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 501–600 of 996
Hou, L., Rong, P., Yang, Y., Fang, J., Wang, J., Wang, Y., Zhang, J., Zhang, S., Zhang, Z., Chen, J. D. Z., et al. (2023) · Brain Sciences · doi:10.3390/brainsci13020253 · Cited by 35
“Ach interacts with a-bungarotoxin-sensitive nicotinic receptors on tissue macrophages, which inhibit the NF-κBp65 signal inflammation pathway, then reduce the release of TNF, IL-1 and other cytokines [24,25].”
BackgroundHesampour, F., Bernstein, C. N., & Ghia, J. (2023) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izad211 · Cited by 38
The autonomic nervous system and inflammation in chronic kidney disease
Zoccali, C., Mallamaci, F., Kanbay, M., Tuttle, K. R., Kotanko, P., Caterina, R. D., Grassi, G. M., & Mancia, G. (2025) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gfaf020 · Cited by 38
Recent Developments in Chimeric NSAIDs as Safer Anti‐Inflammatory Agents
Suthar, S. K., & Sharma, M. (2014) · Medicinal Research Reviews · doi:10.1002/med.21331 · Cited by 35
Autonomic-mediated immunomodulation and potential clinical relevance
Benarroch, E. E. (2009) · Neurology · doi:10.1212/wnl.0b013e3181aebd43 · Cited by 35
Melanocortins as potential therapeutic agents in severe hypoxic conditions
Giuliani, D., Minutoli, L., Ottani, A., Spaccapelo, L., Bitto, A., Galantucci, M., Altavilla, D., Squadrito, F., & Guarini, S. (2012) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2012.04.001 · Cited by 35
Li, P., Liu, H., Sun, P., Wang, X., Wang, C., Wang, L., & Wang, T. (2015) · Experimental Gerontology · doi:10.1016/j.exger.2015.12.005 · Cited by 36
Coelho‐Júnior, H. J., Gambassi, B. B., Diniz, T. A., Fernandes, I. M. D. C., Caperuto, É. C., Uchida, M. C., Lira, F. S., & Rodrigues, B. (2016) · Mediators of Inflammation · doi:10.1155/2016/3957958 · Cited by 37
“Additionally, increase in muscle mass is associated with increase in physical function and mobility [134–136].”
BackgroundGastrointestinal neuroimmune disruption in a mouse model of Gulf War illness
Hernández, S., Fried, D. E., Grubišić, V., McClain, J. L., & Gulbransen, B. D. (2019) · The FASEB Journal · doi:10.1096/fj.201802572r · Cited by 35
“In support, activation of the vagus using nicotinic receptor agonists or AChE inhibitors reduces inflammation by suppressing cytokine synthesis (12, 17, 21, 48).”
MethodChoi, J.-H., Lee, E.-B., Jang, H., Cha, Y., Park, Y., & Lee, S. H. (2021) · Nutrients · doi:10.3390/nu13082890 · Cited by 38
“Studies on the physiology, functional anatomy, and cellular molecular mechanisms of cholinergic anti-inflammatory pathways have shown that key factors of cytokine suppression localize macrophages in the liver and spleen, and activate immediate early cytokine responses [39].”
BackgroundAutonomic tone and C-reactive protein: a prospective population-based study
Singh, P., Hawkley, L. C., McDade, T. W., Cacioppo, J. T., & Masi, C. M. (2009) · Clinical Autonomic Research · doi:10.1007/s10286-009-0019-0 · Cited by 35
“We expected a significant relationship between CRP and cardiac sympathetic tone because macrophage stimulation by epinephrine and norepinephrine can enhance the production of TNFa [8], an inducer of hepatocyte-derived CRP. Univariate analysis revealed a negative correlation between PEP (a negative measure of cardiac s…”
BackgroundInfluentialIncreased vagal modulation in atopic dermatitis
Boettger, M. K., Bär, K., Dohrmann, A., Müller, H. O., Mertins, L., Brockmeyer, N. H., & Agelink, M. W. (2008) · Journal of Dermatological Science · doi:10.1016/j.jdermsci.2008.08.003 · Cited by 36
“The described increase in parasympathetic outflow might reflect a counter-regulatory mechanism to help attenuating inflammation as described previously [11,12].”
