrough, V. B., Sah, R., Wood, S. K., Williamson, J. B., & Spinale, F. G. (2019) · Stress · doi:10.1080/10253890.2019.1621283 · Cited by 48
“Further, a growing body of literature has indicated that parasympathetic activation via cholinergic activity inhibits inflammation, while sympathetic activation leads to the increased release of inflammatory cytokines (Olofsson, Rosas-Ballina, Levine, & Tracey, 2012; Tracey, 2007).”
BackgroundAlpha 7 subunit of nAChR regulates migration of human mesenchymal stem cells.
Schraufstätter, I. U., DiScipio, R. G., & Khaldoyanidi, S. K. (2009) · PubMed · Cited by 47
Johansson, M. E., Ulleryd, M. A., Bernardi, A. I., Lundberg, A. M., Andersson, A., Folkersen, L., Fogelstrand, L., Islander, U., Yan, Z.-Q., & Hansson, G. K. (2014) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.114.303892 · Cited by 47
“The ability of vagal nerve stimulation to control and dampen inflammation has been referred to as the cholinergic antiinflammatory pathway.(4) The effect of vagal anti-inflammatory signaling is mediated by nicotinic receptors containing the α7 subunits (α7nAChR).”
BackgroundLemche, E., Чабан, О., & Lemche, A. V. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00142 · Cited by 50
Meneses, G., Rosetti, M., Espinosa, A., Florentino, A., Bautista, M., Díaz, G., Olvera, G., Bárcena, B., Fleury, A., Adalid-Peralta, L. V., et al. (2018) · PLoS ONE · doi:10.1371/journal.pone.0201375 · Cited by 48
Neuronal regulation of innate lymphoid cells
Klose, C. S. N., & Artis, D. (2018) · Current Opinion in Immunology · doi:10.1016/j.coi.2018.11.002 · Cited by 47
Anti-inflammatory Silent Agonists
Horenstein, N. A., & Papke, R. L. (2017) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.7b00368 · Cited by 48
Hecker, A., Mikulski, Z., Lips, K. S., Pfeil, U., Zakrzewicz, A., Wilker, S., Hartmann, P., Padberg, W. M., Wessler, I. K., Kummer, W., et al. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.1107722 · Cited by 46
“In this scenario, ACh is a unidirectional neuronal messenger “linking mind to immunity” [5, 48].”
BackgroundHiraki, T., Baker, W. B., & Greenberg, J. H. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22812 · Cited by 46
“The cholinergic anti-inflammatory pathway (CAP) is activated by the central cholinergic system in the brain via the efferent fiber of the vagus nerve (Pavlov et al., 2006; Tracey, 2007).”
BackgroundVagus nerve modulation of inflammation: Cardiovascular implications
Olshansky, B. (2015) · Trends in Cardiovascular Medicine · doi:10.1016/j.tcm.2015.03.016 · Cited by 46
“However, the vagus nerve modulates inflammatory responses in various organ systems and in animal models [1,2].”
InfluentialRisk Models for Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis (PEP)
Dimagno, M. J., Spaete, J. P., Ballard, D. D., Wamsteker, E., & Saini, S. D. (2013) · Pancreas · doi:10.1097/mpa.0b013e31827e95e9 · Cited by 45
“Nicotine (present in cigarettes) may activate the nicotinic antiinflammatory pathway,(28) which reduces pancreatic inflammation and severity of experimental pancreatitis,(29) thus mirroring the anti-inflammatory effects of this pathway observed in ulcerative colitis(30) and in other conditions.(28) Nicotine also relax…”
Jiménez‐Castro, M. B., Meroño, N., Mendes-Braz, M., Gracia‐Sancho, J., Martínez-Carreres, L., Cornide‐Petronio, M. E., Casillas-Ramírez, A., Rodés, J., & Peralta, C. (2014) · Journal of Hepatology · doi:10.1016/j.jhep.2014.07.031 · Cited by 46
Regulation of Carcinogenesis by Sensory Neurons and Neuromediators
Erin, N., Shurin, G. V., Baraldi, J. H., & Shurin, M. R. (2022) · Cancers · doi:10.3390/cancers14092333 · Cited by 50
Stress-Related Programming of Autonomic Imbalance: Role in Allergy and Asthma
Wright, R. J. (2012) · Chemical immunology/Fortschritte der Allergielehre/Progress in allergy/Chemical immunology and allergy · doi:10.1159/000336496 · Cited by 45
Neural concomitants of immunity—Focus on the vagus nerve
Thayer, J. F., & Sternberg, E. M. (2009) · NeuroImage · doi:10.1016/j.neuroimage.2009.05.058 · Cited by 46
“Taken together these parasympathetic pathways form what has been termed “the cholinergic anti-inflammatory pathway” (Tracey, 2007).”
