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
Cites
2 retracted
Mioni, C., Bazzani, C., Giuliani, D., Altavilla, D., Leone, S., Ferrari, A., Minutoli, L., Bitto, A., Marini, H., Zaffe, D., et al. (2005) · Critical Care Medicine · doi:10.1097/01.ccm.0000186762.05301.13 · Cited by 148
RetractedWu, X., Gao, J., Yan, J., Owyang, C., & Li, Y. (2004) · Journal of Neurophysiology · doi:10.1152/jn.00791.2003 · Cited by 53
RetractedVagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W., & Tracey, K. J. (2000) · Nature · doi:10.1038/35013070 · Cited by 4,211
Self-citationTracey, K. J. (2002) · Nature · doi:10.1038/nature01321 · Cited by 3,728
Self-citationNicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation
Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., et al. (2003) · Nature · doi:10.1038/nature01339 · Cited by 3,228
Self-citationTargan, S. R., Hanauer, S. B., van Deventer, S. J. H., Mayer, L., Present, D. H., Braakman, T., DeWoody, K. L., Schaible, T. F., & Rutgeerts, P. J. (1997) · New England Journal of Medicine · doi:10.1056/nejm199710093371502 · Cited by 3,135
The anti-inflammatory effect of exercise
Petersen, A. M. W., & Pedersen, B. K. (2005) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00164.2004 · Cited by 3,100 · cited 1×
“Exercise reduces levels of TNF and other cytokines, confers protection against cardiovascular disease and type 2 diabetes, increases vagus nerve activity, and confers protection against the development of atherosclerosis (84–90).”
Gralton, B. (2008) · Art monthly Australia · Cited by 3,001
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738
Shock and Tissue Injury Induced by Recombinant Human Cachectin
Tracey, K. J., Beutler, B., Lowry, S. F., Merryweather, J., Wolpe, S., Milsark, I. W., Hariri, R. J., Fahey, T. J., Zentella, A., Albert, J. D., et al. (1986) · Science · doi:10.1126/science.3764421 · Cited by 2,549
Self-citation
Research works printed but not linked: 6
- Zingarelli, 1994, Am. J. Physiol., 266, H1512
- Balanescu, 2004, Med. Sci. Monit., 10, CR307
- Laversuch, 1997, J. Rheumatol., 24, 1540
- Shi, 1995, Zhongguo Zhong. Xi. Yi. Jie. He. Za Zhi., 15, 536
- Papadopoulos, 2005, Clin. Exp. Rheumatol., 23, 861
- Holguin, 2005, Chest., 127, 1102
Cited by
Sorted by citations
Items 901–996 of 996
Neurophysiological Markers for Monitoring Exercise and Recovery Cycles in Endurance Sports
Reichel, T., Hacker, S., Palmowski, J., Boßlau, T. K., Frech, T., Tirekoglou, P., Weyh, C., Bothur, E., Samel, S., Walscheid, R., et al. (2022) · Journal of Sports Science and Medicine · doi:10.52082/jssm.2022.446 · Cited by 11
“Previous studies have already demonstrated that the vagus nerve plays an important role in the regulation of inflammation (Tracey, 2007).”
ResultHasan, M. Y., Siran, R., & Mahadi, M. K. (2023) · Biology · doi:10.3390/biology12040555 · Cited by 11
“In ischemic stroke models, VNS significantly reduced the release of pro-inflammatory cytokines in circulating plasma as well as their expression in the penumbra area [55,56].”
BackgroundWang, Y., Liu, W.-C., Zhang, J., Geng, P., & Jin, X. (2024) · Brain Hemorrhages · doi:10.1016/j.hest.2024.02.002 · Cited by 12
Long COVID – a critical disruption of cholinergic neurotransmission?
Leitzke, M., Roach, D. T., Hesse, S., Schönknecht, P. O. D., Becker, G., Rullmann, M., Sattler, B., & Sabri, O. (2025) · Bioelectronic Medicine · doi:10.1186/s42234-025-00167-8 · Cited by 9
“Among the MC AChRs (Mishra 2010), the α7nAChRs are the most important (Xu 2020), explaining their central role in limiting the release of proinflammatory cytokines via the CAP (Tracey 2007).”