BackgroundResultKovács, T., Varga, G., Érces, D., et al. (2012) · Shock · doi:10.1097/shk.0b013e31825d1ed0 · Cited by 35
“Another explanation is provided if orally administered PC serves as a slow-release blood choline source, and the choline component of PC is able to influence the inflammatory process through the cholinergic anti-inflammatory pathway (33), including interference with the activation of PMN leukocytes.”
BackgroundDoenlen, R., Krügel, U., Wirth, T., Riether, C., Engler, A., Prager, G., Engler, H., Schedlowski, M., & Pacheco‐López, G. (2010) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2010.2040 · Cited by 36
Doroszkiewicz, J., Mroczko, J., Winkel, I., & Mroczko, B. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm13175057 · Cited by 36
“Because melanocortins are located in the brainstem, they can reduce the expression of proinflammatory cytokines in endotoxemia, sepsis, and other inflammatory diseases by activating various anti-inflammatory pathways via the efferent vagal pathway [137,141,142].”
BackgroundLi, J., Mathieu, S., Harris, R., Ji, J., Anderson, D. J., Malysz, J., Bunnelle, W. H., Waring, J. F., Marsh, K. C., Murtaza, A., et al. (2011) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2011.08.007 · Cited by 35
“…by the central nervous system (CNS) through the cholinergic anti-inflammatory pathway, in which acetylcholine is released from vagus nerves (Tracey, 2002, 2007; Wang et al. 2003) and activates the post-synaptic alpha 7 receptor of in innervated tissues including splenic nerves following…”
BackgroundA neurotransmitter system that regulates macrophage pro-inflammatory functions
Reyes-García, M. G., & García-Tamayo, F. (2009) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2009.06.024 · Cited by 33
Valproic acid potentiates curcumin-mediated neuroprotection in lipopolysaccharide induced rats
Zaky, A., Mahmoud, M., Awad, D., Sabaa, B. M. E., Kandeel, K., & Bassiouny, A. R. (2014) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2014.00337 · Cited by 35
“It was found also that cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases (Tracey, 2007).”
BackgroundSun, R., Zhang, W., Bo, J., Zhang, Z., Lei, Y., Huo, W., Liu, Y., Ma, Z., & Gu, X. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.12.029 · Cited by 33
Westman, M., Saha, S., Morshed, M. M., & Lampa, J. (2010) · Clinical & Experimental Immunology · doi:10.1111/j.1365-2249.2010.04204.x · Cited by 37
Melanocortins and the Cholinergic Anti-Inflammatory Pathway
Giuliani, D., Ottani, A., Altavilla, D., Bazzani, C., Squadrito, F., & Guarini, S. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6354-3_6 · Cited by 34
Chi, F., Wang, L., Zheng, X., Wu, C., Jong, A., Sheard, M. A., Shi, W., & Huang, S. (2011) · PLoS ONE · doi:10.1371/journal.pone.0025016 · Cited by 34
“disorders [37].”
Jiang, J. H., Yang, E. J., Baek, M. G., Kim, S. H., Lee, S. M., & Choi, S. (2011) · Neurodegenerative Diseases · doi:10.1159/000327911 · Cited by 34
A Systems Engineering Perspective on Homeostasis and Disease
Yoram Vodovotz, B., An, G. C., & Androulakis, I. P. (2013) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2013.00006 · Cited by 34
Ueno, T., Ikeda, T., Ikeda, K., et al. (2009) · Journal of Surgical Research · doi:10.1016/j.jss.2009.11.708 · Cited by 34
“Tracey reported that 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 [24].”