BackgroundInfluentialInflaming the Brain: CRPS a Model Disease to Understand Neuroimmune Interactions in Chronic Pain
Linnman, C., Becerra, L. R., & Borsook, D. (2012) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-012-9422-8 · Cited by 45
“These findings provide a potential bridge between the fields of neurology and immunology, in that brain regions associated with immune responses may map onto what has been dubbed an “an immunological homunculus” (Diamond and Tracey 2011; Tracey 2007).”
Neuromodulation Applied to Diseases: The Case of HRV Biofeedback
Gitler, A., Vanacker, L., Couck, M., Leeuw, I. D., & Gidron, Y. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11195927 · Cited by 45
“Resonance frequency breathing using HRV-B may increase the cholinergic anti-inflammatory pathway [86,87].”
BackgroundTvarijonaviciute, A., KOCATÜRK, M., Cansev, M., Tecles, F., Cerón, J. M. C., & Yılmaz, Z. (2011) · Research in Veterinary Science · doi:10.1016/j.rvsc.2011.09.010 · Cited by 44
Chojnacka, K., Papke, R. L., & Horenstein, N. A. (2013) · Bioorganic & Medicinal Chemistry Letters · doi:10.1016/j.bmcl.2013.05.039 · Cited by 44
Central serotonin attenuates LPS-induced systemic inflammation
Mota, C. M. D., Rodrigues-Santos, C., Fernández, R. A. R., Carolino, R. O. G., Antunes‐Rodrigues, J., Anselmo-Franci, J. A., & Branco, L. G. S. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.07.010 · Cited by 44
Voicu, V. A., Thiermann, H., Rădulescu, F. Ș., et al. (2009) · Basic & Clinical Pharmacology & Toxicology · doi:10.1111/j.1742-7843.2009.00486.x · Cited by 44
Mechanisms of Neurologic Failure in Critical Illness
Pustavoitau, A., & Stevens, R. D. (2008) · Critical Care Clinics · doi:10.1016/j.ccc.2007.11.004 · Cited by 45
“The vagus nerve, by releasing acetylcholine in the vicinity of leukocytes in the reticuloendothelial system, is capable of down-regulating cytokine production, a response referred to as the ‘‘cholinergic anti-inflammatory pathway’’ [71], and afferent vagal fibers are activated by proinflammatory cytokines such as IL-1…”
BackgroundLung–brain cross talk in the critically ill
Blanch, L., & Quintel, M. (2016) · Intensive Care Medicine · doi:10.1007/s00134-016-4583-1 · Cited by 43
“The intact brain via an inflammatory reflex of the vagus nerve can balance excessive cytokine production, limiting tissue injury by means of the cholinergic anti-inflammatory pathway [6] (Fig.”
BackgroundSepsis-induced alterations in sleep of rats
Baracchi, F., Ingiosi, A. M., Raymond, R. M., & Opp, M. R. (2011) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00354.2011 · Cited by 42
“Of interest, recent studies of the bidirectional interactions between the CNS and peripheral inflammation have focused on the role of the cholinergic system (55).”
BackgroundXu, T., Yu, Z. H., Liu, Y., Lu, M., Gong, M., Li, Q., Xia, Y., & Xu, B. (2021) · Molecular Neurobiology · doi:10.1007/s12035-021-02609-1 · Cited by 45
“Additionally, low-frequency electrical stimulation of the efferent vagal nerve fibers is thought to possess anti-inflammatory properties and can activate the “cholinergic anti-inflammatory reflex” [69].”
