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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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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Claims the paper makes
80 Not checked yet · 6 No basis given · 4 Own interpretation
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.
plaindirect- Asserted: passes — The authors put it forward as true.
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In 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
plaindirect- Asserted: passes — The authors put it forward as true.
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In 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
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In 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
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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
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In 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
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In 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In 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
plaindirect- Asserted: passes — The authors put it forward as true.
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In 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
plaindirect- Asserted: passes — The authors put it forward as true.
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In 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- 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
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
boosteddirect- Asserted: passes — The authors put it forward as true.
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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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Shedding light on ancient concepts and modern clinical problems
“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).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > References
“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
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Cited by
Sorted by citations
Items 301–400 of 996
Diminished vagal tone is a predictive biomarker of necrotizing enterocolitis‐risk in preterm infants
Doheny, K. K., Palmer, C., Browning, K. N., Jairath, P., Liao, D., He, F., & Travagli, R. A. (2014) · Neurogastroenterology & Motility · doi:10.1111/nmo.12337 · Cited by 65
Effects of nicotine on homeostatic and hedonic components of food intake
Stojakovic, A., Espinosa, E. V. P., Farhad, O. T., & Lutfy, K. (2017) · Journal of Endocrinology · doi:10.1530/joe-17-0166 · Cited by 65
“2003, Tracey 2007).”
Spaziani, R., Bayati, A. I., Redmond, K., Bajaj, H. S., Bienenstock, J., Collins, S. M., & Kamath, M. V. (2007) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2007.01042.x · Cited by 64
Review of Ocular Immune Privilege in the Year 2010: Modifying the Immune Privilege of the Eye
Hori, J., Vega, J. L., & Masli, S. (2010) · Ocular Immunology and Inflammation · doi:10.3109/09273948.2010.512696 · Cited by 64
Matarese, G., Isola, G., Anastasi, G., et al. (2013) · European Journal of Inflammation · doi:10.1177/1721727x1301100217 · Cited by 64
“Transforming Growth Factor P-I (TGF-PI) is known as the one of major anti-inflammatory cytokines (25).”
BackgroundKong, W., Kang, K., Gao, Y., Liu, H., Meng, X., Yang, S.-L., Yu, K., & Zhao, M. (2017) · Europe PMC (PubMed Central) · Cited by 64
Stress and the “extended” autonomic system
Goldstein, D. S. (2021) · Autonomic Neuroscience · doi:10.1016/j.autneu.2021.102889 · Cited by 76
Damage- and Pathogen-Associated Molecular Patterns and Alarmins: Keys to Sepsis?
Denk, S., Perl, M., & Huber-Lang, M. S. (2012) · European Surgical Research · doi:10.1159/000338194 · Cited by 65
Continuous Hemodiafiltration with a Cytokine-Adsorbing Hemofilter for Sepsis
Hirasawa, H., Oda, S., Nakamura, M., et al. (2012) · Blood Purification · doi:10.1159/000342379 · Cited by 64
Maldifassi, M. C., Atienza, G., Arnalich, F., López‐Collazo, E., Cedillo, J. L., Martín-Sánchez, C., Bordas, A., Renart, J., & Montiel, C. (2014) · PLoS ONE · doi:10.1371/journal.pone.0108397 · Cited by 65
“The physiological activation of CAP is critical to ensure the appropriate magnitude of the inflammatory response to an infection or injury since it culminates in T cell release of ACh and the interaction of the neurotransmitter with a7 nAChRs on resident macrophages in the spleen, thereby inhibiting proinflammatory cy…”
BackgroundInfluentialGnatek, Y., Zimmerman, G., Goll, Y., Najami, N., Soreq, H., & Friedman, A. (2012) · Frontiers in Molecular Neuroscience · doi:10.3389/fnmol.2012.00066 · Cited by 66
“Unlike previous studies (mostly in the peripheral nervous system) (Tracey, 2002, 2007; Shytle et al., 2004; Wang et al., 2008), our findings point to muscarinic dependant activation as the underlying pathway.”