BackgroundFeriani, D. J., Souza, G. I. H., Carrozzi, N. M., et al. (2016) · International Journal of Cardiology · doi:10.1016/j.ijcard.2016.10.061 · Cited by 34
Breivik, T. J., Gundersen, Y., Gjermo, P. E., von Hörsten, S., & Opstad, P. K. (2008) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.2008.01095.x · Cited by 34
Acute inflammatory response in the skin of gilthead seabream (Sparus aurata) caused by carrageenin
Campos‐Sánchez, J. C., Mayor-Lafuente, J., González‐Silvera, D., Guardiola, F. A., & Esteban, M. Á. (2021) · Fish & Shellfish Immunology · doi:10.1016/j.fsi.2021.10.009 · Cited by 35
“The inflammatory response may also be regulated through the release of acetylcholine (ACh) from the parasympathetic SNA terminals [80,81].”
Saccaro, L. F., Aimo, A., Emdin, M., & Pico, F. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.716316 · Cited by 34
Gravina, A. G., Pellegrino, R., Durante, T., Palladino, G., Imperio, G., D’Amico, G., Trotta, M. C., Dallio, M., Romeo, M., D’Amico, M., et al. (2023) · Cells · doi:10.3390/cells12141889 · Cited by 33
Vagal blockade of the brain-liver axis deters cancer-associated cachexia
Garrett, A., Darzi, N., Deshmukh, A., Rosenfeld, N., Goldman, O., Adler, L. N., Bab-Dinitz, E., Singer, O., Najafabadi, A. H., Wong, C. W., et al. (2025) · Cell · doi:10.1016/j.cell.2025.07.016 · Cited by 42
EFFECTS OF PHYSOSTIGMINE ON MICROCIRCULATORY ALTERATIONS DURING EXPERIMENTAL ENDOTOXEMIA
Peter, C., Schmidt, K., Hofer, S., Stephan, M., Martin, E., Weigand, M. A., & Walther, A. (2010) · Shock · doi:10.1097/shk.0b013e3181b77e82 · Cited by 33
Bychkov, M. L., Shenkarev, Z. O., Shulepko, M. A., Shlepova, O. V., Kirpichnikov, M. P., & Lyukmanova, E. N. (2019) · PLoS ONE · doi:10.1371/journal.pone.0217339 · Cited by 33
Association between Micronutrients and Heart Rate Variability: A Review of Human Studies
Lopresti, A. L. (2019) · Advances in Nutrition · doi:10.1093/advances/nmz136 · Cited by 37
“It is theorized that the autonomic nervous system via an inflammatory reflex of the vagus nerve (the primary nerve of the PNS), and involving the cholinergic anti-inflammatory pathway, is responsible for a quick reflexive response to inflammation (10).”
BackgroundDing, N., Wei, Q., Deng, W., et al. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/6673610 · Cited by 33
“As such, acupuncture may activate the CAP and the vagus nerve to release ACh and bind to α7nAChRs onmacrophages, thereby inhibiting the release of proinflammatory cytokines [14, 15].”
BackgroundJeong, J., & Park, S. (2015) · Oncotarget · doi:10.18632/oncotarget.4953 · Cited by 33
“Alpha-7 nicotinic acetylcholine receptors (α7nAchR), also known as α7 nicotinic receptors, are a family of nicotinic acetylcholine receptors that regulate long-term memory and consist entirely of α7 subunits [1-3].”
BackgroundNeurodegeneration and Neuroregeneration in Chagas Disease
Chuenkova, M. V., & PereiraPerrin, M. (2011) · Advances in Parasitology/Advances in parasitology · doi:10.1016/b978-0-12-385895-5.00009-8 · Cited by 33
“Finally, damaged vagus nerve, in a negative feedback manner, would decrease its anti-inflammatory reflex and further the inflammation in infected tissues by promoting release of pro-inflammatory cytokines, including TNF-a and IFN-g and extra amounts of NO (Tracey, 2007).”
