The DOI matches its Crossref record; 105 of the 107 references it cites were found in a registry or an index; 2 of the 138 sources its claims cite were checked for support.
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
78 Not checked yet · 6 No basis given · 4 Own interpretation · 2 Partly supported · accuracy not yet measured
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In the paper
“Vagus nerve stimulation of mice in a model of subcutaneous inflammation caused by injecting carrageenan into an air pouch significantly inhibited the recruitment of polymorphonuclear leukocytes to the inflammatory zone (25).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Partly supportedcites [25] Saeed, 2005, J. Exp. Med. sourceExperimental — accuracy not yet measured
The Methods describe vagus nerve stimulation in mice with subcutaneous carrageenan air pouches, and the Results report 60% less leukocyte recruitment than in sham-operated mice. The reported outcome is recruitment of leukocytes overall, not a separately measured reduction in polymorphonuclear leukocytes. (LLM, conf=0.85)
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- Partly supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Reperfusion of ischemic tissues stimulates cytokine overproduction (e.g., TNF, IL-1, HMGB1), which contributes to the pathogenesis of resulting tissue damage (42)(43)(44).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Ischemia/reperfusion.
What the sources say
- Not checked yetcites [42] Izuishi, 2006, J. Immunol. source
- Partly supportedcites [43] Colletti, 1990, J. Clin. Invest. sourceExperimental — accuracy not yet measured
The Results report TNF release after hepatic ischemia/reperfusion in rats, and the Discussion links TNF to subsequent lung and liver injury. The Discussion mentions IL-1 as a possible contributor but does not establish its overproduction after reperfusion; our copy does not mention HMGB1. The study also concerns hepatic ischemia in rats, rather than ischemic tissues generally. (LLM, conf=0.88)
- Not checked yetcites [44] Bernik, 2002, J. Vasc. Surg. source
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“From this emerged the cytokine theory of disease, the concept that cytokines produced by the immune system can cause the signs, symptoms, and damaging aftereffects of disease (Figure 1) (reviewed in ref. 2).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Abstract
What the sources say
- Not checked yetcites [2] Tracey, K.J. 2005.Fatal sequence: the killer within. Dana Press. Washington, DC, USA. 238 pp.
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
plaindirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
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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
plaincorrelational- Asserted: passes — The authors put it forward as true.
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None of the sources cited for this claim have been checked yet.
In the paper
“Nonetheless, together the present results indicate that α7 nAChR-dependent signals, which can be activated via vagus nerve stimulation, regulate cytokine production and the capacity for damage.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 1
What the sources say
hedgeddirect- Asserted: passes — The authors put it forward as true.
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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
plaindirect- Asserted: passes — The authors put it forward as true.
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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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- 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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The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“this cranial nerve, which meanders through the thorax and abdomen and has been termed the single most important nerve in the body, is a primitive extension of the CNS to the visceral organs, including organs of the reticuloendothelial system, such as the spleen and liver, that are major sources of damaging cytokines.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > The cholinergic antiinflammatory pathway
plain- Asserted: passes — The authors put it forward as true.
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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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None of the sources cited for this claim have been checked yet.
In the paper
“Sudden death, increased morbidity and mortality following cardiac surgery in hostile or depressed patients, and increased death rates in patients with sepsis or organ failure are linked clinically to decreased vagus nerve activity (50)(51)(52)(53)(54).”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Figure 4
What the sources say
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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Probably not a substantial claim.
In the paper
“Similar beneficial effects were achieved by administration of nicotine, which activated phosphorylation of STAT3 and its binding to and transactivation of its corresponding DNA-response elements.”
§ Physiology and immunology of the cholinergic antiinflammatory pathway > Experimental arthritis.
What the sources say
- Not checked yetcites [22] de Jonge, 2005, Nat. Immunol. source
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.
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.
- 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
“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.”
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“In younger healthy individuals, it is not uncommon to see an obvious increase in the HF band at night with a decrease during the day (Lombardi et al., 1996; Otsuka et al., 1997).”