BackgroundKnops, M., Werner, C. G., Scherbakov, N., Fiebach, J. B., Dreier, J. P., Meisel, A., Heuschmann, P. U., Jungehülsing, G., von Haehling, S., Dirnagl, U., et al. (2013) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1007/s13539-013-0103-0 · Cited by 42
Minutoli, L. (2012) · Current Medicinal Chemistry · doi:10.2174/092986712799320538 · Cited by 42
Baroreflex impairment and morbidity after major surgery
Toner, A., Jenkins, N., & Ackland, G. L. (2016) · British Journal of Anaesthesia · doi:10.1093/bja/aew257 · Cited by 42
Liu, Y., Yang, J., Bao, J., Li, X., Ye, A., Zhang, G., & Liu, H. (2016) · Placenta · doi:10.1016/j.placenta.2016.11.003 · Cited by 42
Zhang, M., Han, X., Bao, J., Yang, J., Shi, S.-Q., Garfield, R. E., & Liu, H. (2017) · Reproductive Sciences · doi:10.1177/1933719117702247 · Cited by 44
Lankadeva, Y. R., Shehabi, Y., Deane, A. M., Plummer, M. P., Bellomo, R., & May, C. N. (2021) · British Journal of Pharmacology · doi:10.1111/bph.15363 · Cited by 42
“The vagus nerve is proposed to play a critical role in neuro-immune communications during inflammatory stimuli (Tracey, 2007).”
BackgroundInfluentialUnexpected finding of a marked non-neuronal cholinergic system in human knee joint synovial tissue
Grimsholm, O., Rantapää‐Dahlqvist, S., Dalén, T., & Forsgren, S. (2008) · Neuroscience Letters · doi:10.1016/j.neulet.2008.06.082 · Cited by 42
Post-COVID dysautonomias: what we know and (mainly) what we don’t know
Goldstein, D. S. (2024) · Nature Reviews Neurology · doi:10.1038/s41582-023-00917-9 · Cited by 41
“Auricular stimulation, which might increase afferent vagal activity and thereby exert an anti-inflammatory effect 127 , led to decreased levels of C-reactive protein and IL-6 and alleviated depression in patients with PASC included in a randomized clinical trial, without affecting their other…”
Modulation of neuroimmune cytokine networks by antidepressants: implications in mood regulation
Nava, R. G., Adri, A. S., Filgueiras, I. S., Nóbile, A. L., Barcelos, P. M., Corrêa, Y. L. G., de Oliveira, S. F., Cabral‐Miranda, G., Dias, H. D., Schimke, L. F., et al. (2025) · Translational Psychiatry · doi:10.1038/s41398-025-03532-y · Cited by 53
“Through the cholinergic anti-in fl ammatory pathway, vagal activation suppresses macrophage cytokine production via α 7nAChR receptors, effectively dampening systemic in fl ammation [204, 205].”
The Spleen: The Forgotten Organ in Acute Kidney Injury of Critical Illness
Gigliotti, J. C., & Okusa, M. D. (2014) · Nephron Clinical Practice · doi:10.1159/000363255 · Cited by 41
Mihaylova, S., Killian, A., Mayer, K., Pullamsetti, S. S., SCHERMULY, R. T., & Rosengarten, B. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-183 · Cited by 41
“Distal vagus nerve stimulation (VNS) was shown to mitigate the inflammatory response and thereby improve survival in a variety of animal sepsis models [14,15].”