BackgroundRana, A., Ahmed, M., Rub, A., & Akhter, Y. (2015) · Virulence · doi:10.1080/21505594.2015.1062211 · Cited by 33
Dang, X., Eliceiri, B. P., Baird, A., & Costantini, T. W. (2015) · The FASEB Journal · doi:10.1096/fj.14-268037 · Cited by 34
Kiguchi, N., Kobayashi, Y., Maeda, T., Tominaga, S., Nakamura, J., Fukazawa, Y., Ozaki, M., & Kishioka, S. (2012) · Neurochemistry International · doi:10.1016/j.neuint.2012.09.001 · Cited by 34
Peripheral Neural Detection of Danger–Associated and Pathogen–Associated Molecular Patterns
Ackland, G. L., Kazymov, V., Marina, N., Singer, M., & Gourine, A. V. (2013) · Critical Care Medicine · doi:10.1097/ccm.0b013e31827c0b05 · Cited by 33
“In concert with peripheral immune cell signaling, neural mechanisms orchestrate the inflammatory response via autonomic-immune effector pathways (3).”
BackgroundSun, Z., Xiang, Y.-X., Wang, W.-X., Xue, Z., Zhu, L., & Wang, S.-B. (2015) · Neural Regeneration Research · doi:10.4103/1673-5374.155430 · Cited by 33
“Recent studies have shown that VNS may also have a neuroprotective effect in ischemic brain injury (Masada et al., 1996b; Miyamoto et al., 2003; Tracey, 2007; Sun et al., 2012).”
BackgroundPotential effects of stress in critical illness through the role of stress neuropeptides
Papathanassoglou, E. D. E., Giannakopoulou, M. D., Mpouzika, M. D. A., Bozas, E., & Karabinis, A. (2010) · Nursing in Critical Care · doi:10.1111/j.1478-5153.2010.00363.x · Cited by 33
Psychological Distress and Cardiovascular Risk
von Känel, R. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2008.09.015 · Cited by 33
“In spite of these uncertainties, the results from the study by Hamer et al. (15) encourage clinicians to consider behavioral interventions to target intermediate pathways linking psychological distress with CVD manifestation (13, 14 ).”
BackgroundResultInfluentialVagal function indexed by respiratory sinus arrhythmia and cholinergic anti-inflammatory pathway
Tonhajzerová, I., Mokrá, D., & Višňovcová, Z. (2013) · Respiratory Physiology & Neurobiology · doi:10.1016/j.resp.2013.02.002 · Cited by 32
Minutoli, L., Bitto, A., Squadrito, F., Irrera, N., Rinaldi, M., Nicòtina, P. A., Arena, S., Magno, C., Marini, H. R., Spaccapelo, L., et al. (2011) · Endocrinology · doi:10.1210/en.2011-1016 · Cited by 33
“These endogenous peptides, such as ACTH [ACTH-(1-24)], -MSH, shorter fragments, and synthetic analogs as NDP-MSH, modulate the inflammatory response in several conditions, including low-flow states, such as circulatory shock, myocardial ischemia, and ischemic stroke (20, 21, 23, 37).”
BackgroundYin, Q., Wu, Y., Pan, S., et al. (2020) · Drug Design Development and Therapy · doi:10.2147/dddt.s249865 · Cited by 32
Transdermal auricular vagus stimulation for the treatment of postural tachycardia syndrome
Diedrich, A., Urechie, V., Shiffer, D., Rigo, S., Minonzio, M., Cairo, B., Smith, E. C., Okamoto, L. E., Barbic, F., Bisoglio, A., et al. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102886 · Cited by 36
1914G variant of BCHE gene associated with enzyme activity, obesity and triglyceride levels
Lima, J. K., Leite, N., Tureck, L. V., et al. (2013) · Gene · doi:10.1016/j.gene.2013.08.068 · Cited by 32
Taché, Y., & Bernstein, C. N. (2009) · Gastroenterology · doi:10.1053/j.gastro.2009.04.032 · Cited by 32
Emerging concepts in ventilation-induced lung injury
Madahar, P., & Beitler, J. R. (2020) · F1000Research · doi:10.12688/f1000research.20576.1 · Cited by 33
Mabley, J. G., Packer, P., & Szabó, C. (2009) · Molecular Medicine · doi:10.2119/molmed.2008.00105 · Cited by 32
Myasthenia Gravis and the Tops and Bottoms of AChRs
Lindstrom, J. M., Luo, J., & Kuryatov, A. (2008) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1405.007 · Cited by 32
Visceral massage reduces postoperative ileus in a rat model
Chapelle, S. L., & Bove, G. M. (2012) · Journal of Bodywork and Movement Therapies · doi:10.1016/j.jbmt.2012.05.004 · Cited by 31
“…decreases intraperitoneal inflammation by inhibitory actions that have been collectively called the " inflammatory reflex " (for reviews, see Tracey, 2002, 2007, and Van Der Zanden et al., 2009), and has been shown to ameliorate postoperative ileus (de Jonge et al., 2005; The et al., 2007).”