ResultElectrically Evoked Compound Action Potential Recording in Peripheral Nerves
Parker, J. L., Shariati, N. H., & Karantonis, D. M. (2017) · Bioelectronics in Medicine · doi:10.2217/bem-2017-0005 · Cited by 64
Kaniušas, E., Széles, J. C., Kampusch, S., Alfageme-Lopez, N., Yucumá, D., Xie, L., Mayol, J. M., Neumayer, C., Papa, M., & Panetsos, F. (2020) · Frontiers in Physiology · doi:10.3389/fphys.2020.00890 · Cited by 66
“, 2019a,b) in inflammation, respiratory dysfunction and cardiovascular diseases include reduction of pro-inflammatory cytokines (Tracey, 2007; Stavrakis et al., 2015), decrease of inflammation level in chronic inflammatory processes like rheumatoid arthritis, postoperative ileus, inflammatory bowel disease (Crohn’s di…”
BackgroundHenssen, D. J. H. A., Derks, B., van Doorn, M., Verhoogt, N., van Walsum, A. V. C., Staats, P. S., & Vissers, K. C. P. (2019) · Cephalalgia · doi:10.1177/0333102419833076 · Cited by 64
“An extensive body of literature provides evidence for the antiinflammatory effect of VNS (113), which may also play a role in the mechanisms by which (n)VNS ameliorates pain (114).”
BackgroundKopańska, M., Łagowska, A., Kuduk, B., & Banaś-Ząbczyk, A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23042030 · Cited by 62
McDonald, J. L., Cripps, A. W., & Smith, P. K. (2015) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2015/975632 · Cited by 62
Li, W., & Olshansky, B. (2010) · Heart Failure Reviews · doi:10.1007/s10741-010-9184-4 · Cited by 63
“In the past decade, regulatory pathways of cytokine production have been elucidated [11, 33].”
BackgroundInfluentialCancello, R., Zulian, A., Maestrini, S., Mencarelli, M., Barba, A. D., Invitti, C., Liuzzi, A., & Blasio, A. M. D. (2012) · International Journal of Obesity · doi:10.1038/ijo.2011.275 · Cited by 62
Engler, H., Doenlen, R., Riether, C., Engler, A., Niemi, M.-B., Besedovsky, H. O., Rey, A. D., Pacheco-López, G., Feldon, J., & Schedlowski, M. (2009) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2009.01.018 · Cited by 59
“Neuro-endocrine mediators possess potent immunomodulatory properties and have been shown to influence immune responses by affecting the development, the distribution, and the function of immune cells (Elenkov et al., 2000; Sternberg, 2006; Tracey, 2007).”
BackgroundHow poverty affects diet to shape the microbiota and chronic disease
Harrison, C. A., & TAREN, D. L. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2017.121 · Cited by 65
Heart Rate Variability Anatomy and Physiology
Shaffer, F., & Venner, J. (2013) · Biofeedback · doi:10.5298/1081-5937-41.1.05 · Cited by 70
Lu, X., Hong, Z., Tan, Z., Sui, M., Zhuang, Z., Liu, H.-H., Zheng, X., Yan, T.-B., Geng, D.-F., & Jin, D. (2017) · Medical Science Monitor · doi:10.12659/msm.907628 · Cited by 62
“The a7nAchR is mainly expressed in the brain, including neurons, glia, and endothelial cells [40,41].”
BackgroundCurtis, B. J., & Radek, K. A. (2011) · Journal of Investigative Dermatology · doi:10.1038/jid.2011.264 · Cited by 61
“…that the α7 nAChR subtype is a major player involved in AMP suppression in the epidermis (Radek, Elias et al. 2010), which parallels the work by Kevin Tracey and colleagues (Borovikova, Ivanova et al. 2000; Bernik, Friedman et al. 2002; Bernik, Friedman et al. 2002; Tracey 2002; Tracey 2007).”
BackgroundResultInfluentialModulation of Brain Dead Induced Inflammation by Vagus Nerve Stimulation
Hoeger, S., Bergstraesser, C., Selhorst, J., Fontana, J., Birck, R., Waldherr, R., Beck, G. C., Sticht, C., Seelen, M. A., van Son, W. J., et al. (2010) · American Journal of Transplantation · doi:10.1111/j.1600-6143.2009.02951.x · Cited by 61
“In the cholinergic anti-inflammatory pathway, also referred as anti-inflammatory reflex, the vagus nerve is of eminent importance (3).”