BackgroundHarmful molecular mechanisms in sepsis
Rittirsch, D., Flierl, M. A., & Ward, P. A. (2008) · Nature reviews. Immunology · doi:10.1038/nri2402 · Cited by 1,230
“The efferent arm of the inflammatory reflex is the cholinergic anti-inflammatory pathwa”
BackgroundTracey, K. J. (2009) · Nature Reviews Immunology · doi:10.1038/nri2566 · Cited by 1,154
Self-citationThe vagus nerve and the inflammatory reflex – linking immunity and metabolism
Pavlov, V. A., & Tracey, K. J. (2012) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.189 · Cited by 1,040
Self-citationThe immune system’s role in sepsis progression, resolution, and long-term outcome
Delano, M. J., & Ward, P. A. (2016) · Immunological Reviews · doi:10.1111/imr.12499 · Cited by 880
Mechanisms and treatment of organ failure in sepsis
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The Gut Microbiota and Alzheimer’s Disease
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“…effect of vagus nerve stimulation is still unkown, it may activate the anti-inflammatory pathway releasing ACh which binds to (cid:5) -7-nicotinic ACh receptors ( (cid:5) 7 nAChRs) of macrophages to inhibit the release of proinflammatory cytokines (i.e., TNF (cid:5) ) (for review, see [163, 164]).”
Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia
Rosas‐Ballina, M., Ochani, M., Parrish, W. R., Ochani, K., Harris, Y., Huston, J. M., Chavan, S. S., & Tracey, K. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0803237105 · Cited by 762
“Discussion The results herein expand our knowledge of the anatomical basis of the cholinergic antiinflammatory pathway (28, 29).”
BackgroundSelf-citationSilverman, M. N., & Sternberg, E. M. (2012) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2012.06633.x · Cited by 775
Kalogeris, T. J., Baines, C. P., Krenz, M., & Korthuis, R. J. (2016) · Comprehensive physiology · doi:10.1002/cphy.c160006 · Cited by 856
The pathogenesis of rheumatoid arthritis
Alivernini, S., Firestein, G. S., & McInnes, I. B. (2022) · Immunity · doi:10.1016/j.immuni.2022.11.009 · Cited by 765
Sepsis: Current Dogma and New Perspectives
Deutschman, C. S., & Tracey, K. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.04.001 · Cited by 708
“…been suggested that pharmacological agents, including statins and centrally cholinergic agonists, might confer a survival advantage by enhancing vagus nerve and thereby restoring the anti-inflammatory activity of the inflammatory reflex (Werdan et al., 2009; Satapathy et al., 2011; Tracey, 2007).”
BackgroundSelf-citationMechanisms and Therapeutic Relevance of Neuro-immune Communication
Chavan, S. S., Pavlov, V. A., & Tracey, K. J. (2017) · Immunity · doi:10.1016/j.immuni.2017.06.008 · Cited by 678
“An important role for this pathway has been indicated in controlling inflammation in the viscera, which is directly innervated by the vagus nerve, in several inflammatory conditions (Pavlov, 2008; Tracey, 2007).”
Self-citationHomeostasis of the gut barrier and potential biomarkers
Wells, J. M., Brummer, R. J., Derrien, M., MacDonald, T. T., Troost, F. J., Cani, P. D., Théodorou, V., Dekker, J. P., Méheust, A., de Vos, W. M., et al. (2016) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00048.2015 · Cited by 638
Host–pathogen interactions in sepsis
van der Poll, T., & Opal, S. M. (2007) · The Lancet Infectious Diseases · doi:10.1016/s1473-3099(07)70265-7 · Cited by 568
Kemp, A. H., & Quintana, D. S. (2013) · International Journal of Psychophysiology · doi:10.1016/j.ijpsycho.2013.06.018 · Cited by 538
“…dysregulation may be the final common pathway for a host of conditions and diseases, including cardiovascular disease and mortality (Thayer et al., 2010b), which may be attributable to impairment in the cholinergic anti-inflammatory pathway (Pavlov and Tracey, 2012; Tracey, 2002b, 2007).”
BackgroundMethodInfluentialBennett, J. M., Reeves, G., Billman, G. E., & Sturmberg, J. P. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00316 · Cited by 531
“α7 nAChR stimulation inhibits NF-κB from altering inflammatory expression; resulting in decreased cytokine production and anti-inflammatory effects (43, 44).”
BackgroundBrowning, K. N., & Travagli, R. A. (2014) · Comprehensive Physiology · doi:10.1002/cphy.c130055 · Cited by 541
“The discovery that vagal nerve stimulation suppresses cytokine production potently lead to the recognition of a vagally mediated cholinergic anti-inflammatory pathway, whereby activation of vagal afferents by inflammatory mediators results in the reflex activation of vagal efferent pathways to dampen cytokine producti…”
New Insights into the Placebo and Nocebo Responses
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“Pavlovian Conditioning of Placebo Effects: Neuroimmune Responses The behavioral conditioning of immune responses is based on the intense crosstalk between the CNS and the peripheral immune system (Meisel et al., 2005; Sternberg, 2006; Tracey, 2007).”