Wiley, C. R., Pourmand, V., Stevens, S., Jarczok, M. N., Fischer, J. E., Boschiero, D., Poggiogalle, E., Koenig, J., Thayer, J. F., & Williams, D. P. (2025) · Physiological Reports · doi:10.14814/phy2.70313 · Cited by 13
“Overall, a core set of physiological structures that involve the vagus nerve is responsible for a quick reflexive action in response to inflammation, known as the cholinergic anti-inflammatory pathway (Pavlov et al., 2003; Pavlov & Tracey, 2005; Tracey, 2007).”
Changes in peptidergic neurotransmission during postoperative ileus in rat circular jejunal muscle
Goetz, B., Benhaqi, P., Glatzle, J., Müller, M. H., Schmitt, S. M., Brändli, A. W., Kreis, M. E., & Kasparek, M. S. (2013) · Neurogastroenterology & Motility · doi:10.1111/nmo.12275 · Cited by 10
Placebo Effects in Complementary and Alternative Medicine
Walach, H. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-397928-5.00019-2 · Cited by 10
Ricon‐Becker, I., Fogel, E., Cole, S. W., Haldar, R., Lev‐Ari, S., & Gidron, Y. (2021) · Comprehensive Psychoneuroendocrinology · doi:10.1016/j.cpnec.2021.100057 · Cited by 12
“High vagal activity may inhibit cancer progression via its antiinflammatory and anti-viral effects [33,2,14,34] In contrast CTRA is characterized by up-regulated expression of pro-inflammatory genes and down-regulated anti-viral genes, and, as can be expected, was associated with increased cancer progression [21].”
BackgroundBloom, O., Tracey, K. J., & Pavlov, V. A. (2022) · Current Opinion in Neurology · doi:10.1097/wco.0000000000001036 · Cited by 10
Self-citationEbelt, H., & Werdan, K. (2010) · Der Internist · doi:10.1007/s00108-009-2560-2 · Cited by 10
Effect of Acupuncture on Postoperative Adhesive Intestinal Obstruction
Tseng, C., & Tseng, A. (2015) · Acupuncture in Medicine · doi:10.1136/acupmed-2015-010843 · Cited by 10
Watanabe, A., Ichiki, T., Kojima, H., Takahara, Y., Hurt‐Camejo, E., Michaëlsson, E., Sankoda, C., Ikeda, J., Inoue, E., Tokunou, T., et al. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.11.006 · Cited by 10
“Endogenous anti-inflammatory mechanisms such as IL-10 ameliorate inflammatory responses and maintain homeostasis [6].”
BackgroundGoetz, B., Benhaqi, P., Müller, M. H., Kreis, M. E., & Kasparek, M. S. (2012) · Neurogastroenterology & Motility · doi:10.1111/nmo.12020 · Cited by 10
Wogonin attenuates the deleterious effects of traumatic brain injury in anesthetized Wistar rats
Umemoto, Y., Patel, A., Huynh, T., & Chitravanshi, V. C. (2019) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2019.01.035 · Cited by 10
Papaioannou, V. E., & Pnevmatikos, I. (2019) · Nutrition and Metabolic Insights · doi:10.1177/1178638819847486 · Cited by 10
Effect of CHRFAM7A Δ2bp gene variant on secondary inflammation after spinal cord injury
Lin, M., Huang, W., Kabbani, N., Theiss, M. M., Hamilton, J. F., Ecklund, J. M., Conley, Y. P., Yoram Vodovotz, B., Brienza, D. M., Wagner, A. K., et al. (2021) · PLoS ONE · doi:10.1371/journal.pone.0251110 · Cited by 11
“The cellular responses to the primary mechanical injury produce a secondary cascade of cellular and biochemical events that activate resident astrocytes and pericytes, and recruitment of fibroblasts and Schwann cells from the periphery, leading to the development of lasting glial and fibrotic scars in the injured spin…”
BackgroundTell, D., Burr, R. L., Mathews, H. L., & Janusek, L. W. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.745864 · Cited by 10
Inflammatory reflex disruption in COVID ‐19
Hajiasgharzadeh, K., Jafarlou, M., Mansoori, B., Dastmalchi, N., Baradaran, B., & Khabbazi, A. (2022) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12703 · Cited by 11
“As a logical mechanism to control the release of the undesired cytokines, some studies investigated the role of the endogenous inflammatory reflex and the efferent arm of this reflex, which is called the “cholinergic anti-inflammatory pathway (CAP)” in the modulation of chronic inflammation (10) (Figure 1).”