BackgroundNeural reflex pathways in intestinal inflammation: hypotheses to viable therapy
Willemze, R. A., Luyer, M. D. P., Buurman, W. A., & de Jonge, W. J. (2015) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2015.56 · Cited by 41
Kim, H., Kim, S. R., Je, J., Jeong, K., Kim, S., Kim, H. J., Chang, K. C., & Park, S. W. (2018) · Experimental & Molecular Medicine · doi:10.1038/s12276-018-0061-x · Cited by 42
Rangon, C.-M., Krantic, S. M., Moyse, E., & Fougère, B. (2020) · Journal of Alzheimer s Disease Reports · doi:10.3233/adr-200273 · Cited by 40
“In addition, the vagus nerve and its brainstem centers down-regulate inflammatory and immune responses via two neural connections: i) the noradrenergic projection from the vagal sensory nucleus NTS to the neuroendocrine paraventricular nucleus of the hypothalamus, stimulating the secretion of the anti-inflammatory glu…”
BackgroundInfluentialIntegrative medicine considerations for convalescence from mild-to-moderate COVID-19 disease
Alschuler, L. N., Chiasson, A. M., Horwitz, R., STERNBERG, E. M., Crocker, R. L., Weil, A., & Maizes, V. (2020) · EXPLORE · doi:10.1016/j.explore.2020.12.005 · Cited by 39
“nervous system and vagus nerve release of acetylcholine, provide a brake to the stress response and boost the anti-inflammatory components of the immune response.(116) All mind-body practices, including, but not limited to meditation, yoga, Tai Chi, and guided imagery,”
Sleep Disruption and Cancer: Chicken or the Egg?
Berisha, A., Shutkind, K., & Borniger, J. C. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.856235 · Cited by 44
“Since the characterization of the cholinergic anti-inflammatory pathway, a plethora of studies have established the role of local and systemic inflammation in the activation of vagal efferent fibers, resulting in suppression of cytokine release from macrophages (Tracey, 2007).”
BackgroundEffect of endotoxin on heart rate dynamics in rats with cirrhosis
Haddadian, Z., Eftekhari, G., Mazloom, R., Jazaeri, F., Dehpour, A. R., & Mani, A. R. (2013) · Autonomic Neuroscience · doi:10.1016/j.autneu.2013.02.022 · Cited by 41
“According to this model, brain modulates systemic inflammatory responses to endotoxin by activation of vagal efferent fibers and acetylcholine can attenuate the release of cytokines through activation ofα7-nicotinic receptors on macrophage (Tracey, 2007).”
BackgroundPattern of metalloprotease activity and myofiber regeneration in skeletal muscles of mdx mice
Bani, C., Lagrota-Cândido, J., Pinheiro, D. F., Leite, P. E. C., Salimena, M. C., Henriques‐Pons, A., & Quírico‐Santos, T. (2008) · Muscle & Nerve · doi:10.1002/mus.20970 · Cited by 40
Jeremias, I. C., Victorino, V. J., Barbeiro, H. V., Kubo, S. A., Prado, C. M., de Lima, T. M., & Soriano, F. G. (2015) · Molecular Neurobiology · doi:10.1007/s12035-015-9538-y · Cited by 41
“peripheral vagus nerve through the efferent arm (cholinergic anti-inflammatory pathway), and the primary released neurotransmitter ACh regulates cytokine production specifically via α7nAChR-dependent signaling [8, 19, 20].”
BackgroundEngel, T., Ben‐Horin, S., & Beer-Gabel, M. (2015) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000508 · Cited by 40
“The evidence for such effects came from observations indicating that cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases and that stimulation of the vagus nerve results in lower serum and organ tumor necrosis factor and other proinflammatory cytokine and attenuation of inflam…”
BackgroundResultTang, Q., Wu, X., Weng, W., Li, H., Feng, J., Mao, Q., Gao, G., & Jiang, J. (2017) · PeerJ · doi:10.7717/peerj.2986 · Cited by 41
Inflammation in stroke: the role of cholinergic, purinergic and glutamatergic signaling
Martín, A., Domercq, M., & Matute, C. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418774267 · Cited by 40
A new hypothesis for the pathophysiology of complex regional pain syndrome
Russo, M. A., Georgius, P., & Santarelli, D. M. (2018) · Medical Hypotheses · doi:10.1016/j.mehy.2018.07.026 · Cited by 43
Falvey, A., Metz, C. N., Tracey, K. J., & Pavlov, V. A. (2021) · International Immunology · doi:10.1093/intimm/dxab068 · Cited by 40
Self-citationHajiasgharzadeh, K., Mirnajafi‐Zadeh, J., & Mani, A. R. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.10.013 · Cited by 40
İlçöl, Y. Ö., Yılmaz, Z., Cansev, M., & Ulus, İ. H. (2009) · Shock · doi:10.1097/shk.0b013e3181971b02 · Cited by 40
“endotoxin; that is, nicotinic cholinergic activation reduces the inflammation (21, 22), whereas muscarinic cholinergic activation enhances it (32Y33).”