Neural regulation of immunity: molecular mechanisms and clinical translation
Pavlov, V. A., & Tracey, K. J. (2017) · Nature Neuroscience · doi:10.1038/nn.4477 · Cited by 552
Self-citationThe microbiome: a key regulator of stress and neuroinflammation
Rea, K., Dinan, T. G., & Cryan, J. F. (2016) · Neurobiology of Stress · doi:10.1016/j.ynstr.2016.03.001 · Cited by 508
“…can detect the release of inflammatory mediators from the gut, and communicate this sensory information to the brainstem, resulting in efferent cholinergic vagal suppression of peripheral inflammatory cytokines, such as TNF a and IL-1b in the spleen (Rosas-Ballina and Tracey, 2009; Tracey, 2007).”
Specialized pro-resolving lipid mediators in the inflammatory response: An update
Bannenberg, G., & Serhan, C. N. (2010) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2010.08.002 · Cited by 464
“The counter-regulation of the inflammatory response is achieved by several physiological mechanisms acting at the systemic level; an increase in circulating levels of glucocorticoids, activation of the acute-phase response, and antiinflammatory cholinergic efferent neural pathways provide systemically active and prote…”
BackgroundParasympathetic Nervous System and Heart Failure
Olshansky, B., Sabbah, H. N., Hauptman, P. J., & Colucci, W. S. (2008) · Circulation · doi:10.1161/circulationaha.107.760405 · Cited by 460
Molecular and functional neuroscience in immunity
Pavlov, V. A., Chavan, S. S., & Tracey, K. J. (2018) · Annual Review of Immunology · doi:10.1146/annurev-immunol-042617-053158 · Cited by 444
“(88–90), sepsis (88, 91), arthritis (92), IBD (93–95), hemorrhagic shock (96), postoperative ileus (97), renal ischemia and reperfusion injury (98), and other models of inflammatory and autoimmune conditions (69, 99, 100).”
InfluentialSelf-citationClark, J. A., & Coopersmith, C. M. (2007) · Shock · doi:10.1097/shk.0b013e31805569df · Cited by 443
“For example, in multiple experimental models of critical illness, an inflammatory reflex has been described where the parasympathetic vagus nerve inhibits cytokine release (118).”
BackgroundPavlov, V. A., Parrish, W. R., Rosas‐Ballina, M., Ochani, M., Gallowitsch‐Puerta, M., Ochani, K., Chavan, S. S., Al‐Abed, Y., & Tracey, K. J. (2008) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2008.06.011 · Cited by 437
Self-citationAnti-inflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke
Lee, S.-T., Chu, K., Jung, K.-H., Kim, S.-J., Kim, D.-H., Kang, K.-M., Hong, N. H., Kim, J.-H., Ban, J.-J., Park, H.-K., et al. (2008) · Brain · doi:10.1093/brain/awm306 · Cited by 424
“To investigate whether NSCs interact with spleen to reduce cerebral inflammation, we performed a splenectomy prior to ICH induction, which eliminated the effect of NSCs-iv-2 h transplantation on brain water content and inflammatory infiltrations.”
BackgroundMicroRNA-132 Potentiates Cholinergic Anti-Inflammatory Signaling by Targeting Acetylcholinesterase
Shaked, I., Meerson, A., Wolf, Y., Avni, R., Greenberg, D., Gilboa-Geffen, A., & Soreq, H. (2009) · Immunity · doi:10.1016/j.immuni.2009.09.019 · Cited by 366
Sharkey, K. A., & Mawe, G. M. (2022) · Physiological Reviews · doi:10.1152/physrev.00018.2022 · Cited by 447
Energy regulation and neuroendocrine–immune control in chronic inflammatory diseases
Straub, R. H., Cutolo, M., Buttgereit, F., & Pongratz, G. (2010) · Journal of Internal Medicine · doi:10.1111/j.1365-2796.2010.02218.x · Cited by 382
Autonomic Nervous System and Immune System Interactions
Kenney, M., & Ganta, C. K. (2014) · Comprehensive physiology · doi:10.1002/cphy.c130051 · Cited by 441
Neural reflexes in inflammation and immunity
Andersson, U., & Tracey, K. J. (2012) · The Journal of Experimental Medicine · doi:10.1084/jem.20120571 · Cited by 388
“The resultant efferent reflex signals regulate B cell trafficking and influence the nature of the adaptive immune response.”