BackgroundLi, M., Xue, J., Liu, J., et al. (2010) · Therapeutic Apheresis and Dialysis · doi:10.1111/j.1744-9987.2010.00850.x · Cited by 10
Nutritional stimulation of the autonomic nervous system
Luyer, M. D. P. (2011) · World Journal of Gastroenterology · doi:10.3748/wjg.v17.i34.3859 · Cited by 10
Romero-Carbente, J. C., Guzmán‐Mejía, F., Cruz, S. L., López‐Rubalcava, C., & González‐Espinosa, C. (2014) · Inflammation Research · doi:10.1007/s00011-014-0748-y · Cited by 10
Silva, R. L., Castanheira, F. V. S., Figueiredo, J. G., Bassi, G. S., Ferreira, S. H., Cunha, F. Q., Cunha, T. M., & Kanashiro, A. (2016) · Inflammation · doi:10.1007/s10753-016-0372-9 · Cited by 11
“In the last decade, the discovery of cholinergic anti-inflammatory pathway (or Breflex inflammatory^), an elaborated crosstalk between the nervous and immune systems involving neural and cellular interactions, has suggested novel approaches to modulate exacerbated inflammatory responses [13].”
Heart-rate variability depression in porcine peritonitis-induced sepsis without organ failure
Jarkovská, D., Valešová, L., Chvojka, J., Beneš, J., Danihel, V., Švíglerová, J., Nalos, L., Matějovič, M., & Štengl, M. (2017) · Experimental Biology and Medicine · doi:10.1177/1535370217700521 · Cited by 11
Yang, Y., Peng, Y. S., & Yang, J. (2018) · Tropical Journal of Pharmaceutical Research · doi:10.4314/tjpr.v17i4.15 · Cited by 10
“The regulatory influence of the efferent vagus nerve on expression of pro-inflammatory cytokines is mediated through the cholinergic antiinflammatory route which involves α7nAChRdependent signal cascade [7].”
BackgroundTime-dependent effect of clonidine on microvascular permeability during endotoxemia
Schmidt, K., Hernekamp, J. F., Philipsenburg, C., Zivkovic, A. R., Brenner, T., & Hofer, S. (2015) · Microvascular Research · doi:10.1016/j.mvr.2015.07.002 · Cited by 10
Letter To the Editor: Autonomic dysfunction in autoimmune diseases: consequence or cause?
Mravec, B. (2007) · Lupus · doi:10.1177/0961203307081843 · Cited by 10
Cui, Y., Wu, C., Xu, D., & Tang, J. (2024) · BMC Cardiovascular Disorders · doi:10.1186/s12872-024-03739-9 · Cited by 9
“Neuronal signaling can limit the immune and inflammation response by controlling cytokine release to prevent tissue damage [36].”
BackgroundOwens, M. M., Dalal, S., Radovic, A., Fernandes, L., Hassan, S., Herndon, M. B., Cooper, C. M., Singh, K., & Beaumont, É. (2024) · Autonomic Neuroscience · doi:10.1016/j.autneu.2024.103162 · Cited by 9
Nozu, T., Miyagishi, S., Ishioh, M., et al. (2024) · Neurogastroenterology & Motility · doi:10.1111/nmo.14925 · Cited by 9
Reimers-Wessberg, M., Xu, H., Fastbom, J., Seiger, Å., & Eriksdotter, M. (2024) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvae091 · Cited by 9
“33 , 34 Li et al. 35 reported that peripheral blockade of the α 7-nAChR significantly increased the cardioprotective effects of donepezil in HF rats, whereas central blockade did not, suggesting that the peripheral activation of the α 7-nAChR plays an important role in cholinergic pharmacotherapy…”
Nozu, T., Miyagishi, S., Ishioh, M., Takakusaki, K., & Okumura, T. (2025) · Peptides · doi:10.1016/j.peptides.2025.171394 · Cited by 9
Relationships between changes in entropy of the EEG and parameters of the immunity
Popadynets’, O., Гоженко, А. І., Badiuk, N. S., Żukow, W., Kovbasnyuk, M. M., Korolyshyn, T. A., & Popovych, I. L. (2020) · Pedagogy and Psychology of Sport · doi:10.12775/pps.2020.06.01.003 · Cited by 9
Grolaux, P. J. (2019) · Journal of Neurology and Neuromedicine · doi:10.29245/2572.942x/2019/5.1251 · Cited by 9
The infant microbiome and implications for central nervous system development
Parsons, E., Claud, K., & Petrof, E. O. (2020) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2020.04.007 · Cited by 9
Mapping the peripheral nervous system in the whole mouse via compressed sensing tractography
Garrett, A., Rakhilin, N., Wang, N., McKey, J., Cofer, G. P., Anderson, R. B., Capel, B., Johnson, G. A., & Shen, X. (2021) · Journal of Neural Engineering · doi:10.1088/1741-2552/ac0089 · Cited by 10
“By knowing the exact neural fiber targets, clinicians can minimize off-target effects, increasing viability of the existing therapy for diseases such as rheumatoid arthritis [72], inflammatory bowel disease [73], and diabetes [74].”