BackgroundRodrigues, B., Lira, F. S., Consolim‐Colombo, F. M., Rocha, J. A., Caperuto, É. C., Angelis, K. D., & Irigoyen, M. C. (2014) · Mediators of Inflammation · doi:10.1155/2014/702473 · Cited by 31
“Clinical and experimental evidence, or lack of them, regarding relationship between alterations on cardiac autonomic regulation and local or systemic inflammation response after MI will be discussed.”
BackgroundSun, R., Liu, Y., Hou, B., Lei, Y., Bo, J., Zhang, W., Sun, Y., Zhang, Y., Zhang, Z., Liu, Z., et al. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.02.017 · Cited by 31
Dumortier, L., & Bricout, V. (2019) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2019.10.018 · Cited by 33
Moriyama, K., Kato, Y., Hasegawa, D., et al. (2020) · Journal of Artificial Organs · doi:10.1007/s10047-020-01173-0 · Cited by 31
Sarin-induced brain damage in rats is attenuated by delayed administration of midazolam
Chapman, S., Yaakov, G., Egoz, I., et al. (2015) · NeuroToxicology · doi:10.1016/j.neuro.2015.05.001 · Cited by 31
Disorders of the Cholinergic System in COVID-19 Era—A Review of the Latest Research
Kopańska, M., Batoryna, M., Bartman, P., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23020672 · Cited by 31
“They did not find any significant expression of the native CHRNA7 subunit, which was not surprising since the expression of the native CHRNA7 subunit is mostly present in the neuronal system and resident cells and much less in the non-neuronal system, especially in the circulating cells [15,16].”
BackgroundSARS-CoV-2 spike ectodomain targets α7 nicotinic acetylcholine receptors
O’Brien, B. C. V., Weber, L., Hueffer, K., & Weltzin, M. M. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104707 · Cited by 34
“Activation of α 7 nAChRs in the cholinergic anti-in fl ammatory pathway suppresses the production of pro-in fl ammatory cytokines (81 – 83).”
Nicolussi, E.-M., Huck, S., Lassmann, H., & Bradl, M. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.03.010 · Cited by 31
“At first glance, these results look contradictory, especially in light of other findings supporting a role of cholinergic anti-inflammatory signalling in sepsis, hemorrhagic shock, reperfusion injury, pancreatitis, experimental arthritis, and ileus (for review see Tracey, 2007).”
ResultRiley, T. P., Neal‐McKinney, J. M., Buelow, D. R., Konkel, M. E., & Simasko, S. M. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2013.01.009 · Cited by 31
“in regulating inflammatory responses in the intestinal tract has been demonstrated (Borovikova et al., 2000; Tracey, 2007; van der Zanden et al., 2009); leading to the concept of a vagally dependent cholinergic anti-inflammatory pathway (Tracey, 2002).”