BackgroundInfluentialSelf-citationZhang, Y., Popović, Z., Bibevski, S., Fakhry, I., Sica, D. A., Wagoner, D. R. V., & Mazgalev, T. N. (2009) · Circulation Heart Failure · doi:10.1161/circheartfailure.109.873968 · Cited by 377
Expression and Function of the Cholinergic System in Immune Cells
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Heart rate variability and inflammation: A meta-analysis of human studies
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Compensatory anti-inflammatory response syndrome
Cavaillon, J., & Adib‐Conquy, M. (2008) · Thrombosis and Haemostasis · doi:10.1160/th08-07-0421 · Cited by 367
Targeting HMGB1 in inflammation
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Self-citationBreath of Life: The Respiratory Vagal Stimulation Model of Contemplative Activity
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“An anti-inflammatory reflex, known as the cholinergic anti-inflammatory pathway has been put forward from findings in animal studies on rats (Tracey, 2002, 2007; Pavlov and Tracey, 2015).”
BackgroundMonitoring Immune Dysfunctions in the Septic Patient: A New Skin for the Old Ceremony
Monneret, G., Venet, F., Pachot, A., & Lepape, A. (2008) · Molecular Medicine · doi:10.2119/2007-00102.monneret · Cited by 353
Parrish, W. R., Rosas‐Ballina, M., Gallowitsch‐Puerta, M., Ochani, M., Ochani, K., Yang, L., Hudson, L., Lin, X., Patel, N. B., Johnson, S. M., et al. (2008) · Molecular Medicine · doi:10.2119/2008-00079.parrish · Cited by 335
Self-citationTobacco smoking, but not Swedish snuff use, increases the risk of multiple sclerosis
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Current Directions in the Auricular Vagus Nerve Stimulation I – A Physiological Perspective
Kaniušas, E., Kampusch, S., Tittgemeyer, M., Panetsos, F., Gines, R. F., Papa, M., Kiss, A., Podesser, B. K., Cassara, A. M., Tanghe, E., et al. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00854 · Cited by 344
“…13 | Article 854 rheumatoid arthritis, see a clinical trial in Becker (2007), inflammatory bowel disease (Crohn’s disease, ulcerative colitis), and postoperative ileus in order to restore intestinal homeostasis, as reviewed in Tracey (2007), Marshall et al. (2015), and Bonaz and Pellissier (2016).”
BackgroundAnti-inflammatory effect of vagus nerve stimulation in a rat model of inflammatory bowel disease
Meregnani, J., Clarençon, D., Vivier, M., Peinnequin, A., Mouret, C., Sinniger, V., Picq, C., Job, A., Canini, F., Jacquier-Sarlin, M., et al. (2011) · Autonomic Neuroscience · doi:10.1016/j.autneu.2010.10.007 · Cited by 310
“So far, all studies investigating the anti-inflammatory effect of VNS were performed acutely in anesthetized animals and the frequency range commonly used for this purpose was 5–10 Hz (Bernik et al., 2002b; Naritoku et al., 1995; Tracey, 2007).”
Backgroundvan de Pavert, S. A., Olivier, B. J., Goverse, G., Vondenhoff, M. F. R., Greuter, M., Beke, P., Kusser, K. L., Höpken, U. E., Lipp, M., Niederreither, K., et al. (2009) · Nature Immunology · doi:10.1038/ni.1789 · Cited by 311
“Another example of neuronal influence on the immune system is the immune-modulating effect of the vagus nerv”
BackgroundInoue, T., Abe, C., Sung, S. J., Moscalu, S., Jankowski, J., Huang, L., Ye, H., Rosin, D. L., Guyenet, P. G., & Okusa, M. D. (2016) · Journal of Clinical Investigation · doi:10.1172/jci83658 · Cited by 316
“In the inflammatory reflex, mediators of inflammation are sensed by the peripheral and central nervous system, and CAP signaling is initiated in brain stem nuclei of the vagus nerve and can be activated by vagus nerve stimulation (VNS) (12).”
BackgroundVagus nerve stimulation: from epilepsy to the cholinergic anti‐inflammatory pathway
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“Detailed anatomical analysis has suggested the lymphoid organs are innervated by the peripheral nervous system (Sternberg, 2006), the sympathetic nervous system (Nance and Sanders, 2007), and the parasympathetic nervous system (Tracey, 2007).”
