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 801–900 of 996
Setting Our Own Terms: How We Used Ritual to Become Human
Rossano, M. J. (2011) · Studies in neuroscience, consciousness and spirituality · doi:10.1007/978-94-007-2079-4_3 · Cited by 15
Editorial: Hemopexin: newest member of the anti-inflammatory mediator club
Fink, M. P. (2009) · Journal of Leukocyte Biology · doi:10.1189/jlb.0309137 · Cited by 15
Fazeli, M. S., Pourrahmat, M., Massah, G., Lee, K., Lavoie, P. M., Fazeli, M., Alison Esser, R., & Collet, J. (2020) · International Journal of Therapeutic Massage & Bodywork Research Education & Practice · doi:10.3822/ijtmb.v13i3.501 · Cited by 14
The role of microRNAs in nicotine signaling
Hajiasgharzadeh, K., Naghipour, B., Shahabi, P., Dastmalchi, N., & Alipour, M. R. (2023) · EXCLI journal · doi:10.17179/excli2023-6096 · Cited by 14
Cantone, A. F., Burgaletto, C., Benedetto, G. D., Pannaccione, A., Secondo, A., Bellanca, C. M., Augello, E., Munafò, A., Tarro, P., Bernardini, R., et al. (2024) · Cells · doi:10.3390/cells13040309 · Cited by 14
“Studies conducted using antisense oligonucleotides of the α 7 subunit revealed α 7 nAChR as the main player of the above-mentioned process [32], shedding light on its role in orchestrating the choline-mediated anti-inflammatory effects [33–36].”
BackgroundUpdating functional brain units: Insights far beyond Luria
Peña‐Casanova, J., Sánchez‐Benavides, G., & Sigg-Alonso, J. (2024) · Cortex · doi:10.1016/j.cortex.2024.02.004 · Cited by 16
Heart Rate Variability, Deceleration Capacity of Heart Rate, and Death: A Veteran Twins Study
Huang, M., Shah, A. J., Lampert, R. J., Bliwise, D. L., Johnson, D. A., Clifford, G. D., Sloan, R. P., Goldberg, J. H., Ko, Y., Poian, G. D., et al. (2024) · Journal of the American Heart Association · doi:10.1161/jaha.123.032740 · Cited by 19
“The vagus, in particular, is involved in the regulation of the inflammatory reflex through the cholinergic anti-inflammatory pathway, 56 and HRV metrics indexing vagal function have been inversely associated There were 55 discordant pairs for mortality in the within-pair analysis.”
Recent Data about the Use of Corticosteroids in Sepsis—Review of Recent Literature
Lazăr, A. E. (2024) · Biomedicines · doi:10.3390/biomedicines12050984 · Cited by 17
“The management of inflammation involves a complex interaction between the neuroendocrine and immune systems [9].”
BackgroundGupta, A., & Agarwal, V. (2024) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-024-03205-5 · Cited by 15
“The CAP necessitates the involvement of the vagus nerve and α7nAChR receptors (Tracey 2007).”
Inhibition of Allergen-Induced Basophil Activation by ASM-024, a Nicotinic Receptor Ligand
Watson, B. M., Oliveria, J. P., Nusca, G. M., Smith, S. G., Beaudin, S., Dua, B., Watson, R. M., Assayag, E. I., Cormier, Y. F., Sehmi, R., et al. (2014) · International Archives of Allergy and Immunology · doi:10.1159/000370068 · Cited by 14
Ay, İ., & Ay, H. (2012) · Autonomic Neuroscience · doi:10.1016/j.autneu.2012.12.001 · Cited by 14
“Such mechanisms may include inhibition of neuronal excitability (Zagon et al., 2000), activation of anti-inflammatory pathways (Tracey, 2007), and inhibition of excitotoxicity (Miyamoto et al., 2003).”
BackgroundBrevetoxin-2 induces an inflammatory response in an alveolar macrophage cell line
Sas, K. M., & Baatz, J. E. (2010) · International Journal of Hygiene and Environmental Health · doi:10.1016/j.ijheh.2010.06.007 · Cited by 14
Integrated Multimorbidity Management in Primary Care: Why, What, How, and How To?