BackgroundWang, J., Chen, F., Zheng, P., Deng, W., Yuan, J., Peng, B., Wang, R., Liu, W., Zhao, H., Wang, Y.-Q., et al. (2012) · Experimental Neurology · doi:10.1016/j.expneurol.2012.03.024 · Cited by 41
Jae, S. Y., Heffernan, K. S., Yoon, E. S., Lee, M., Fernhall, B., & Park, W. H. (2009) · Molecular Medicine · doi:10.2119/molmed.2009.00057 · Cited by 40
Costantini, T. W., Dang, X., Yurchyshyna, M. V., Coimbra, R. S. M., Eliceiri, B. P., & Baird, A. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00018 · Cited by 40
Hashimoto, T., Ichiki, T., Watanabe, A., Hurt‐Camejo, E., Michaëlsson, E., Ikeda, J., Inoue, E., Matsuura, H., Tokunou, T., Kitamoto, S., et al. (2014) · Vascular Pharmacology · doi:10.1016/j.vph.2014.03.006 · Cited by 39
“It has been well known that endogenous anti-inflammatory humoral mechanisms prevent excessive inflammatory responses and maintain homeostasis [6].”
BackgroundComplementary and Alternative Interventions in Atopic Dermatitis
Lee, J.-H., & Bielory, L. (2010) · Immunology and Allergy Clinics of North America · doi:10.1016/j.iac.2010.06.006 · Cited by 39
Hypothalamic inflammation and the central nervous system control of energy homeostasis
Pimentel, G. D., Ganeshan, K., & Carvalheira, J. B. C. (2014) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2014.06.005 · Cited by 42
von Känel, R., Barth, J., Kohls, S., Saner, H. E., Znoj, H., Saner, G., & Schmid, J. (2009) · Journal of Cardiology · doi:10.1016/j.jjcc.2008.11.008 · Cited by 45
Dissection of N,N-diethyl-N′-phenylpiperazines as α7 nicotinic receptor silent agonists
Quadri, M., Papke, R. L., & Horenstein, N. A. (2015) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2015.12.017 · Cited by 43
Neuroimmune Interactions in Inflammation and Acute Kidney Injury
Inoue, T., Tanaka, S., & Okusa, M. D. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00945 · Cited by 39
“Brain Behav Immun (2007) 21(6):736–45.”
InfluentialThe nicotinic acetylcholine receptor α7 subunit is an essential negative regulator of bone mass
Mito, K., Sato, Y., Kobayashi, T., Miyamoto, K., Nitta, E., Iwama, A., Matsumoto, M., Nakamura, M., Sato, K., & Miyamoto, T. K. (2017) · Scientific Reports · doi:10.1038/srep45597 · Cited by 39
Chen, Z., Liu, X., & Kenny, P. J. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106860 · Cited by 42
“For example, activation of α 7 nAChRs on resident macrophages leads to an anti-inflammatory response that is likely to influence the activity of hypothalamic feeding circuits and pancreatic inlets [102,103].”
Mineur, Y. S., & Picciotto, M. R. (2023) · Journal of Neurochemistry · doi:10.1111/jnc.15943 · Cited by 38
Schmidt, J. M., Sow, D., Crimmins, M., Albers, D. J., Agarwal, S., Claassen, J., Connolly, E. S., Elkind, M. S. V., Hripcsak, G. M., & Mayer, S. A. (2014) · Neurocritical Care · doi:10.1007/s12028-014-9966-y · Cited by 38
“This leads to reductions in HRV [6] that reliably precede the onset of the systemic inflammatory response syndrome (SIRS) [7, 8].”