Nizri, E., Irony-Tur-Sinai, M., Lory, O., Orr‐Urtreger, A., Lavi, E., & Brenner, T. (2009) · The Journal of Immunology · doi:10.4049/jimmunol.0902212 · Cited by 315
Procaccini, C., Jirillo, E., & Matarese, G. (2012) · Molecular Aspects of Medicine · doi:10.1016/j.mam.2011.10.012 · Cited by 299
Farsalinos, K. E., Barbouni, A., & NIAURA, R. S. (2020) · Internal and Emergency Medicine · doi:10.1007/s11739-020-02355-7 · Cited by 303
Cardiac autonomic balance versus cardiac regulatory capacity
Berntson, G. G., Norman, G. J., Hawkley, L. C., & Cacioppo, J. T. (2008) · Psychophysiology · doi:10.1111/j.1469-8986.2008.00652.x · Cited by 290
“Sympathetic adrenergic modulation has complex effects on the immune system and can either enhance or suppress the release of pro-inflammatory cytokines such as tumor necrosis factor (TNF) and interleukin 1 (IL1), whereas the parasympathetic division represents an important component of what has been termed the choline…”
BackgroundA Cross-Sectional Study of Cannabidiol Users
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Li, G., Bauer, S., Nowak, M., Norwood, B. A., Tackenberg, B., Rosenow, F., Knake, S., Oertel, W. H., & Hamer, H. M. (2011) · Seizure · doi:10.1016/j.seizure.2010.12.005 · Cited by 275
Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis
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“Neural control of the acute inflammatory response is partly reflexive through a cholinergic anti-inflammatory pathway, with afferent vagal signaling to the brain triggered by local tissue damage and related inflammatory stimuli and efferent vagal activity inhibiting cytokine production through ACTH (adrenocorticotropi…”
BackgroundCancer cachexia—pathophysiology and management
Suzuki, H., Asakawa, A., Amitani, H., Nakamura, N., & Inui, A. (2013) · Journal of Gastroenterology · doi:10.1007/s00535-013-0787-0 · Cited by 285
“Although the molecular mechanisms and cellular targets mediating ghrelin inhibition of NF-jB activation remain to be determined, the vagus nerve may play an important role in the ghrelin-mediated inhibition of proinflammatory cytokine release [150, 152].”
BackgroundRR Interval Variability Is Inversely Related to Inflammatory Markers: The CARDIA Study
Sloan, R. P., McCreath, H., Tracey, K. J., Sidney, S., Liu, K., & Seeman, T. (2007) · Molecular Medicine · doi:10.2119/2006-00112.sloan · Cited by 264
“This, in turn, activates an opposing, efferent response via the cholinergic antiinflammatory pathway, which serves to inhibit inflammation and prevent damage (5,6).”
BackgroundSelf-citationInflammatory Responses in Brain Ischemia
Kawabori, M., & Yenari, M. A. (2015) · Current Medicinal Chemistry · doi:10.2174/0929867322666150209154036 · Cited by 273
“Vagal nerve stimulation has been shown to inhibit the release of proinflammatory cytokines and improves outcomes in different stroke models [300].”
BackgroundPathophysiology and Treatment of Septic Shock in Neonates
Wynn, J. L., & Wong, H. R. (2010) · Clinics in Perinatology · doi:10.1016/j.clp.2010.04.002 · Cited by 260
The Neuroimmune Basis of Anti-inflammatory Acupuncture
Kavoussi, B., & Ross, B. E. (2007) · Integrative Cancer Therapies · doi:10.1177/1534735407305892 · Cited by 263
“The parasympathetic origin of the nonspecific antiinflammatory actions of acupuncture is supported by the observation that the direct electrical stimulation of the efferent vagus nerve in LPS-challenged wildtype mice inhibits the synthesis of TNF in organs rich in cells of the monocyte-macrophage system.(40) Tracey et…”
BackgroundPavlov, V. A., & Tracey, K. J. (2015) · Immunologic Research · doi:10.1007/s12026-015-8718-1 · Cited by 254
“A role for activation of the cholinergic anti-inflammatory pathway by utilizing a7nAChR agonists or centrally acting acetylcholinesterase inhibitors in ameliorating inflammation and alleviating disease severity has been shown in various disease models, including septic shock, severe sepsis, hemorrhagic shock, rheumato…”
BackgroundSelf-citationPerfect timing: circadian rhythms, sleep, and immunity — an NIH workshop summary
Haspel, J. A., Anafi, R. C., Brown, M. K., Cermakian, N., Depner, C. M., Desplats, P., Gelman, A. E., Haack, M., Jelić, S., Kim, B., et al. (2020) · JCI Insight · doi:10.1172/jci.insight.131487 · Cited by 261
“One opportunity cited by Workshop participants was to better understand how circadian rhythms in autonomic tone contribute to neuroimmune reflexes, such as those that influence sepsis outcomes (123, 124).”