BackgroundPsychological Stress, Vascular Inflammation, and Atherogenesis
Lu, X., Zhao, Y., Zhang, Y., & Jiang, F. (2013) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e3182858fac · Cited by 61
Resolution of inflammation pathways in preeclampsia—a narrative review
Perucci, L. O., Júnior, M. D. C., Dusse, L. M. S., Gomes, K. B., & Sousa, L. P. (2017) · Immunologic Research · doi:10.1007/s12026-017-8921-3 · Cited by 61
von Känel, R., Nelesen, R. A., Mills, P. J., Ziegler, M. G., & Dimsdale, J. E. (2007) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2007.09.009 · Cited by 61
Huang, M., Gedansky, A., Hassett, C. E., Price, C. L., Fan, T. H., Stephens, R. S., Nyquist, P., Uchino, K., & Cho, S.-M. (2021) · Neurocritical Care · doi:10.1007/s12028-021-01309-x · Cited by 60
“Further, lung injury leads to release of systemic inflammatory mediators that can cross the blood–brain barrier and cause cerebral dysfunction [13].”
BackgroundVagus Nerve Stimulation in Ischemic Stroke
Andalib, S., Divani, A. A., Ayata, C., Baig, S. S., Arsava, E. M., Topçuoğlu, M. A., Cáceres, E. L., Parikh, V., Desai, M. J., Majid, A., et al. (2023) · Current Neurology and Neuroscience Reports · doi:10.1007/s11910-023-01323-w · Cited by 65
“The neural pathways of the vagus nerve that detect inflammation are sensitive to lower concentrations of tissue inflammatory molecules, prompting a reaction even when these agents are not abundant enough to reach the brain via the bloodstream [37, 38].”
Erős, G., Varga, G., Váradi, R., Czóbel, M., Kaszaki, J., Ghyczy, M., & Boros, M. (2008) · European Surgical Research · doi:10.1159/000167856 · Cited by 59
“However, choline participates in a wide range of other responses, including interference with the mechanism of activation of leukocytes or macrophages [”
BackgroundGuan, L., Collet, J., Mazowita, G., & Claydon, V. E. (2018) · Frontiers in Neurology · doi:10.3389/fneur.2018.00090 · Cited by 62
“In addition, both SNS and the humoral anti-inflammatory pathway are triggered, releasing stress hormones that include cortisol and catecholamines to elicit anti-inflammatory effects (25, 30).”
BackgroundInfluentialIntachai, K., Chattipakorn, S. C., Chattipakorn, N., & Shinlapawittayatorn, K. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19092466 · Cited by 61
“Over the past few years, a growing number of studies have shown that the cholinergic anti-inflammatory pathway (CAP) can modulate various aspects of both the innate and adaptive immune response [70,71].”
BackgroundThe Hormone Ghrelin Prevents Traumatic Brain Injury Induced Intestinal Dysfunction
Bansal, V., Ryu, S., Blow, C., Costantini, T., Loomis, W., Eliceiri, B., Baird, A., Wolf, P., & Coimbra, R. (2010) · Journal of Neurotrauma · doi:10.1089/neu.2010.1372 · Cited by 56
Cholinergic modulation of inflammation.
Pavlov, V. A. (2008) · PubMed Central · Cited by 59
Garzoni, L., Faure, C. C., & Frasch, M. G. (2013) · Frontiers in Integrative Neuroscience · doi:10.3389/fnint.2013.00057 · Cited by 57
Moriwaki, Y., Watanabe, Y., Shinagawa, T., Kai, M., Miyazawa, M., Okuda, T., Kawashima, K., Yabashi, A., Waguri, S., & Misawa, H. (2009) · Neurosciences research · doi:10.1016/j.neures.2009.04.014 · Cited by 63
Impact of 5-HT3 receptor antagonists on peripheral and central diseases
Fakhfouri, G., Rahimian, R., Ghia, J., et al. (2012) · Drug Discovery Today · doi:10.1016/j.drudis.2012.02.009 · Cited by 58
Mentation on the immunological modulation of gastrointestinal motility
Bauer, A. J. (2008) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2008.01105.x · Cited by 56
Neuroendocrine Immunoregulation in Multiple Sclerosis
Deckx, N., Lee, W.-P., Berneman, Z. N., & Cools, N. (2013) · Clinical and Developmental Immunology · doi:10.1155/2013/705232 · Cited by 62
“Twomechanisms demonstrating the inhibitory activity of the PNS on innate immune cells have been described [108].”