BackgroundGiuliani, D., Ottani, A., Neri, L., Zaffe, D., Grieco, P., Jochem, J., Cavallini, G. M., Catania, A., & Guarini, S. (2017) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.11.004 · Cited by 38
Maldifassi, M. C., Martín-Sánchez, C., Atienza, G., Cedillo, J. L., Arnalich, F., Bordas, A., Zafra, F., Giménez, C., Rueda-Extremera, M., Renart, J., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003443 · Cited by 38
Roesner, J. P., Petzelbauer, P., Koch, A. H., Tran, N., Iber, T., Vagts, D. A., Scheeren, T., Vollmar, B., Nöldge-Schomburg, G. E. F., & Zacharowski, K. D. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181959a12 · Cited by 38
“This increases the myocardial oxygen demand to a level that cannot be achieved (3, 4).”
BackgroundAntagonism of α2A-adrenoceptor: a novel approach to inhibit inflammatory responses in sepsis
Zhang, F., Wu, R., Qiang, X., et al. (2009) · Journal of Molecular Medicine · doi:10.1007/s00109-009-0555-z · Cited by 38
“It is now widely accepted that the vagus nerve can inhibit the proinflammatory response [20, 21].”
Cecal Ligation and Puncture Alters Glucocorticoid Receptor Expression
Abraham, M. N., Jimenez-Harrison, D., Fernandes, T., & Deutschman, C. S. (2018) · Critical Care Medicine · doi:10.1097/ccm.0000000000003201 · Cited by 38
Charlie‐Silva, I., Araújo, A. P. C., Guimarães, A. T. B., Veras, F. P., Braz, H. L. B., de Pontes, L. G., Jorge, R. J. B., Belo, M. A. D. A., Fernandes, B. H. V., Nóbrega, R. H., et al. (2021) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2021.126463 · Cited by 41
“As discussed by Osman (2020), CAP constitutes a neural mechanism that modulates inflammation through the release of acetylcholine (ACh), that have led to increased AChE synthesis to decompose higher levels of this neurotransmitter [see details in Tracey (2007)].”
Artificial and human intelligence for early identification of neonatal sepsis
Sullivan, B. A., Kausch, S. L., & Fairchild, K. D. (2022) · Pediatric Research · doi:10.1038/s41390-022-02274-7 · Cited by 43
Illanes, S., Liesz, A., Sun, L., et al. (2010) · Neuroscience Letters · doi:10.1016/j.neulet.2010.11.065 · Cited by 37
Tian, H., Sun, T., Dong, H., Wang, T., Li, Z., Han, S., Qi, Z., Dong, Z., Lv, C., & Wang, X. (2014) · International Urology and Nephrology · doi:10.1007/s11255-014-0747-5 · Cited by 37
Tapking, C., Popp, D., Herndon, D. N., Branski, L. K., Hundeshagen, G., Armenta, A. M., Busch, M., Most, P., & Kinsky, M. P. (2019) · Shock · doi:10.1097/shk.0000000000001465 · Cited by 39
“As shown by the work of Tracey et al, one potential therapeutic target to control excessive production of inflammatory cytokines such as TNF-a, IL-1b, and IL-6 is the ‘‘Cholinergic anti-inflammatory pathway’’ (128, 129).”
MethodOttani, A., Giuliani, D., Galantucci, M., Spaccapelo, L., Novellino, E., Grieco, P., Jochem, J., & Guarini, S. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.03.052 · Cited by 38
Deficiency of α7 Cholinergic Receptors Facilitates Bacterial Clearance inEscherichia coliPeritonitis
Giebelen, I. A. J., Moine, A. L., van den Pangaart, P. S., Sadis, C., Goldman, M., Florquin, S., & van der Poll, T. (2008) · The Journal of Infectious Diseases · doi:10.1086/590432 · Cited by 36
Vagal stimulation in brain dead donor rats decreases chronic allograft nephropathy in recipients
Hoeger, S., Fontana, J., Jarczyk, J., Selhorst, J., Waldherr, R., Krämer, B. K., Schnuelle, P., & Yard, B. A. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft451 · Cited by 37
“It is of eminent importance in the cholinergic anti-inflammatory pathway, also referred as inflammatory reflex [1].”
BackgroundLi, D., Liu, J., Liu, B., et al. (2010) · Journal of Cellular Physiology · doi:10.1002/jcp.22424 · Cited by 37
“Recent studies have shown that in immune cells, especially macrophages, a7-nAChR plays a key role in the cholinergic modulation of TNF-a expression (Ulloa, 2005; Cai et al., 2009).”