BackgroundInnate Inflammatory Responses in Stroke: Mechanisms and Potential Therapeutic Targets
Kim, J. Y., Kawabori, M., & Yenari, M. A. (2014) · Current Medicinal Chemistry · doi:10.2174/0929867321666131228205146 · Cited by 253
“When the vagus nerve is activated by pro- inflammatory cytokines, it releases acetylcholine, which results in inhibition of the release of more pro-inflammatory mediators by macrophages [307, 308].”
BackgroundEditorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system
Farsalinos, K. E., NIAURA, R. S., Houezec, J. L., Barbouni, A., Tsatsakis, A. M., Kouretas, D., Vantarakis, A., & Poulas, K. A. (2020) · Toxicology Reports · doi:10.1016/j.toxrep.2020.04.012 · Cited by 251
“While for decades common thinking suggested that every immune response to antigenic invasion was always beneficial in averting potential damage, studies in the 1980s identified that immune cells produce proteins with pleiotropic properties, having the potential to be either beneficial or harmful [13].”
Lukaszewicz, A., Grienay, M., Resche‐Rigon, M., Pirracchio, R., Faivre, V., Boval, B., & Payen, D. M. (2009) · Critical Care Medicine · doi:10.1097/ccm.0b013e3181ab858a · Cited by 288
Inflammation-Associated Co-morbidity Between Depression and Cardiovascular Disease
Halaris, A. (2016) · Current Topics in Behavioral Neurosciences · doi:10.1007/7854_2016_28 · Cited by 233
Singer, P., Shapiro, H., Theilla, M., Anbar, R., Singer, J., & Cohen, J. D. (2008) · Intensive Care Medicine · doi:10.1007/s00134-008-1142-4 · Cited by 241
“which are implicated in the pathophysiology of sepsis [70].”
BackgroundStress-induced neuroinflammation: mechanisms and new pharmacological targets
Munhoz, C. D., García‐Bueno, B., Madrigal, J. L. M., Lepsch, L. B., Scavone, C., & Leza, J. C. (2008) · Brazilian Journal of Medical and Biological Research · doi:10.1590/s0100-879x2008001200001 · Cited by 231
The Neurology of the Immune System: Neural Reflexes Regulate Immunity
Rosas‐Ballina, M., & Tracey, K. J. (2009) · Neuron · doi:10.1016/j.neuron.2009.09.039 · Cited by 226
“This is the basis for the ‘‘cytokine theory of disease,’’ the paradigm that cytokines are necessary and sufficient for disease pathogenesis (Tracey, 2007).”
BackgroundSelf-citationLymph nodes are innervated by a unique population of sensory neurons with immunomodulatory potential
Huang, S., Ziegler, C. G. K., Austin, J., Mannoun, N., Vukovic, M., Ordovás-Montañés, J., Shalek, A. K., & von Andrian, U. H. (2020) · Cell · doi:10.1016/j.cell.2020.11.028 · Cited by 234
Immunodepression, Infections, and Functional Outcome in Ischemic Stroke
Westendorp, W. F., Dames, C., Nederkoorn, P. J., & Meisel, A. (2022) · Stroke · doi:10.1161/strokeaha.122.038867 · Cited by 234
Autonomic regulation of cellular immune function
Bellinger, D. L., & Lorton, D. (2014) · Autonomic Neuroscience · doi:10.1016/j.autneu.2014.01.006 · Cited by 217
“Tracy and colleagues (Tracey, 2007; Rosas-Ballina et al., 2008; Rosas-Ballina and Tracey, 2009) have coined the term “the cholinergic anti-inflammatory reflex” in reference to the pathway mediating immune responses resulting from efferent vagal stimulation.”