Transdermal Nicotine Treatment and Progression of Early Parkinson’s Disease
Oertel, W. H., Müller, H., Unger, M. M., Schade‐Brittinger, C., Balthasar, K., Articus, K., Brinkman, M., Venuto, C. S., Tracik, F. M., Eberling, J. L., et al. (2023) · NEJM Evidence · doi:10.1056/evidoa2200311 · Cited by 30
Device Therapy to Modulate the Autonomic Nervous System to Treat Heart Failure
Lopshire, J. C., & Zipes, D. P. (2012) · Current Cardiology Reports · doi:10.1007/s11886-012-0292-8 · Cited by 30
Protective effects of melanocortins on short-term changes in a rat model of traumatic brain injury*
Bitto, A., Polito, F., Irrera, N., Calò, M., Spaccapelo, L., Marini, H. R., Giuliani, D., Ottani, A., Rinaldi, M., Minutoli, L., et al. (2011) · Critical Care Medicine · doi:10.1097/ccm.0b013e318236efde · Cited by 29
“In our present investigation, in TBI rats, we detected high serum levels of IL-6 and HMGB-1, which correlate with trauma severity and may be responsible for systemic responses that could involve other organs; particularly, HMGB-1 is a key mediator of systemic inflammation, and it is considered a necessary and sufficie…”
BackgroundRetractedNeuroimmune aspects of food intake
Bienenstock, J., Forsythe, P., Karimi, K., & Kunze, W. (2009) · International Dairy Journal · doi:10.1016/j.idairyj.2009.12.002 · Cited by 30
Thirdhand smoke component can exacerbate a mouse asthma model through mast cells
Yu, M., Mukai, K., Tsai, M. M., & Galli, S. J. (2018) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2018.04.001 · Cited by 30
Immunopharmacological aspects of the cytokine system
Simbirtsev, A. S. (2019) · Bulletin of Siberian Medicine · doi:10.20538/1682-0363-2019-1-84-95 · Cited by 32
“90 заболеваний [16, 17] и понятие цитокин-опосредованных заболеваний.”
Acetylcholinesterase inhibitors in Alzheimer's disease influence Zinc and Copper homeostasis
Giacconi, R., Giuli, C., Casoli, T., Balietti, M., Costarelli, L., Provinciali, M., Basso, A., Piacenza, F., Postacchini, D., Galeazzi, R., et al. (2019) · Journal of Trace Elements in Medicine and Biology · doi:10.1016/j.jtemb.2019.06.001 · Cited by 30
Kobrzycka, A. T., Napora, P., Pearson, B. L., Pierzchała, K., Szewczyk, R., & Wieczorek, M. (2019) · Journal of Neuroinflammation · doi:10.1186/s12974-019-1544-y · Cited by 28
Jo, B. G., Kim, S., & Namgung, U. (2020) · Molecular Medicine · doi:10.1186/s10020-020-00247-2 · Cited by 31
“The vagus nerve transmits neural activity originated from the central nervous system into the innate and adaptive immune cells in the visceral organs and regulates their pathophysiological function (Tracey 2007; Bonaz et al.”
BackgroundCardiorespiratory Fitness, Inflammation, and the Incident Risk of Pneumonia
Jae, S. Y., Heffernan, K. S., Kurl, S., Kunutsor, S. K., Kim, C., Johnson, B. D., Franklin, B. A., & Laukkanen, J. A. (2021) · Journal of Cardiopulmonary Rehabilitation and Prevention · doi:10.1097/hcr.0000000000000581 · Cited by 29
Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury
Bassi, T. G., Rohrs, E. C., Fernandez, K. C., et al. (2021) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.202101-0076oc · Cited by 30
“The hippocampal inflammation observed in the mechanically ventilated groups might have been triggered by the activation of the neuroimmunological reflex (32, 33).”
BackgroundInfluentialPohanka, M., Snopková, S., Havlíčková, K., Boštík, P., Šinkorová, Z., Fusek, J., Kuča, K., & Pikula, J. (2011) · Current Medicinal Chemistry · doi:10.2174/092986711794480140 · Cited by 30
“In this regard, the CAP is an important part of immunity that can be easily stimulated by drugs [127-129].”
BackgroundThe Pathophysiology of Septic Shock
Nduka, O. O., & Parrillo, J. E. (2011) · Critical Care Nursing Clinics of North America · doi:10.1016/j.ccell.2010.12.003 · Cited by 38
“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.”