Sturmberg, J. P., Botelho, R. J., & Kissling, B. (2016) · Journal of Comorbidity · doi:10.15256/joc.2016.6.95 · Cited by 14
Pinder, N., Bruckner, T. M., Lehmann, M., Motsch, J., Brenner, T., Larmann, J., Knebel, P., Hoppe‐Tichy, T., Swoboda, S., Weigand, M. A., et al. (2019) · Journal of Critical Care · doi:10.1016/j.jcrc.2019.04.012 · Cited by 14
Orofacial Motor Functions and Temporomandibular Disorders in Patients With Sjögren's Syndrome
Zanin, M. C., Garcia, D. M., Rocha, E. M., & de Felício, C. M. (2019) · Arthritis Care & Research · doi:10.1002/acr.24001 · Cited by 14
“It is not clear whether orofacial performance impairment in SS involves mechanisms associated with the central nervous system, tryptophan and other nutrient and metabolic dysfunctions, autoimmune damage to the masticatory tissues, or other factors during the progression of SS (2,41,42).”
BackgroundScabia, G., Cancello, R., Dallanoce, C., Berger, S., Matera, C., Dattilo, A., Zulian, A., Barone, I., Ceccarini, G., Santini, F., et al. (2020) · Journal of Endocrinological Investigation · doi:10.1007/s40618-020-01182-z · Cited by 14
Pismataro, M. C., Horenstein, N., Stokes, C., Quadri, M., Amici, M. D., Papke, R., & Dallanoce, C. (2020) · European journal of medicinal chemistry · doi:10.1016/j.ejmech.2020.112669 · Cited by 14
Pulsed Ultrasound of the Spleen Prolongs Survival of Rats With Severe Intra-abdominal Sepsis
Zhang, A. Y., Charles, E. J., Xing, J., Sawyer, R. G., & Yang, Z. (2020) · Journal of Surgical Research · doi:10.1016/j.jss.2020.11.005 · Cited by 14
CHRNA2: a new paradigm in beige thermoregulation and metabolism
Ma, Y., Liu, S., Jun, H., & Wu, J. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.11.009 · Cited by 15
Magawa, S., Lear, C. A., Beacom, M. J., King, V. J., Kasai, M., Galinsky, R., Ikeda, T., Gunn, A. J., & Bennet, L. (2022) · Scientific Reports · doi:10.1038/s41598-022-05799-3 · Cited by 14
Minami, S., Shen, V., Le, D., Krabbe, G., Asgarov, R., Perez-Celajes, L., Lee, C., Li, J., Donnelly‐Roberts, D. L., & Gan, L. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.07.016 · Cited by 15
“Since α7 nAChRs in particular have been implicated in the cholinergic anti-inflammatory pathway [20], we examined whether specific agonists of the α7 nAChR could attenuate LPS-induced NF-κB in Grn−/− macrophages.”
BackgroundZiegler, D., Strom, A., Straßburger, K., Nowotny, B., Zahiragic, L., Nowotny, P., Carstensen‐Kirberg, M., Herder, C., Szendroedi, J., & Roden, M. (2015) · PLoS ONE · doi:10.1371/journal.pone.0124242 · Cited by 14
“Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases [5], and the myocardial inflammatory response and impairment during experimental endotoxemia are aggravated following vagotomy [6].”
BackgroundResultZabrodskii, P. F., Гришин, В. А., & Borodavko, V. K. (2013) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-013-2179-0 · Cited by 14
Keely, S. J. (2011) · The Journal of Physiology · doi:10.1113/jphysiol.2010.204263 · Cited by 14
Park, H., Park, H., Mun, D., Kim, M. S., Pak, H., Lee, M., & Joung, B. (2017) · Heart Rhythm · doi:10.1016/j.hrthm.2017.09.039 · Cited by 15
Human Nicotinic Acetylcholine Receptors: Part II. Non-Neuronal Cholinergic System
Shulepko, M. A., Kulbatskii, D. S., Bychkov, M. L., & Lyukmanova, E. N. (2019) · Russian Journal of Bioorganic Chemistry · doi:10.1134/s1068162019020122 · Cited by 14
Nicotinic Acetylcholine Receptors of PC12 Cells
Mussina, K., Toktarkhanova, D., & Filchakova, O. (2020) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-020-00846-x · Cited by 15
“In particular, vagus nerve stimulation leads to release of acetylcholine with a subsequent activation of α7 receptors on inflammatory cells that results in inhibition of pro-inflammatory cytokines release (Rosas-Ballina and Tracey 2009; Tracey 2007).”