BackgroundNeuroinflammation and Cognitive Aging
Ownby, R. L. (2010) · Current Psychiatry Reports · doi:10.1007/s11920-009-0082-1 · Cited by 212
“Although cholinesterase inhibitors and memantine are the only medications specifically approved for the treatment of Alzheimer’s disease, at least one report suggests that the cholinesterase inhibitor galantamine may have neuroprotective effects [44], perhaps by activating the cholinergic anti-inflammatory pathway [45…”
BackgroundSun, P., Zhou, K., Wang, S., Li, P., Chen, S., Lin, G., Zhao, Y., & Wang, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0069424 · Cited by 209
“Normally, a low-frequency range of stimulation (1-5Hz) was used for investigating the anti-inflammatory effect of the activation of vagal efferents [32], however, vagal afferents may also be activated.”
MethodGene-specific control of the TLR-induced inflammatory response
Foster, S. L., & Medzhitov, R. M. (2008) · Clinical Immunology · doi:10.1016/j.clim.2008.08.015 · Cited by 213
“So inflammation is primarily considered to be regulated through negative feedback [1,14].”
BackgroundLiu, C.-H., Yang, M.-H., Zhang, G.-Z., Wang, X.-X., Li, B., Li, M., Woelfer, M., Walter, M., & Wang, L. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01732-5 · Cited by 210
“protects against systemic inflammation via the CAP that vagus nerve-released acetylcholine inhibits TNF-α release [90] or the connections of the vagus nerve with the spleen [91].”
BackgroundFarsalinos, K. E., Barbouni, A., & NIAURA, R. S. (2020) · Internal and Emergency Medicine · doi:10.1007/s11739-020-02457-2 · Cited by 206
“Nicotine is an agonist of the cholinergic anti-inflammatory pathway that regulates host immune and inflammatory responses [36] [37] [38] [39] .”
BackgroundGhrelin Attenuates Sepsis-induced Acute Lung Injury and Mortality in Rats
Wu, R., Dong, W., Zhou, M., Zhang, F., Marini, C. P., Ravikumar, T. S., & Wang, P. (2007) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.200604-511oc · Cited by 206
“Acetylcholine released by stimulation of the vagus nerve binds to the a7 subunit of the nicotinic acetylcholine receptor expressed on macrophages, suppressing proinflammatory cytokine production by an NF-kB‐dependent pathway (49, 50 ).”
BackgroundFlierl, M. A., Rittirsch, D., Huber-Lang, M. S., Sarma, J. V., & Ward, P. A. (2008) · Molecular Medicine · doi:10.2119/2007-00105.flierl · Cited by 204
Identification of cytokine-specific sensory neural signals by decoding murine vagus nerve activity
Zanos, T. P., Silverman, H. A., Levy, T. J., Tsaava, T., Battinelli, E., Lorraine, P. W., Ashe, J. M., Chavan, S. S., Tracey, K. J., & Bouton, C. E. (2018) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1719083115 · Cited by 203
Self-citationNeural aspects of immunomodulation: Focus on the vagus nerve
Thayer, J. F., & Sternberg, E. M. (2010) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2010.07.247 · Cited by 212
“Challenges and opportunities Tracey (2007) has suggested that future research on the connections between the brain and the immune system may reveal an immunological homunculus.”
BackgroundInfluentialAlpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases
Bencherif, M., Lippiello, P. M., Lucas, R., & Marrero, M. B. (2010) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-010-0525-1 · Cited by 207
“substantial interest due to the obvious relevance to a variety of debilitating human diseases [63].”
BackgroundImportance of T Lymphocytes in Brain Injury, Immunodeficiency, and Recovery after Cerebral Ischemia
Brait, V. H., Arumugam, T. V., Drummond, G. R., & Sobey, C. G. (2012) · Journal of Cerebral Blood Flow & Metabolism · doi:10.1038/jcbfm.2012.6 · Cited by 198
Cytokines and the immunomodulatory function of the vagus nerve
Johnston, G. R., & Webster, N. R. (2009) · British Journal of Anaesthesia · doi:10.1093/bja/aep037 · Cited by 205
The crosstalk between autonomic nervous system and blood vessels.
Sheng, Y., & Zhu, L. (2018) · PubMed Central · Cited by 196
Gigliotti, J. C., Huang, L., Ye, H., Bajwa, A., Chattrabhuti, K., Lee, S., Klibanov, A. L., Kalantari, K., Rosin, D. L., & Okusa, M. D. (2013) · Journal of the American Society of Nephrology · doi:10.1681/asn.2013010084 · Cited by 196
Badran, B. W., Mithoefer, O. J., Summer, C. E., LaBate, N. T., Glusman, C. E., Badran, A. W., DeVries, W. H., Summers, P. M., Austelle, C. W., McTeague, L. M., et al. (2018) · Brain stimulation · doi:10.1016/j.brs.2018.04.004 · Cited by 197
“The vagus nerve (CN X) is a mixed sensory and motor nerve that has efferent projections travelling throughout the abdomen, targeting nearly every major organ and is highly involved in the parasympathetic nervous system [1,2].”