BackgroundNovel nervous system mechanisms in visceral pain
Winter, B. Y. D., Deiteren, A., & Man, J. G. D. (2016) · Neurogastroenterology & Motility · doi:10.1111/nmo.12785 · Cited by 30
Hypnotherapy for Inflammatory Bowel Disease Across the Lifespan
Szigethy, E. (2015) · American Journal of Clinical Hypnosis · doi:10.1080/00029157.2015.1040112 · Cited by 31
“It has been hypothesized that these anti-inflammatory effects of hypnotherapy may be related to increases in vagal parasympathetic activity, a known anti-inflammatory pathway (Andersson & Tracey, 2012; Bonaz & Bernstein, 2013; Tracey, 2007).”
BackgroundÇetınkaya, M., Cansev, M., Çekmez, F., et al. (2012) · Journal of Surgical Research · doi:10.1016/j.jss.2012.11.032 · Cited by 29
“[45] Tracey KJ.”
BackgroundLow cardiac vagal tone index by heart rate variability differentiates bipolar from major depression
Hage, B., Britton, B., Daniels, D., Heilman, K., Porges, S., & Halaris, A. (2019) · World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1376113 · Cited by 29
“Vagal nerve efferent inputs regulating inflammation via the cholinergic anti-inflammatory pathway (CAIP) are well documented (Pavlov and Tracey 2009; Tracey 2007), and measurements of inflammatory biomarkers in mood disorders can differentiate at least some of these patients from healthy subjects…”
BackgroundInfluentialSepsis in the critically ill patient: current and emerging management strategies
Heming, N., Azabou, É., Cazaumayou, X., Moine, P., & Annane, D. (2020) · Expert Review of Anti-infective Therapy · doi:10.1080/14787210.2021.1846522 · Cited by 32
Cell Senescence and Central Regulators of Immune Response
Lunin, S. M., Novoselova, E. G., Glushkova, O. V., Parfenyuk, S. B., Novoselova, T. V., & Khrenov, M. O. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23084109 · Cited by 28
“In contrast, the parasympathetic nervous system inhibits the activity of the immune system and inflammation [81,82], thus completing the so-called immune reflex.”
BackgroundNeuronal regulation of innate lymphoid cell responses
Yano, H., & Artis, D. (2022) · Current Opinion in Immunology · doi:10.1016/j.coi.2022.102205 · Cited by 28
Percutaneous Auricular Vagus Nerve Stimulation Reduces Inflammation in Critical Covid-19 Patients
Seitz, T., Széles, J. C., Kitzberger, R., Holbik, J., Grieb, A., Wolf, H. M., Akyaman, H., Lucny, F., Tychera, A., Neuhold, S., et al. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.897257 · Cited by 33
“The vagus nerve is involved in multiple pathways within immune reflexes: the anti-inflammatory hypothalamic-pituitary-adrenal axis (HPAA) and the cholinergic anti-inflammatory pathway (ChAIP) (Borovikova et al., 2000; Tracey, 2007; Bonaz, Sinniger and Pellissier, 2016).”
BackgroundNicotinic acetylcholine receptor activation reduces skeletal muscle inflammation of mdx mice
Leite, P. E. C., Lagrota-Cândido, J., Moraes, L., D'Elia, L., Pinheiro, D. F., da Silva, R. F., Yamasaki, E. N., & Quírico‐Santos, T. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.06.005 · Cited by 29
“The nAChRα7 subunit is considered a regulator of macrophage/monocyte activation for the release of molecules (TNFα, IL-1β, HMGB1) involved in inflammatory responses and apoptotic pathways (Pavlov and Tracey, 2005; Tracey, 2007; Ulloa, 2005; Wang et al., 2003; Yoshikawa et al., 2006).”
BackgroundSallam, M. Y., El‐Gowilly, S. M., El‐Gowelli, H. M., El‐Lakany, M. A., & El‐Mas, M. M. (2018) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2018.07.008 · Cited by 30
Loss of vagal tone aggravates systemic inflammation and cardiac impairment in endotoxemic rats
Schulte, A., Lichtenstern, C., Henrich, M., Weigand, M. A., & Uhle, F. (2014) · Journal of Surgical Research · doi:10.1016/j.jss.2014.01.022 · Cited by 30
“Electrical stimulation of the efferent vagal nerve fibers with low frequency is supposed to own anti-inflammatory properties and is able to activate the “cholinergic anti-inflammatory reflex” [24].”