BackgroundHernández, S., Morales‐Soto, W., Grubišić, V., Fried, D. E., & Gulbransen, B. D. (2020) · Neuropharmacology · doi:10.1016/j.neuropharm.2020.108264 · Cited by 13
“24 inflammation by suppressing cytokine synthesis (10, 16, 59, 60).”
BackgroundMethod650 W 168th St, W. B. B., Jacobsen, T. D., Hernandez, P., & Chahine, N. O. (2021) · European Cells and Materials · doi:10.22203/ecm.v041a37 · Cited by 14
“While inflammation is a necessary step in wound healing, persistent inflammation can damage tissues and may contribute to pain (Tracey, 2007).”
BackgroundQuest for the cardiovascular holy grail: mammalian myocardial regeneration
Vela, D. C., & Buja, L. M. (2007) · Cardiovascular Pathology · doi:10.1016/j.carpath.2007.05.001 · Cited by 14
Donoso, M. V., Gómez, C. R., Orriantia, M. Á., Pérez, V., Torres, C. A., Coddou, C., Nelson, P., Maisey, K. R., Morales, B., Fernández, R., et al. (2008) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2008.09.018 · Cited by 14
“Stimulation of the vagus nerve significantly inhibits TNFa release in animals receiving lethal doses of endotoxin, and the authors established that the effect is attributable to acetylcholine (ACh), the main neurotransmitter of the vagus nerve [review by Tracey, 2007].”
Chronic nicotine exposure and acute kidney injury: new concepts and experimental evidence
Speeckaert, M. M., Delanghe, J., & Vanholder, R. C. (2013) · Nephrology Dialysis Transplantation · doi:10.1093/ndt/gft019 · Cited by 14
“In contrast to the adverse events of chronic nicotine, several studies reported anti-inflammatory effects of nicotinic acetylcholine receptor agonists in ulcerative colitis, sepsis, hypersensitivity pneumonitis, experimental type 1 diabetes and even in renal ischaemic-reperfusion injury [23–25].”
ResultWongsripuemtet, P., Ohnuma, T., Minić, Ž., et al. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14020557 · Cited by 13
Igarashi, S., Nozu, T., Ishioh, M., Kumei, S., Saito, T., Toki, Y., Hatayama, M., Yamamoto, M., Shindo, M., Tanabe, H., et al. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114262 · Cited by 14
Effects triggered in the periphery by acupuncture
Lund, I., & Lundeberg, T. (2015) · Acupuncture and Related Therapies · doi:10.1016/j.arthe.2015.08.002 · Cited by 13
Pohanka, M., Karasová, J. Ž., Musílek, K., Kuča, K., Jung, Y., & Kassa, J. (2010) · Journal of Enzyme Inhibition and Medicinal Chemistry · doi:10.3109/14756361003733613 · Cited by 13
Role of ghrelin on growth hormone/insulin-like growth factor-1 axis during endotoxemia
Faim, F. D. L., Passaglia, P., Batalhão, M. E., et al. (2019) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2019.08.004 · Cited by 13
Neuromodulation as a new avenue for resuscitation in hemorrhagic shock
Powell, K., Shah, K. A., Hao, C., Wu, Y.-C., John, A., Narayan, R. K., & Li, C. (2019) · Bioelectronic Medicine · doi:10.1186/s42234-019-0033-z · Cited by 13
“Inflammatory cytokines play a pivotal role in the pathogenesis of HS (Tracey 2007).”