BackgroundTranscutaneous Auricular Vagus Nerve Stimulation: From Concept to Application
Wang, Y., Li, S., Wang, D., Wu, M., He, J., Zhang, J., Zhao, B., Hou, L.-W., Wang, J., Wang, L., et al. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00619-y · Cited by 203
Hulse, E. J., Davies, J. O. J., Simpson, A. J., Sciuto, A. M., & Eddleston, M. (2014) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.201406-1150ci · Cited by 193
Pisetsky, D. S., Erlandsson-Harris, H., & Andersson, U. (2008) · Arthritis Research & Therapy · doi:10.1186/ar2440 · Cited by 190
Critical Neurotransmitters in the Neuroimmune Network
Hodo, T., de Aquino, M. T. P., Shimamoto, A., & Shanker, A. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01869 · Cited by 192
“The ACh thus released activates the cognate α7 nicotinic ACh receptors (α7nAChR) on neighboring monocytes and macrophages (44, 60, 61).”
BackgroundAlpha7 Nicotinic Acetylcholine Receptor Is a Target in Pharmacology and Toxicology
Pohanka, M. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms13022219 · Cited by 188
Cunningham, C. M., & MacLullich, A. M. J. (2012) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2012.07.012 · Cited by 181
“The trial was based on the dual role of acetylcholine as a neuromodulator and as an endogenous inhibitor of systemic inflammatory responses to endotoxemia (Tracey, 2007).”
Oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men
Clodi, M., Vila, G., Geyeregger, R., Riedl, M., Stulnig, T. M., Struck, J., Luger, T. A., & Luger, A. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90263.2008 · Cited by 184
“It has been reported that direct electrical stimulation of the efferent vagus nerve attenuates cytokine release in endotoxemia, whereas vagotomy exacerbates the inflammatory response to endotoxins (27).”
BackgroundTranslational neurocardiology: preclinical models and cardioneural integrative aspects
Ardell, J. L., Andresen, M. C., Armour, J. A., Billman, G. E., Chen, P., Foreman, R. D., Herring, N., O’Leary, D. S., Sabbah, H. N., Schultz, H. D., et al. (2016) · The Journal of Physiology · doi:10.1113/jp271869 · Cited by 176
“The Journal of Physiology C© 2016 The Physiological Society receptors as well as inhibition of pro-inflammatory cytokines (Tracey, 2007; Jänig, 2014a) and normalization of nitric oxide signalling (Sabbah, 2011; Sabbah et al. 2011b).”
BackgroundInfluentialUpregulation of Phagocyte-Derived Catecholamines Augments the Acute Inflammatory Response
Flierl, M. A., Rittirsch, D., Nadeau, B. A., Sarma, J. V., Day, D. E., Lentsch, A. B., Huber-Lang, M. S., & Ward, P. A. (2009) · PLoS ONE · doi:10.1371/journal.pone.0004414 · Cited by 168
“According to its afferent and efferent arms, this effect has been termed ‘‘inflammatory reflex’’ [2] or ‘‘cholinergic anti-inflammatory pathway’’ [6].”
Marques, A. H., Silverman, M. N., & STERNBERG, E. M. (2010) · NeuroImmunoModulation · doi:10.1159/000258725 · Cited by 168
Field, R. H., Gossen, A., & Cunningham, C. M. (2012) · Journal of Neuroscience · doi:10.1523/jneurosci.4673-11.2012 · Cited by 165
“…rivastigmine was recently tested as a treatment for intensive care unit (ICU) delirium (van Eijk et al., 2010) based both on the known neuromodulatory role of acetylcholine and on its suppression of peripheral macrophage function via vagal stimulation of 7-nicotinic receptors (Tracey, 2007).”
BackgroundArina, P., & Singer, M. (2021) · Current Opinion in Anaesthesiology · doi:10.1097/aco.0000000000000963 · Cited by 182
“An imbalance between sympathetic and parasympathetic pathways can compromise neural control of inflammation and immunity [25,26].”
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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