Hirobumi, I. (2023) · Cureus · doi:10.7759/cureus.33777 · Cited by 9
“Tracey proposed an inflammatory protective system in the vagus nerve system and named it the inflammatory reflex [12].”
BackgroundSchnekenberg, L. G., Sedghi, A., Schoene, D., Pallesen, L., Barlinn, J., Woitek, F. J., Linke, A. H.-P., Puetz, V., Barlinn, K., Mangner, N., et al. (2023) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd10070297 · Cited by 11
“This constitutes a negative feedback loop whereby the parasympathetic system down-regulates the inflammatory response back to homeostasis [32,33].”
BackgroundAlpha-7 Nicotinic Receptor Agonist Protects Mice Against Pulmonary Emphysema Induced by Elastase
Banzato, R., Pinheiro, N. M., Novelli, F. P. R. S., Olivo, C. R., Taguchi, L., Santos, S. D. O., Fukuzaki, S., Teodoro, W. R., Lopes, F. D. T. Q. S., Tibério, I. D. F. L. C., et al. (2024) · Inflammation · doi:10.1007/s10753-023-01953-9 · Cited by 10
“Nicotine and α7nAChR activation are known to reduce cytokine expression and inflammatory cell recruitment [58, 59].”
Ahmadi‐Soleimani, S. M., Ghasemi, S., Rahmani, M. A., Gharaei, M., Bezanaj, M. M., & Beheshti, F. (2024) · Scientific Reports · doi:10.1038/s41598-024-61932-4 · Cited by 10
“Then, Ach release via cholinergic terminal promotes the suppression of further cytokine secretion by macrophages through activation of α7-nicotinic acetylcholine receptors 75 .”
BackgroundEnhanced pain perception in rheumatoid arthritis: Novel considerations
Wood, P. B. (2009) · Current Pain and Headache Reports · doi:10.1007/s11916-009-0071-4 · Cited by 9
Forgotten Features of Head Zones and Their Relation to Diagnostically Relevant Acupuncture Points
Ots, T., Mayor, D. F., Beißner, F., Henke, C., & Unschuld, P. U. (2009) · Deutsche Zeitschrift für Akupunktur · doi:10.1016/j.dza.2009.05.005 · Cited by 9
Right atrium cholinergic deficit in septic rats
Contreras, P., Migliaro, E. R., & Suhr, B. (2013) · Autonomic Neuroscience · doi:10.1016/j.autneu.2013.10.002 · Cited by 9
“The activation of vagal afferent and efferent signaling has been related to the inflammatory reflex that attenuates the host response to pathogens thatmight itself becomedeleterious if left uncontrolled (Tracey, 2007).”
BackgroundExercise training, inflammation and heart failure: working out to cool down
Guasch, E., Benito, B., & Nattel, S. (2010) · The Journal of Physiology · doi:10.1113/jphysiol.2010.194134 · Cited by 9
“Although reparative in early phases, continuous cytokine production can lead to tissue damage, fibrosis and necrosis (Tracey, 2007).”
BackgroundThe impact of cortisol in steatotic and non‐steatotic liver surgery
Cornide‐Petronio, M. E., Bujaldon, E., Mendes-Braz, M., León, C. G. A.-D., Jiménez‐Castro, M. B., Álvarez‐Mercado, A. I., Gracia‐Sancho, J., Rodés, J., & Peralta, C. (2017) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.13156 · Cited by 9
Pittel, Z., Lazar, S., Gez, R., & Chapman, S. (2017) · NeuroToxicology · doi:10.1016/j.neuro.2017.11.002 · Cited by 9
“Shytle et al. (2004) found that the immune system is regulated by the cholinergic system and affected by ACh release via the vagus (Tracey, 2007); 6.”