BackgroundJarczok, M. N., Koenig, J., & Thayer, J. F. (2021) · Scientific Reports · doi:10.1038/s41598-021-82168-6 · Cited by 12
Behavioural Fever Promotes an Inflammatory Reflex Circuit in Ectotherms
Sanhueza, N., Fuentes, R., Aguilar, A., Carnicero, B., Vega, K., Muñoz, D., Contreras, D., Moreno, N., Troncoso, E., Mercado, L. A., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22168860 · Cited by 13
“Additionally, the cholinergic pathway confers protection in peripheral organs, inflammatory conditions, and fever [13,14].”
BackgroundDevelopments and new vistas in the field of melanocortins
Leone, S., Noera, G., & Bertolini, A. (2015) · BioMolecular Concepts · doi:10.1515/bmc-2015-0023 · Cited by 13
“This neural inflammation-sensing pathway triggers in real time a nervous reflex response (even when the inflammatory agents are present in tissues in quantities not high enough to reach the brain through the bloodstream) with activation of efferent vagus fibers, acethylcholine release in organs of the reticuloendothel…”
BackgroundTsai, M., Chung, S., Liang, J., Ko, Y., Hsu, W., Lai, H., & Chang, K. (2010) · Shock · doi:10.1097/shk.0b013e3181ab9ee0 · Cited by 13
“expression of proinflammatory cytokines (5, 6).”
Noelker, C., Stuckenholz, V., Reese, J., Alvarez‐Fischer, D., Sankowski, R., Rausch, T. K., Oertel, W. H., Hartmann, A., van Patten, S., Al‐Abed, Y., et al. (2012) · Neurodegenerative Diseases · doi:10.1159/000342714 · Cited by 13
Mechanical Stretch and Cytokines
Henrotin, Y., Pesesse, L., & Sanchez, C. (2011) · Springer eBooks · doi:10.1007/978-94-007-2004-6 · Cited by 14
Grigoryev, E. V., SHUKEVICH, D. L., Плотников, Г. П., Kudryavtsev, A. N., & Сергеевич, Р. А. (2019) · Annals of critical care · doi:10.21320/1818-474x-2019-2-48-57 · Cited by 13
“В окончаниях селезеночных нервов норэпинефрин, выбрасываемый аксонами, взаимодействует с подвидами Т-клеток, которые экспрессируют холинацетилтрансферазу, фермент, лимитирующий биосинтез ацетилхолина [39, 40].”
Heart Rate Variability Predicts Treatment Outcome in Major Depression
(2017) · Journal of Psychiatry and Brain Science · doi:10.20900/jpbs.20170017 · Cited by 13
“The critical link here is that diminution in vagal tone likely leads to disinhibition of the body’s inflammatory response mediated, in part, by the Cholinergic Anti-inflammatory Pathway (CAIP) ([5]).”
BackgroundInfluentialPham, G. S., Shimoura, C. G., Chaudhari, S. K., Kulp, D. V., & Mathis, K. W. (2020) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00201.2020 · Cited by 13
Zhou, M., Aziz, M., Ochani, M., & Wang, P. (2020) · Molecular Medicine · doi:10.1186/s10020-020-00195-x · Cited by 13
“The activation of the vagus nerve during infection results in a protective advantage to the host, while a defect with the antiinflammatory pathway of the vagus nerve contributes to disease pathology (Tracey 2007; Tracey 2005).”
BackgroundInfluentialHan, R., Peng, Z., Zhuo, M., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1702185 · Cited by 12
Balint, E. M., Grüner, B., Haase, S., Kaw-Geppert, M., Thayer, J. F., Gündel, H., & Jarczok, M. N. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.928979 · Cited by 15
Niche Roles for Dexmedetomidine in the Intensive Care Unit
Wiegand, A. M., Behal, M. L., Robbins, B. T., et al. (2023) · Annals of Pharmacotherapy · doi:10.1177/10600280221151170 · Cited by 12
Pluta, R. M., Miziak, B., & Czuczwar, S. J. (2023) · Molecules · doi:10.3390/molecules28155624 · Cited by 12
“Activation of the acetylcholine receptor is known to inhibit the generation of TNF-α, IL-1, and pro-inflammatory cytokines that induce the inflammatory effect of microglia [45,97].”