BackgroundBench-to-bedside review: Brain-lung interaction in the critically ill – a pending issue revisited
Gonzalvo, R., Martı́, O., Blanch, L. L., & López‐Aguilar, J. (2007) · Critical Care · doi:10.1186/cc5930 · Cited by 58
Neuroprotective Effects of Trigeminal Nerve Stimulation in Severe Traumatic Brain Injury
Chiluwal, A., Narayan, R. K., Chaung, W. W., Mehan, N. D., Wang, P., Bouton, C. E., Golanov, E. V., & Li, C. (2017) · Scientific Reports · doi:10.1038/s41598-017-07219-3 · Cited by 58
Mechanisms of Yogic Practices in Health, Aging, and Disease
Kuntsevich, V. I., Bushell, W. C., & Theise, N. D. (2010) · Mount Sinai Journal of Medicine A Journal of Translational and Personalized Medicine · doi:10.1002/msj.20214 · Cited by 57
Zhang, Y., Ilsar, I., Sabbah, H. N., David, T. B., & Mazgalev, T. N. (2008) · Heart Rhythm · doi:10.1016/j.hrthm.2008.10.043 · Cited by 57
Okamoto, L. E., Raj, S. R., Gamboa, A. C., Shibao, C. A., Arnold, A. C., Garland, E. M., Black, B. K., Farley, G., Diedrich, A., & Biaggioni, I. (2015) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00409.2015 · Cited by 58
“A possible explanation of this association may be an impaired “cholinergic anti-inflammatory pathway” (56).”
BackgroundFrasch, M. G., Szynkaruk, M., Prout, A. P., Nygard, K. L., Cao, M., Veldhuizen, R. A. W., Hammond, R. R., & Richardson, B. S. (2016) · Journal of Neuroinflammation · doi:10.1186/s12974-016-0567-x · Cited by 57
“This decrease in CAP activity also decreases short-term heart rate variability (HRV), e.g., as measured by the beat-to-beat HRV measures, such as root mean square of successive differences in R-R intervals of ECG (RMSSD), a measure of vagal modulation of HRV [1, 2].”
BackgroundMethodInfluentialRech, J., Hess, A., Finzel, S., Kreitz, S., Sergeeva, M., Englbrecht, M., Doerfler, A., Saake, M., & Schett, G. (2013) · Arthritis & Rheumatism · doi:10.1002/art.37761 · Cited by 60
“Since key outcome measures in RA are based on the patient’s perception of the disease, rather than objective measures (6), fast improvement of disease symptoms in RA patients receiving TNFi is not surprising, and led to the hypothesis that interference with reflex arches between the peripheral inflammatory process and…”
Comite, G. D., Rossi, C. M., Marinosci, A., Lolmède, K., Baldissera, E. M., Aiello, P., Müeller, R. B., i, M. H., Voll, R. E., Rovere, P. Q., et al. (2008) · Journal of Leukocyte Biology · doi:10.1189/jlb.0608358 · Cited by 57
“Conversely, a defective regulation of the parasympathetic nervous system, which suppresses the production of inflammatory cytokines, tissue injury, and cell damage in peripheral organs [8], has been suggested in RA patients [9].”
BackgroundStuckenholz, V., Bacher, M., Balzer‐Geldsetzer, M., Alvarez‐Fischer, D., Oertel, W. H., Dodel, R. C., & Noelker, C. (2013) · Journal of Parkinson s Disease · doi:10.3233/jpd-120157 · Cited by 57
“Based on the ‘cytokine theory of disease’, an overproduction of a large variety of cytokines may promote inflammation and may contribute to the clinical manifestations of disease [6].”