BackgroundImmunosenescence in neurocritical care
Inoue, S., Saito, M., & Kotani, J. (2018) · Journal of Intensive Care · doi:10.1186/s40560-018-0333-5 · Cited by 10
Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia
Tripathi, V., Mishra, A., Pathak, Y., Jain, A., & Prakash, H. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.94492 · Cited by 9
Development of a Nostalgic Remembering Intervention
Fleury, J., Komnenich, P., Coon, D. W., & Volk-Craft, B. E. (2020) · The Journal of Cardiovascular Nursing · doi:10.1097/jcn.0000000000000762 · Cited by 9
“Increased vagal activity in feeling safe decreases the production of proinflammatory cytokines and may dampen systemic inflammation.(22) Higher HRValso results in greater emotional well-being,(23) self-regulation of emotion,(24) improved social function, and feelings of connectedness.”
BackgroundCostantini, T. W., Coimbra, R. S. M., Weaver, J. L., & Eliceiri, B. P. (2021) · The Journal of Trauma: Injury, Infection, and Critical Care · doi:10.1097/ta.0000000000003470 · Cited by 10
“This cholinergic anti-inflammatory pathway is critical in obtaining inflammatory homeostasis in the host and limiting organ failure after severe infection or injury.(5) Cholinergic agonists or vagal nerve signaling fail to attenuate the proinflammatory response to injury and infection in knockout mice that lack the α7…”
BackgroundWang, J., Liu, J., Gao, L., Li, G., Sun, Y., & Shi, B. (2021) · Cancer Management and Research · doi:10.2147/cmar.s336268 · Cited by 9
Accurate and continuous measurement of oxygen deficit during haemorrhage in pigs
Roesner, J. P., Koch, A. H., Bateman, R. M., Scheeren, T., Zander, R., Nöldge-Schomburg, G. E. F., & Zacharowski, K. D. (2008) · Resuscitation · doi:10.1016/j.resuscitation.2008.10.020 · Cited by 9
Zhang, Z., Bai, X., Du, K., et al. (2011) · Journal of Surgical Research · doi:10.1016/j.jss.2011.10.037 · Cited by 9
“major vagus nerve neurotransmitter [30].”
BackgroundCao, L., Graham, S. L., & Pilowsky, P. M. (2016) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00486.2015 · Cited by 9
“Long-term efferent vagal inhibition may adversely influence cholinergic anti-inflammation pathways (56, 57).”
BackgroundNonpharmacological, Biomechanical Approaches to Control Inflammation in Acute Kidney Injury
Tanaka, S., Inoue, T., Hossack, J. A., & Okusa, M. D. (2017) · The Nephron journals/Nephron journals · doi:10.1159/000477218 · Cited by 9
Reduced expression of VAChT increases renal fibrosis
Silva, R. C., Terra, F. F., Guise, Y. F. S., Prado, M. A. M., Prado, V. F., Hiyane, M. I., Malheiros, D. M. A. C., Prado, C. M., Câmara, N. O. S., & Braga, T. T. (2016) · Pathophysiology · doi:10.1016/j.pathophys.2016.07.002 · Cited by 9
Septischer Kreislaufschock und septische Kardiomyopathie
Müller‐Werdan, U., & Werdan, K. (2005) · Springer eBooks · doi:10.1007/3-540-26587-2_11 · Cited by 9
Graham, R. S., Zachs, D. P., Cotero, V. E., D’Agostino, C. A., Ntiloudi, D., Kaiser, C. R. W., Graf, J. F., Wallace, K. D., Ramdeo, R., Coleman, T. R., et al. (2020) · medRxiv · doi:10.1101/2020.07.14.20153528 · Cited by 8
“S1), which is consistent with previous reports using implanted vagus nerve stimulators (18, 44).”
ResultSelf-citationNazmi, A., Griffin, É. W., Field, R. H., Doyle, S., Hennessy, E., O’Donnell, M., Rehill, A. M., McCarthy, A. W., Healy, D., Doran, M. M., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.18.427123 · Cited by 10
“Relationship to cholinergic signalling These data are consistent with prior demonstrations that ACh exerts anti-inflammatory influence on peripheral macrophages, suppressing LPS-induced IL-1β and TNF-α expression (Wang et al., 2003) agonism at the α7-nAChR (Tracey, 2007).”