BackgroundWang, C., Wu, B., Lin, R., Cheng, Y., Huang, J., Chen, Y., & Bai, J. (2024) · Frontiers in Neurology · doi:10.3389/fneur.2024.1516242 · Cited by 12
“Activation of these receptors enhances the neurons’ resistance to ischemic or other types of injuries (157).”
Inflammatory response to burn trauma: nicotine attenuates proinflammatory cytokine levels.
Claaßen, L., Papst, S., Reimers, K., Stukenborg-Colsman, C. M., Steinstraesser, L., Vogt, P. M., Kraft, T., & Niederbichler, A. D. (2014) · Europe PMC (PubMed Central) · Cited by 12
Gateway reflex: neural activation-mediated immune cell gateways in the central nervous system
Kamimura, D., Ohki, T., Arima, Y., & Murakami, M. (2018) · International Immunology · doi:10.1093/intimm/dxy034 · Cited by 12
Neuroanatomy of the Autonomic Nervous System
Darby, S. A. (2013) · Elsevier eBooks · doi:10.1016/b978-0-323-07954-9.00010-4 · Cited by 14
Childhood parental warmth and heart rate variability in midlife: Implications for health
Alen, N. V., Sloan, R. P., Seeman, T. E., & Hostinar, C. E. (2020) · Personal Relationships · doi:10.1111/pere.12329 · Cited by 11
Stavely, R. G., Rahman, A. A., Sahakian, L., Prakash, M. D., Robinson, A. M., Hassanzadeganroudsari, M., Filippone, R. T., Fraser, S. J., Eri, R. D., Bornstein, J. C., et al. (2022) · Inflammatory Bowel Diseases · doi:10.1093/ibd/izac060 · Cited by 13
Cytidine-5-diphosphocholine reduces microvascular permeability during experimental endotoxemia
Schmidt, K., Hernekamp, J. F., Doerr, M., Zivkovic, A. R., Brenner, T., Walther, A., Weigand, M. A., & Hofer, S. (2015) · BMC Anesthesiology · doi:10.1186/s12871-015-0086-9 · Cited by 12
“inflammatory processes to a non-toxic range, thereby minimizing tissue injury [5, 6].”
BackgroundComputational Approaches for Translational Clinical Research in Disease Progression
McGuire, M. F., Iyengar, M. S., & Mercer, D. (2011) · Journal of Investigative Medicine · doi:10.2310/jim.0b013e318224d8cc · Cited by 12
Gonçalves, J. F., Duarte, M. M. M. F., Fiorenza, A. M., Spanevello, R. M., Mazzanti, C. M. D. A., Schmatz, R., Bagatini, M. D., Antes, F. G., da Costa, P., Abdalla, F. H., et al. (2012) · BioMetals · doi:10.1007/s10534-012-9582-2 · Cited by 12
Abdel‐Salam, O. M. E., Abdel-Rahman, R. F., Sleem, A. A., Mosry, F. A., & Sharaf, H. A. (2013) · Journal of Neural Transmission · doi:10.1007/s00702-013-1053-6 · Cited by 10
“Sensory fibers in the vagus nerve transmit information to the brain and serve as the sensory arm of the inflammatory reflex (Tracey 2007).”
BackgroundThe Evolution of an Inflammatory Response
Lowry, S. F. (2009) · Surgical Infections · doi:10.1089/sur.2009.018 · Cited by 12
“A reduction in parasympathetic activity may be associated with diminished capacity to exert vagal cholinergic control over proinflammatory mediator activity [47].”
Prevention of epidural fibrosis in rats by local or systemic administration of citicoline
Savran, M., Bekâr, A., Cansev, M., et al. (2012) · Turkish Neurosurgery · doi:10.5137/1019-5149.jtn.6008-12.0 · Cited by 12
The Neuroimmune Communicatome in Inflammation
Olofsson, P. S., Metz, C. N., & Pavlov, V. A. (2017) · Wiley-VCH eBooks · doi:10.1002/9783527692156.ch59 · Cited by 14
Plaschke, K., Do, T., Uhle, F., Brenner, T., Weigand, M. A., & Kopitz, J. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19020442 · Cited by 12
“Electrical stimulation of the efferent vagal nerve fibers with low frequency is thought to possess anti-inflammatory properties and is able to activate the “cholinergic anti-inflammatory reflex” [31].”