Lewine, J. D., Paulson, K. M., Bangera, N. B., & Simon, B. J. (2018) · Neuromodulation Technology at the Neural Interface · doi:10.1111/ner.12864 · Cited by 57
Ottaviani, M. M., Vallone, F., Micera, S., & Recchia, F. A. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.866957 · Cited by 56
Li, C. (2015) · Medical Science Monitor · doi:10.12659/msm.891407 · Cited by 56
“The clinical potential of VNS is not necessarily limited to systemic inflammation, as found, for example, in the experimental models of sepsis, ischemia/reperfusion, refractory partial epilepsy, hemorrhagic shock, myocardial ischemia, ileus, experimental arthritis, and pancreatitis [6,7].”
BackgroundReyt, S., Picq, C. A., Sinniger, V., Clarençon, D., Bonaz, B. L., & Olivier David, A. (2010) · NeuroImage · doi:10.1016/j.neuroimage.2010.05.021 · Cited by 55
“VNS was performed using biphasic pulses with the following parameters: 1mA, 5Hz, 500 µ s pulse width and cycle of 9 s ON / 51 s OFF.”
Annoni, E. M., Xie, X., Lee, S. W., Libbus, I., KenKnight, B. H., Osborn, J. W., & Tolkacheva, E. G. (2015) · Physiological Reports · doi:10.14814/phy2.12476 · Cited by 55
“By decreasing the level of cytokine synthesis, the magnitude of the inflammatory response is dampened (Tracey 2007).”
BackgroundPapathanassoglou, E. D. E., Miltiadous, P., & Karanikola, M. N. K. (2014) · Biological Research For Nursing · doi:10.1177/1099800414555411 · Cited by 55
“Previous authors (Oke & Tracey, 2008; Tracey, 2007) have described the cholinergic anti-inflammatory pathway through which the central nervous system (CNS) is involved in the regulation of systemic inflammation via efferent vagus nerve signals.”
Enteric glia cells are critical to limiting the intestinal inflammatory response after injury
Langness, S. M., Kojima, M., Coimbra, R. S. M., Eliceiri, B. P., & Costantini, T. W. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00371.2016 · Cited by 55
“To limit inflammation, the body has a reflexive, anti-inflammatory circuit mediated through the vagus nerve (53).”
BackgroundTreating disorders across the lifespan by modulating cholinergic signaling with galantamine
Metz, C. N., & Pavlov, V. A. (2020) · Journal of Neurochemistry · doi:10.1111/jnc.15243 · Cited by 59
“Discoveries about 20 years ago have considerably advanced our understanding of the regulation of inflammation by identifying neural cholinergic signaling as a key component (Hoover, 2017; Pavlov et al., 2003; Tracey, 2002, 2007).”
BackgroundSpaccapelo, L., Bitto, A., Galantucci, M., Ottani, A., Irrera, N., Minutoli, L., Altavilla, D., Novellino, E., Grieco, P., Zaffe, D., et al. (2011) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2011.09.015 · Cited by 56
Anatabine Ameliorates Experimental Autoimmune Thyroiditis
Caturegli, P., Remigis, A. D., Ferlito, M., et al. (2012) · Endocrinology · doi:10.1210/en.2012-1452 · Cited by 54
“possess antiinflammatory properties (10).”
BackgroundCostantini, T. W., Dang, X., Coimbra, R. S. M., Eliceiri, B. P., & Baird, A. (2014) · Journal of Leukocyte Biology · doi:10.1189/jlb.4ru0814-381r · Cited by 55
“On the other, the Tracey laboratories [1, 3, 6–8] have clearly established that efferent signaling via a7nAChR activation regulates systemic cytokine responses by controlling spleen inflammatory cell function.”
BackgroundFlierl, M. A., Rittirsch, D., Chen, A. J., Nadeau, B. A., Day, D. E., Sarma, J. V., Huber-Lang, M. S., & Ward, P. A. (2008) · PLoS ONE · doi:10.1371/journal.pone.0002560 · Cited by 54
“In addition to the hypothalamic-pituitary-adrenal (HPA) axis, the autonomic nervous system seems to be key in this ‘‘verbal exchange’’, modulating inflammation via the adrenergic sympathetic and vagusmediated, parasympathetic nervous systems [9,10].”