BackgroundResultInfluentialVagus nerve stimulation rescues persistent pain following orthopedic surgery in adult mice
Wu, P. Y., Caceres, A. I., Chen, J., Sokoloff, J., Huang, M., Baht, G. S., Nackley, A. G., Jordt, S., & Terrando, N. (2024) · Pain · doi:10.1097/j.pain.0000000000003181 · Cited by 9
“47 Notably, cholinergic stimulation modulates the immune response in several conditions ranging from sepsis to rheumatoid arthritis, 62 and its implications for perioperative care have been recently high-lighted.”
Anti-inflammatory Principles of the Plant Family Amaryllidaceae
Nair, J. J., & Staden, J. V. (2024) · Planta Medica · doi:10.1055/a-2369-8104 · Cited by 10
Förster, C. Y. (2024) · Biomolecules · doi:10.3390/biom14121511 · Cited by 9
“In general, the VN is associated with three reflex pathways that show unquestionable advantages in decreasing inflammation: the anti-inflammatory vago-vagal reflex and the cholinergic anti-inflammatory pathway have been well described [42,43].”
Кручинова, С. В., Нургалиевна, Г. М., Муратович, Н. А., Sokolskaya, M. A., Гилевич, И. В., Татаринцева, З. Г., Karibova, M., Danilov, V., Simakin, N., Shvartz, E. N., et al. (2025) · Journal of Clinical Medicine · doi:10.3390/jcm14061866 · Cited by 8
Ruiz-Pablos, M., Paiva, B., & Zabaleta, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1710571 · Cited by 11
Zhou, J., Pavlović, D., Rüb, J., Masur, S., SPASSOV, A. W., Whynot, S., Hung, O. R., Kern, H., Abdo, I. S., Shukla, R., et al. (2014) · Clinical Hemorheology and Microcirculation · doi:10.3233/ch-131743 · Cited by 8
Zhan, G., Wang, Y., Yang, N., Luo, A., & Li, S. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i7.561 · Cited by 8
Stockfelt, L., Xu, Y., Gudmundsson, A., et al. (2022) · Inhalation Toxicology · doi:10.1080/08958378.2022.2065388 · Cited by 8
“Inflammation and the ANS are connected, however, through the cholinergic anti-inflammatory pathway (Borovikova et al. 2000; Tracey 2007).”
BackgroundStrandhave, C., Svensson, M. H. S., Krarup, H. B., et al. (2013) · International Journal of Nephrology · doi:10.1155/2013/650847 · Cited by 8
“Tracey [35] first described this cholinergic antiinflammatory pathway as a plausible, molecular mechanism for the association between HRV and hs-CRP.”
BackgroundNeurogenic Bladder: Recurrent Urinary Tract Infections—Beyond Antibiotics
Castle, A. C., Park, A., Mitchell, A. J., et al. (2018) · Current Bladder Dysfunction Reports · doi:10.1007/s11884-018-0481-4 · Cited by 8
Upregulation of the high-affinity choline transporter in colon relieves stress-induced hyperalgesia
Lin, M., & Yu, B. (2018) · Journal of Pain Research · doi:10.2147/jpr.s164186 · Cited by 8
“However, an increasing body of evidence indicates that the antinociceptive effects may be associated with the cholinergic anti-inflammatory pathway, 27 interaction with opioid systems, 6 increase in the release of inhibitory neurotransmitters, such as glycine 28 and gamma-aminobutyric acid, 29 and…”
Halaris, A. E., & Leonard, B. E. (2019) · Neurology Psychiatry and Brain Research · doi:10.1016/j.npbr.2019.05.005 · Cited by 11
Eftekhari, G., Shojaei, A., Raoufy, M. R., Azizi, H., Semnanian, S., & Mani, A. R. (2019) · Shock · doi:10.1097/shk.0000000000001453 · Cited by 8
“The NTS is involved in the regulation of visceral function including cardiovascular, respiratory, gastrointestinal as well as the immune system (45, 47).”