The physiological significance and potential clinical applications of ghrelin
Akamizu, T., & Kangawa, K. (2011) · European Journal of Internal Medicine · doi:10.1016/j.ejim.2011.12.001 · Cited by 28
“Although the molecular mechanisms and cellular targets mediating ghrelin inhibition of NFκB activation remain to be determined, the vagus nerve may play an important role in the ghrelin-mediated inhibition of proinflammatory cytokine release [50,54].”
BackgroundKiss, P., Vadasz, G., Kiss-Illes, B., Horváth, G., Tamás, A., Reglődi, D., & Koppán, M. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms141122258 · Cited by 28
“Also, extensive research has recently been focused on a potential link between the immune and neuronal systems, mainly in the context of pathogenesis, in which sustained or excessive inflammation has been associated with neurotoxicity and several neuropathologies [15–18].”
Therapeutic applications of ghrelin to cachexia utilizing its appetite-stimulating effect
Akamizu, T., & Kangawa, K. (2011) · Peptides · doi:10.1016/j.peptides.2011.05.018 · Cited by 27
Yılmaz, Z., Özarda, Y., Cansev, M., Eralp, O., KOCATÜRK, M., & Ulus, İ. H. (2010) · Blood Coagulation & Fibrinolysis · doi:10.1097/mbc.0b013e328338ce31 · Cited by 28
Meta-analysis: Tobacco smoking may enhance the risk of acute pancreatitis
Sun, X., Huang, X., Zhao, R., Chen, B., & Xie, Q. (2015) · Pancreatology · doi:10.1016/j.pan.2015.03.001 · Cited by 27
Mapping the immunological homunculus
Diamond, B., & Tracey, K. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1100329108 · Cited by 28
“These intriguing findings provide a glimpse into the future, when it is likely that sensory and motor brain regions associated with immune responses will be mapped as an immunological homunculus (2).”
BackgroundSelf-citationHanes, W. M., Olofsson, P. S., Kwan, K., Hudson, L., Chavan, S. S., Pavlov, V. A., & Tracey, K. J. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00142 · Cited by 27
Self-citationvon Känel, R., Thayer, J. F., & Fischer, J. E. (2009) · Annals of Noninvasive Electrocardiology · doi:10.1111/j.1542-474x.2009.00293.x · Cited by 28
A review on oxidative stress in organophosphate-induced neurotoxicity
Lorke, D. E., & Öz, M. (2025) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2025.106735 · Cited by 33
Ancient Neurons Regulate Immunity
Tracey, K. J. (2011) · Science · doi:10.1126/science.1206353 · Cited by 27
Self-citationSchmeltz, L. R., Blevins, T., Aronoff, S. L., Özer, K., Leffert, J. D., Goldberg, M. A., Horowitz, B. S., Bertenshaw, R. H., Troya, P., Cohen, A. E., et al. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2013-2951 · Cited by 28
Deepika, A., Devi, B. I., Shukla, D. P., et al. (2018) · Journal of Neurotrauma · doi:10.1089/neu.2017.5151 · Cited by 27
Gauthier, A. G., Lin, M., Wu, J., Kennedy, T. P., Daley, L.-A., Ashby, C. R., & Mantell, L. L. (2021) · Journal of Immunotoxicology · doi:10.1080/1547691x.2021.1875085 · Cited by 28
“…the risk of severe COVID-19, nicotine has anti-inflammatory efficacy which activates the cholinergic anti- inflammatory pathway by stimulating a7 nicotinic cholinergic receptors (a7nAChR) (Borovikova et al. 2000; Tracey 2007; Ni et al. 2011; Hartmann-Boyce and Lindson 2020; Tindle et al. 2020).”
Background
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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