BackgroundInterorgan communication networks in the kidney–lung axis
Komaru, Y., Bai, Y. Z., Kreisel, D., & Herrlich, A. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00760-7 · Cited by 42
“…above, afferent vagal nerve fibres sense peripheral inflammation and efferent cholinergic vagal signals induce the release of anti-inflammatory factors, including IL-10, and blunt the release of pro-inflammatory cytokines from α7nAChR + splenic immune cells, particularly CD4 + T cells 60 .”
Sepsis Immunopathology: Perspectives of Monitoring and Modulation of the Immune Disturbances
Skirecki, T., Zielińska-Borkowska, U., Złotorowicz, M., & Hoser, G. (2012) · Archivum Immunologiae et Therapiae Experimentalis · doi:10.1007/s00005-012-0166-1 · Cited by 37
Wu, S., Li, Y., Shi, Z., Lin, Z., Rao, Z., Tai, S., Chu, M., Li, L., & Lin, J. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.006510 · Cited by 36
“It is well established that the beneficial effects of the CAP are mediated by acetylcholine receptors.(13,14) In addition, the a7nicotinic acetylcholine receptor (a7-nAChR) subunit, which plays a crucial role in CAP, is expressed widely on the surface of inflammatory cells, and it significantly influences the antiinfl…”
BackgroundAnnoni, E. M., Helden, D. A. V., Guo, Y. Y., Levac, B., Libbus, I., KenKnight, B. H., Osborn, J. W., & Tolkacheva, E. G. (2019) · Frontiers in Physiology · doi:10.3389/fphys.2019.00025 · Cited by 37
“Several studies have demonstrated the ability of VNS to reduce systemic inflammation through the activation of the cholinergic antiinflammatory pathway, reducing cytokine synthesis and the inflammatory response (Tracey, 2007; Zhang et al., 2009).”
BackgroundRole of neurons in the control of immune defense
Hoffman, C. L., & Aballay, A. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.04.005 · Cited by 36
Fernández-Cabezudo, M. J., Lorke, D. E., Azimullah, S., Mechkarska, M., Hasan, M. Y., Petroianu, G. A., & al-Ramadi, B. K. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03238.x · Cited by 36
The Stressed Host Response to Infection: The Disruptive Signals and Rhythms of Systemic Inflammation
Lowry, S. F. (2009) · Surgical Clinics of North America · doi:10.1016/j.suc.2008.09.004 · Cited by 36
“A reduction in parasympathetic activity may be associated with diminished capacity to exert vagal cholinergic control over proinflammatory mediator activity.(44) Reductions in implied vagal nerve activity have now been noted during inflammatory conditions associated with endotoxinemic conditions in humans(45) and in e…”
BackgroundGHRELIN HYPORESPONSIVENESS CONTRIBUTES TO AGING-RELATED HYPERINFLAMMATION IN SEPTIC SHOCK
Wu, R.-Q., Zhou, M., Dong, W., Ji, Y.-X., Miksa, M., Marini, C., Ravikumar, T., & Wang, P. (2009) · Annals of Surgery · doi:10.1097/sla.0b013e3181ad85d6 · Cited by 37
“An underlying defect in the activity of the cholinergic anti-inflammatory pathway may trigger an overwhelming and self-destructive immune response to an otherwise innocuous immunologic stimulus and thus contribute to disease pathogenesis.(41,42) Although it is not currently known whether vagus nerve activity in the he…”
BackgroundAnti-Inflammatory Properties of CB1-Receptor Antagonist Involves β2 Adrenoceptors
Mnich, S. J., Hiebsch, R. R., Huff, R. M., et al. (2010) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.109.163998 · Cited by 36
“4a demonstrated that ablation of the parasympathetic nervous system and the anti-inflammatory activity, thought to be mediated by cholinergic neurons (Tracey, 2007), does not alter the effectiveness of our CB1-receptor antagonist.”
BackgroundWang, S., Peng, L., Gai, Z., Zhang, L., Jong, A., Cao, H., & Huang, S. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00148 · Cited by 42
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
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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
Are you an author, or do you see a problem with this page? Request a review