BackgroundSen, S., Kumral, Z. N. Ö., Memi, G., et al. (2020) · Physiology International · doi:10.1556/2060.2020.00025 · Cited by 8
Multi-scale network targeting: A holistic systems-biology approach to cancer treatment
Paul, D., & Komarova, N. L. (2021) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2021.08.004 · Cited by 8
Li, C.-L., Wang, C.-C., Pai, H.-T., Tu, S.-L., Hou, P.-Y., Huang, C., Huang, M., & Chang, Y. (2022) · Disease Markers · doi:10.1155/2022/8316335 · Cited by 8
“In the cholinergic system, α7nAChRs facilitates many different pathways, it is extensively studied in association with the antiinflammatory pathways [17].”
BackgroundGoto, D., Nagata, S., Naito, Y., Isobe, S., Iwakura, T., Fujikura, T., Ohashi, N., Kato, A., Miyajima, H., Sugimoto, K., et al. (2022) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00334.2021 · Cited by 8
Frank, N., Nagai, M., & Förster, C. Y. (2023) · Exploration of Neuroprotective Therapy · doi:10.37349/ent.2023.00056 · Cited by 8
Functional magnetic resonance imaging studies of acupuncture mechanisms: a critique
Beißner, F. (2010) · Focus on Alternative and Complementary Therapies · doi:10.1111/j.2042-7166.2010.01048.x · Cited by 8
Fink, M. P. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181abf5f4 · Cited by 8
Year in review 2009: Critical Care - shock
Stahl, W., Bracht, H., Radermacher, P., & Thomas, J. (2010) · Critical Care · doi:10.1186/cc9261 · Cited by 8
“While catecholamines exhibit a friend and foe character [11], acetylcholine – the key mediator of the cholinergic anti-infl ammatory pathway – can directly inhibit cytokine activation via the α 7 subunit of the nicotinic acetylcholine receptor expressed on macrophages, and thus can dampen the infl ammatory response […”
BackgroundPerseguini, N. M., Verlengia, R., Milan, J. C., Minatel, V., Rehder‐Santos, P., Takahashi, A. C. D. M., Santana-Lemos, B. A. A., Calado, R. T., Ferreira-Filho, P. J., Porta, A., et al. (2014) · International Journal of Cardiology · doi:10.1016/j.ijcard.2014.10.123 · Cited by 8
Lee, C.-C., Lo, Y., Ho, L., et al. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149317 · Cited by 8
“To evaluate the chondroprotective effects of HS-Ck on TNF-α-induced activation of NF-κB and STAT-3 transcriptional factors in porcine chondrocytes, we further investigated the suppressive effects of HS-Ck on TNF-α-induced transcriptional activation of NF-κB and STAT-3 by using electrophoretic mobility shift assay (EMS…”
BackgroundInfluentialBock, K., Plaaß, C., Coger, V., Peck, C., Reimers, K., Stukenborg-Colsman, C. M., & Claaßen, L. (2016) · SAGE Open Medicine · doi:10.1177/2050312116637529 · Cited by 8
The Response to Burn Injury in Mice With Human Hematolymphoid Systems
Costantini, T. W., Meads, M., Dang, X., et al. (2015) · Annals of Surgery · doi:10.1097/sla.0000000000001123 · Cited by 8
Sudden Infant Death Syndrome, Infection, Prone Sleep Position, and Vagal Neuroimmunology
Goldwater, P. N. (2017) · Frontiers in Pediatrics · doi:10.3389/fped.2017.00223 · Cited by 9
“Vagal stimulation has been shown in animal models to prevent cytokine release and damage during sepsis, endotoxemia, ischemia/reperfusion injury, and hypotensive shock (36).”
Nederhoff, M. G. J., Fransen, D., Verlinde, S. A. M. W., Brans, M. A. D., Pasterkamp, G., & Bleys, R. L. A. W. (2019) · Autonomic Neuroscience · doi:10.1016/j.autneu.2019.102580 · Cited by 8
“…a healthy physical situation, the immune functions are well balanced since overactivity might lead to unnecessary inflammatory harm while underperformance may give way for infectious disease or illness caused by malfunctioning cells that are not discarded (Tracey, 2007; Sundman and Olofsson, 2014).”