BackgroundCervical sympathetic block regulates early systemic inflammatory response in severe trauma patients
Wen, L. (2013) · Medical Science Monitor · doi:10.12659/msm.883833 · Cited by 56
“Interestingly, the stimulation of parasympathetic nerves may also suppress systemic inflammatory response [17,18].”
BackgroundChen, X.-H. (2011) · World Journal of Emergency Medicine · doi:10.5847/wjem.j.1920-8642.2011.02.002 · Cited by 61
Nicotinic acetylcholine receptors modulate osteoclastogenesis
Mandl, P., Hayer, S., Karonitsch, T., Scholze, P., Győri, D., Sykoutri, D., Blüml, S., Mócsai, A., Poór, G., Huck, S., et al. (2016) · Arthritis Research & Therapy · doi:10.1186/s13075-016-0961-x · Cited by 55
Chapleau, M. W., Rotella, D. L., Reho, J. J., Rahmouni, K., & Stauss, H. M. (2016) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00043.2016 · Cited by 56
Parasympathetic innervation of vertebrobasilar arteries: is this a potential clinical target?
Roloff, E. V. L., Tomiak‐Baquero, A. M., Kasparov, S., & Paton, J. F. R. (2016) · The Journal of Physiology · doi:10.1113/jp272450 · Cited by 59
Kiguchi, N., Kobayashi, D., Saika, F., Matsuzaki, S., & Kishioka, S. (2018) · Journal of Neuroinflammation · doi:10.1186/s12974-018-1133-5 · Cited by 54
“Regarding the anti-inflammatory property of nAChR, α7 nAChR is most well-characterized, and administration of nicotine or selective α7 nAChR agonists attenuates various rodent models of inflammatory diseases through the downstream pathway of the α7 nAChR [26, 43, 44].”
BackgroundSturmberg, J. P., Bennett, J. M., Picard, M. A., & SEELY, A. J. E. (2015) · Frontiers in Physiology · doi:10.3389/fphys.2015.00169 · Cited by 54
“Acetylcholine, the neurotransmitter of the parasympathetic nervous system (PNS), can decrease NF-κB activity via nicotinic acetylcholinergic receptors; resulting in reduced immune cell activity (Tracey, 2007).”
BackgroundSingle whole-body exposure to sarin vapor in rats: Long-term neuronal and behavioral deficits
Grauer, E., Chapman, S., Rabinovitz, I., et al. (2007) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2007.11.006 · Cited by 53
“This initial pro-inflammatory response may be due to cholinergic cell death reported to occur within hours after sarin exposure as acetylcholine was shown to have anti-inflammatory activity (Tracey, 2007).”
BackgroundProut, A. P., Frasch, M. G., Veldhuizen, R. A. W., Hammond, R. R., Ross, M. G., & Richardson, B. S. (2009) · American Journal of Obstetrics and Gynecology · doi:10.1016/j.ajog.2009.08.020 · Cited by 52
Stimulation of acetylcholine receptors impairs host defence during pneumococcal pneumonia
Giebelen, I. A. J., Leendertse, M., Florquin, S., & van der Poll, T. (2008) · European Respiratory Journal · doi:10.1183/09031936.00103408 · Cited by 53
Neurovascular control and neurogenic inflammation in diabetes
Schaper, N. C., Huijberts, M. S., & Pickwell, K. (2008) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.862 · Cited by 52
“most neuropathic foot ulcers heal within weeks [31] and very recently it was reported that wound closure was unimpaired in a relative small number of type 2 DM patients with neuropathy after a skin biopsy in the foot [32].”