BackgroundNicotinic Acetylcholine Receptors in HIV: Possible Roles During HAND and Inflammation
Capó-Vélez, C. M., Delgado‐Vélez, M., Báez-Pagán, C. A., & Lasalde‐Dominicci, J. A. (2018) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-018-0603-8 · Cited by 12
“Although the importance of the CAP is evident, so far it has not been studied extensively in patients infected with HIV.”
BackgroundInfluentialXu, L., Zhang, X., Feng, Q., et al. (2018) · ACS Chemical Neuroscience · doi:10.1021/acschemneuro.8b00369 · Cited by 12
Congenital laryngomalacia: Is it an inflammatory disease? The role of vitamin D
Hassan, M. M., Emam, A. M., Mahmoud, A. M., Awad, A., Rezk, I., Abou‐Taleb, A., Mohamed, M., & Elmagd, E. A. A. (2019) · The Laryngoscope · doi:10.1002/lary.27997 · Cited by 11
“Depressed vagal nerve activity might facilitate the inflammatory response underlying andworsening the disease.(25) Mucosal edema of the laryngeal structures has been reported in laryngomalacia.”
BackgroundMcDonald, H., Peart, J. N., Kurniawan, N. D., et al. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110165 · Cited by 12
“The CAP is mediated through vagal efferent firing leading to an acetylcholine-dependent interaction with the α-7 nicotinic acetylcholine receptor (α7nAChR) subunit on monocytes and macrophages and ultimately a reduction in inflammatory cytokine production [18].”
BackgroundInfluentialOYTOKINES IN THE PATHOGENESIS OF INFECTIOUS AND NONINFECTIOUS HUMAN DISEASES
Simbirtsev, A. S. (2013) · Medical academic journal · doi:10.17816/maj13318-41 · Cited by 12
Point-of-care measured serum cholinesterase activity predicts patient outcome following severe burns
Schmidt, K., Zivkovic, A. R., Thiele, M., Horter, J., Brenner, T., Weigand, M. A., Kleinschmidt, S., & Hofer, S. (2020) · Burns · doi:10.1016/j.burns.2020.10.027 · Cited by 12
50 Years of Sepsis Investigation/Enlightenment Among Adults—The Long and Winding Road
Dellinger, R. P., Levy, M. M., Schorr, C., & Townsend, S. R. (2021) · Critical Care Medicine · doi:10.1097/ccm.0000000000005203 · Cited by 12
Bitzinger, D., Zausig, Y. A., Paech, C., Gruber, M. A., Busse, H., Sinner, B., Graf, B. M., & Trabold, B. (2013) · Immunobiology · doi:10.1016/j.imbio.2013.01.003 · Cited by 12
Li, H., Qian, Z., Li, J., et al. (2011) · Medical Science Monitor · doi:10.12659/msm.882041 · Cited by 12
“Stimulation of the cholinergic anti-inflammatory pathway by pharmacological methods can attenuate the systemic inflammatory response to endotoxin-induced sepsis [6].”
BackgroundMiwa, K., Shibayama, N., Moriguchi, T., et al. (2009) · Journal of Clinical Laboratory Analysis · doi:10.1002/jcla.20287 · Cited by 12
Anti‐inflammatory activity of Eugenia punicifolia extract on muscular lesion of mdx dystrophic mice
Leite, P. E. C., de Almeida, K. B., Lagrota-Cândido, J., Trindade, P., da Silva, R. F., Ribeiro, M. G. L., Lima‐Araújo, K. G., Santos, W. C., & Quírico‐Santos, T. (2010) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22906 · Cited by 12
Prefrontal tDCS modulates autonomic responses in COVID-19 inpatients
Pinto, T. P., Inácio, J. C., de Aguiar, E., Ferreira, A. S., Sudo, F. K., Tovar-Moll, F., & Rodrigues, E. C. (2023) · Brain Stimulation · doi:10.1016/j.brs.2023.03.001 · Cited by 11
Namba, M. D., Xie, Q., & Barker, J. M. (2023) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2023.07.021 · Cited by 10
The anterior chamber of the eye technology and its anatomical, optical, and immunological bases
Yang, S.-N., Shi, Y., & Berggren, P. (2024) · Physiological Reviews · doi:10.1152/physrev.00024.2023 · Cited by 13
Thal, S. C., Shityakov, S., Salvador, E., & Förster, C. Y. (2025) · Biomolecules · doi:10.3390/biom15040499 · Cited by 15
“In the cholinergic anti-inflammatory pathway, acetylcholine is released at the synapses of efferent VN fibers when an infection activates the VN. [127,128].”