Pulmonary insufficiency in acute stroke: risk factors and mechanisms of development
Chuchalin, A. G., Gusev, E. I., Martynov, M. Y., Kim, T. G., & Shogenova, L. V. (2020) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro20201200717 · Cited by 8
Castel, A., Burns, P., Benito, J., Liu, H. L., Kuthiala, S., Durosier, L. D., Frank, Y., Cao, M., Paquet, M., Fecteau, G., et al. (2021) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2021.109257 · Cited by 8
Causal relationships between the parameters of gas discharge visualization and phagocytosis
Babelyuk, V., Гоженко, А. І., Dubkova, G. I., Babelyuk, N., Żukow, W., Kindzer, B., Kovbasnyuk, M. M., & Popovych, I. L. (2021) · Journal of Education Health and Sport · doi:10.12775/jehs.2021.11.06.029 · Cited by 8
“According to KJ Tracey’s [30] conception of immunological homunculus the CNSs structures that are projected onto certain EEG loci are responsible for certain immune functions.”
ResultRespiratory Sinus Arrhythmia as a Physiological Resilience Marker for Children’s Health
Alen, N. V., Deer, L. K., & Hostinar, C. E. (2022) · Psychosomatic Medicine · doi:10.1097/psy.0000000000001057 · Cited by 9
“Consistent with this finding, animal models have experimentally revealed that stimulation of the vagus nerve can dampen cytokine production through the cholinergic anti-inflammatory pathway, leading to better inflammatory-based disease prognosis (21).”
BackgroundResultDu, X., Dong, B., Li, C., et al. (2017) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2017.4793 · Cited by 8
“α-MSH receptors can be found on the surface of peripheral immune and glial cells with immune effects within the central nervous system, α-MSH can directly affect immune cells by interacting with its receptors (18).”
InfluentialImplications of a Local Overproduction of Tumor Necrosis Factor-α in Complex Regional Pain Syndrome
Walker, S., & Drummond, P. D. (2011) · Pain Medicine · doi:10.1111/j.1526-4637.2011.01273.x · Cited by 8
Pedersen, S. S., Kupper, N. H. M., & van Domburg, R. T. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr156 · Cited by 8
Li, S., Li, M., Yuan, T., Wang, G., Zeng, J., Shi, Z., Liu, J., & Su, J. (2024) · Chemistry & Biodiversity · doi:10.1002/cbdv.202400290 · Cited by 7
Leem, Y., Park, J., Park, J., Kim, D., Park, J.-M., Kim, S., Kang, J. L., & Kim, H.-S. (2025) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2025.117871 · Cited by 7
Neural and Endocrine Regulation of Immunity
Ogidi, O. I., Dike, N. I., & Sogoi, B. P. (2025) · Advances in medical diagnosis, treatment, and care (AMDTC) book series · doi:10.4018/979-8-3693-7432-0.ch002 · Cited by 7
Tanaka, S. (2024) · Clinical and Experimental Nephrology · doi:10.1007/s10157-024-02494-7 · Cited by 8
“The efferent arm of the inflammatory reflex is referred to as the cholinergic antiin-flammatory pathway (CAP) [52].”
Background
Metadata
- Authors
- Tracey, K. J.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Corresponding author
- Tracey, Kevin J.
- ORCID
- Tracey, Kevin J.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-02-01
- Volume
- 117
- Issue
- 2
- Pages
- 289-296
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC1783813
- OpenAlex
- W2002797282
- Semantic Scholar
- 76a50e9232b81d22a72d6631b636a0d756df76b8
- Cited by
- 1,563
- References
- 107
- Citations by year
- 2026: 73 · 2025: 58 · 2024: 76 · 2023: 58 · 2022: 72 · 2021: 89 · 2020: 92 · 2019: 76 · 2018: 79 · 2017: 87 · 2016: 78 · 2015: 78 · 2014: 88 · 2013: 87 · 2012: 89
- FWCI
- 8.72
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Defense Advanced Research Projects Agency
- Advanced Research Projects Agency
- National Institute of General Medical Sciences
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- cholinergic anti-inflammatory pathway, vagus nerve, cytokine production, neuroimmune regulation, sepsis, endotoxemia, ischemia-reperfusion injury, hemorrhagic shock, arthritis, humoral theory, terrain theory, cholinergic agonists, neuroprotection, tissue damage, multiple organ failure
- MeSH terms
- Animals, Brain, Cholinergic Fibers, Humans, Inflammation, Models, Biological, Cytokines, History, 20th Century, History, 21st Century, History, Ancient
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