BackgroundPerga, S., Martire, S., Montarolo, F., Navone, N. D., Calvo, A., Fuda, G., Marchet, A., Leotta, D., Chiò, A., & Bertolotto, A. (2017) · Neurotoxicity Research · doi:10.1007/s12640-017-9724-y · Cited by 53
“On the contrary, L-dopa and dopamine agonists used for PD, as well as cholinesterase inhibitors (donepezil and rivastigmine) used for AD, may be associated with a reduced NF-kB activity and suppression of the inflammatory response (Takeuchi and Fukunaga 2004; Beck et al. 2004; Tracey 2007; Sun et al. 2013; Pacheco et…”
BackgroundMethodThe role of the vagus nerve in stroke
Mravec, B. (2010) · Autonomic Neuroscience · doi:10.1016/j.autneu.2010.08.009 · Cited by 53
“Stimulation of the vagus nerve may through inhibition of peripheral and central inflammation, induction of trophic processes, and modulation of locus coeruleus activity (Follesa et al., 2007; Naqui et al., 1999; Tracey, 2007) influence the migration and vitality of administered therapeutic cells and therefore can pote…”
InfluentialImmunological signaling networks: Integrating the body's immune response1,2
Lippolis, J. D. (2007) · Journal of Animal Science · doi:10.2527/jas.2007-0620 · Cited by 54
“However, excessive expression of cytokines can lead to fever, edema, pain, tissue damage, systemic inflamma- tory response syndrome, and possibly death (Tracey, 2007).”
BackgroundHosur, V., & Loring, R. H. (2010) · Molecular Pharmacology · doi:10.1124/mol.110.066381 · Cited by 52
Kul’chyns’kyi, A. B., Kyjenko, V. M., Żukow, W., & Popovych, I. L. (2017) · Open Medicine · doi:10.1515/med-2017-0030 · Cited by 51
“He and his colleagues [5-8, 16-20] believe that the crucial role in immunomodulation is played by the parasympathetic nervous system, both afferent and efferent.”
BackgroundInfluentialCytokine release syndrome after radiation therapy: case report and review of the literature
Barker, C. A., Kim, S. K., Budhu, S., Matsoukas, K., Daniyan, A. F., & D’Angelo, S. P. (2018) · Journal for ImmunoTherapy of Cancer · doi:10.1186/s40425-017-0311-9 · Cited by 52
“The pervasive innervation of the anatomic region of RT in this case (abdomen and pelvis) by the vagus nerve may also be a contributor to the autonomic physiologic response observed during CRS [19].”
BackgroundWhere there is depression, there is inflammation… sometimes!
Glassman, A. H., & Miller, G. E. (2007) · Biological Psychiatry · doi:10.1016/j.biopsych.2007.05.032 · Cited by 51
The role of the vagus nerve in fibromyalgia syndrome
Martins, D. F., Viseux, F., Salm, D. C., Ribeiro, A. C. A., da Silva, H. K. L., Seim, L. A., Bittencourt, E. B., Bianco, G., Moré, A. O. O., Reed, W. R., et al. (2021) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2021.10.021 · Cited by 58
Shah, K. G., Wu, R., Jacob, A., et al. (2009) · Molecular Medicine · doi:10.2119/molmed.2009.00100 · Cited by 51
Daulatzai, M. A. (2012) · Sleep Disorders · doi:10.1155/2012/251096 · Cited by 51
“The efferent parasympathetic pathways constitute the “cholinergic anti-inflammatory pathway” [182, 183].”
BackgroundLi, F., Chen, Z., Pan, Q., Shu-kun, F., Lin, F., Ren, H., Han, H., Billiar, T. R., Sun, F., & Li, Q. (2013) · Shock · doi:10.1097/shk.0b013e31827aa1f6 · Cited by 51
Ghyczy, M., Torday, C., Kaszaki, J., et al. (2008) · Shock · doi:10.1097/shk.0b013e31816f204a · Cited by 51
“It is now well established that vagus nerve stimulation or nicotinergic !7 agonists are efficacious in experimental animal models of endotoxemia, sepsis, and inflammation (35).”