Limitations and advances in new treatments and future perspectives of corneal blindness
Antunes-Foschini, R., Adriano, L., Murashima, A. D. A. B., et al. (2021) · Arquivos Brasileiros de Oftalmologia · doi:10.5935/0004-2749.20210042 · Cited by 11
“Second, the anabolic agents and growth factors present in the LFU are useful in the therapeutic approaches to prevent or treat corneal blindness.”
ResultInfluentialTaylor, J. B., Ford, K. R., Queen, R. M., Owen, E. C., & Gisselman, A. S. (2021) · International Journal of Sports Physical Therapy · doi:10.26603/001c.21152 · Cited by 11
Abid, N.-U.-H., & Mani, A. R. (2022) · Physiological Reports · doi:10.14814/phy2.15261 · Cited by 12
“Crucially, this has been suggested to inhibit the production of pro- inflammatory cytokine generation as an attempt to dampen systemic inflammation (Mazloom et al., 2013; Rosas- Ballina et al., 2011; Tracey, 2007).”
BackgroundChoudhary, R. C., Ahmed, U., Shoaib, M., Alper, E., Rehman, A., Kim, J. H., Shinozaki, K., Volpe, B. T., Chavan, S. S., Zanos, S. P., et al. (2022) · Bioelectronic Medicine · doi:10.1186/s42234-022-00092-0 · Cited by 11
“…metabolic homeostasis, modulating immune function (Borovikova et al., 2000), mitochondrial function (Xue et al., 2017), sepsis (Borovikova et al., 2000; Tracey, 2007), rheumatoid arthritis (Koopman et al., 2016), and hemorrhagic shock (Levy et al., 2013) have been demonstrated in multiple…”
BackgroundSelf-citationNewell‐Rogers, M. K., Duong, A., Nazarali, R., Tobin, R. P., Rogers, S. K., & Shapiro, L. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23179851 · Cited by 12
“There are also a small number of sensory afferents that innervate the spleen, providing the CNS with vital information on the inflammatory state [32].”
BackgroundAcetylcholine Receptors in Mesenchymal Stem Cells
Alqahtani, S. S., Butcher, M. C., Ramage, G., et al. (2022) · Stem Cells and Development · doi:10.1089/scd.2022.0201 · Cited by 11
Modulation of inflammatory response and pain by mind-body therapies as meditation
Moreno, J. J. (2023) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2023.100036 · Cited by 13
Keary, T. A., Galioto, R., Hughes, J. W., Waechter, D. M., Spitznagel, M. B., Rosneck, J. S., Josephson, R., & Gunstad, J. (2012) · Cardiovascular Psychiatry and Neurology · doi:10.1155/2012/392490 · Cited by 14
“An additional explanation implicates the inflammatory cytokines of the vagus nerve; more specifically, both slowed HR recovery and cognitive dysfunction may be a reflection of an underlying dysregulation of the cholinergic anti-inflammatory pathway [46].”
BackgroundZhang, P., Qin, L., & Zhang, G. (2010) · Inflammation Research · doi:10.1007/s00011-010-0160-1 · Cited by 11
“inflammatory pathway [21].”
Çelik, A., Koç, F., Kadı, H., Ceyhan, K., & Erkorkmaz, Ü. (2012) · The Anatolian Journal of Cardiology · doi:10.5152/akd.2012.067 · Cited by 11
Zhao, M. F., Jia, H.-H., Liu, L., Bi, X., Xu, M., Yu, X., He, X., & Zang, W. (2017) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2017.04.001 · Cited by 11
Influence of Psychological Stress on Chronic Fatigue Syndrome
Oka, T. (2013) · Advances in Neuroimmune Biology · doi:10.3233/nib-130077 · Cited by 10
“Stimulation of the vagus nerve exerts anti-inflammatory actions by inhibiting proinflammatory cytokine release [60, 61].”
BackgroundBreivik, T. J., Bogen, I. L., Haug, K. H., Fonnum, F., Opstad, P.-K., Eide, D. M., & Myhre, O. (2014) · Neurochemistry International · doi:10.1016/j.neuint.2014.04.002 · Cited by 11
New Pharmacological Targets for Asthma Drug Development
Righetti, R. F. (2014) · Journal of Allergy & Therapy · doi:10.4172/2155-6121.1000170 · Cited by 11
“Studies have suggested that the interaction of ACh with the nicotinic alpha-7 receptor primarily occurs in macrophages and induces an inhibition of NF-kappa B translocation to the nucleus and consequently a reduction in the inflammatory cytokines release [161].”
BackgroundAntinociceptive and anti-inflammatory effects of a Geissospermum vellosii stem bark fraction
Lima, J. A., da Costa, T. W. R., Silva, L. L., Miranda, A. L. P., & Pinto, A. C. (2016) · Anais da Academia Brasileira de Ciências · doi:10.1590/0001-3765201520140374 · Cited by 13
“Considering all of the stated anti-infl ammatory roles that are mediated by the cholinergic system (Borovikova et al. 2000b, Tracey 2002, 2007, Wang et al. 2003, 2004, Shytle et al. 2004, Kamal et al. 2009) and the previously described PPAC fraction anticholinesterase activity (Lima et al. 2009),…”
BackgroundWedn, A. M., El‐Gowilly, S. M., & El‐Mas, M. M. (2019) · Pharmacological Reports · doi:10.1016/j.pharep.2019.04.013 · Cited by 11
Alshehri, M., Alqahtani, A., Alenazi, A. M., Aldhahi, M., Alothman, S., Gray, C., Alqahtani, B., Khunti, K., & Kluding, P. (2020) · BMC Cardiovascular Disorders · doi:10.1186/s12872-020-01402-7 · Cited by 12
“It should also be noted that impaired vagal function could limit anti-inflammatory production and thus contribute to atherosclerosis [40, 41].”
BackgroundChen, X.-H. (2011) · World Journal of Emergency Medicine · doi:10.5847/wjem.j.issn.1920-8642.2011.02.002 · Cited by 11
Tracey, K. J. (2024) · Genes & Development · doi:10.1101/gad.352287.124 · Cited by 13
“…out neurosurgeon Penfeld ’ s handheld electrodes to stimulate brain tissues and correlate tissue locations with specific behavior in patients and instead use pharmacogenetic and optogenetic methods in mice to identify specific brain neurons modulating specific immune responses (Tracey 2007).”
MethodSelf-citation
Metadata
- Authors
- Tracey, K. J.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Corresponding author
- Tracey, Kevin J.
- ORCID
- Tracey, Kevin J.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-02-01
- Volume
- 117
- Issue
- 2
- Pages
- 289-296
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1783813
- OpenAlex
- W2002797282
- Semantic Scholar
- 76a50e9232b81d22a72d6631b636a0d756df76b8
- Cited by
- 1,563
- References
- 107
- Citations by year
- 2026: 73 · 2025: 58 · 2024: 76 · 2023: 58 · 2022: 72 · 2021: 89 · 2020: 92 · 2019: 76 · 2018: 79 · 2017: 87 · 2016: 78 · 2015: 78 · 2014: 88 · 2013: 87 · 2012: 89
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- cholinergic anti-inflammatory pathway, vagus nerve, cytokine production, neuroimmune regulation, sepsis, endotoxemia, ischemia-reperfusion injury, hemorrhagic shock, arthritis, humoral theory, terrain theory, cholinergic agonists, neuroprotection, tissue damage, multiple organ failure
- MeSH terms
- Animals, Brain, Cholinergic Fibers, Humans, Inflammation, Models, Biological, Cytokines, History, 20th Century, History, 21st Century, History, Ancient
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