Yuan, S., Zhang, X., Bo, Y., Li, W., Zhang, H., & Jiang, Q. (2014) · Brain Research · doi:10.1016/j.brainres.2014.10.005 · Cited by 51
Cellular Regulation of the Inflammatory Response
Janssen, W. J., & Henson, P. M. (2011) · Toxicologic Pathology · doi:10.1177/0192623311428477 · Cited by 53
“Resurging interest in inflammation, for example as participating in obesity, cardiovascular disease, or cancer, has led to a focus on the cytokines, chemokines, and other inflammatory mediators that orchestrate the process (Libby 2002; Nathan 2002; Tracey 2007; Hotamisligil 2006) to an extent that often downplays the…”
BackgroundSeptic encephalopathy: when cytokines interact with acetylcholine in the brain
Zhang, Q., Sheng, Z.-Y., & Yao, Y.-M. (2014) · Military Medical Research · doi:10.1186/2054-9369-1-20 · Cited by 53
“The trial was based on the dual role of acetylcholine as a neuromodulator as well as an endogenous inhibitor of systemic inflammatory response to endotoxemia [46].”
BackgroundZivkovic, A. R., Decker, S., Zirnstein, A. C., Sigl, A., Schmidt, K., Weigand, M. A., Hofer, S., & Brenner, T. (2018) · Mediators of Inflammation · doi:10.1155/2018/1942193 · Cited by 53
Jiang, Y., Cao, Z., Ma, H., et al. (2018) · Neurochemical Research · doi:10.1007/s11064-018-2639-z · Cited by 51
Khuanjing, T., Palee, S., Chattipakorn, S. C., & Chattipakorn, N. (2019) · Acta Physiologica · doi:10.1111/apha.13396 · Cited by 50
HeRO monitoring to reduce mortality in NICU patients
Fairchild, K. D., & Aschner, J. L. (2012) · Research and Reports in Neonatology · doi:10.2147/rrn.s32570 · Cited by 50
“The vagus nerve plays a key role in host defense against pathogens via the “cholinergic antiinflammatory pathway”.(15) In this response, vagus nerve firing leads to dampening of inflammatory cytokine production by leukocytes, via nicotinic cholinergic receptors.”
Autonomic balance determines the severity of COVID-19 courses
Leitzke, M., Stefanovic, D., Meyer, J.-J., Schimpf, S., & Schönknecht, P. (2020) · Bioelectronic Medicine · doi:10.1186/s42234-020-00058-0 · Cited by 49
Effect of galantamine on adjuvant-induced arthritis in rats
Gowayed, M. A., Refaat, R., Ahmed, W. M., & El-Abhar, H. S. (2015) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2015.07.038 · Cited by 49
Erdur, H., Scheitz, J. F., Grittner, U., et al. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.07.001 · Cited by 50
“In contrast, it has been shown that vagal tone contributes to immunoregulatory functions limiting systemic inflammation and neuroinflammation [21].”
BackgroundNeural therapy—A review of the therapeutic use of local anesthetics
Weinschenk, S. W. (2012) · Acupuncture and Related Therapies · doi:10.1016/j.arthe.2012.12.004 · Cited by 51
Daulatzai, M. A. (2012) · Neurochemical Research · doi:10.1007/s11064-011-0680-2 · Cited by 49
Behavioral despair associated with a mouse model of Crohn's disease: Role of nitric oxide pathway
Heydarpour, P., Rahimian, R., Fakhfouri, G., Khoshkish, S., Fakhraei, N., Salehi-Sadaghiani, M., Wang, H., Abbasi, A., Dehpour, A. R., & Ghia, J. (2015) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2015.08.004 · Cited by 49
“Afferent signals carried in the vagus nerve can activate cholinergic anti-inflammatory pathway and inhibit cytokine release (Tracey, 2007).”
Heart-brain interactions in mental stress-induced myocardial ischemia
Soufer, R., Jain, H., & Yoon, A. (2009) · Current Cardiology Reports · doi:10.1007/s11886-009-0020-1 · Cited by 48
Mravec, B., Gidron, Y., & Hulín, I. (2007) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2007.12.002 · Cited by 47
Yu, X., Zhang, F., & Chen, B. (2020) · Trials · doi:10.1186/s13063-019-3892-4 · Cited by 49
“acetylcholine receptor (AChR) on macrophages and other cells [31].”
BackgroundRETRACTED: Exploring the therapeutic promise of targeting HMGB1 in rheumatoid arthritis
Kaur, I., Behl, T., BUNGAU, S. G., Kumar, A., Mehta, V., Setia, D., Uddin, M. S., Zengin, G., Aleya, L., & Arora, S. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118164 · Cited by 50
Retracted
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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