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Reflex control of immunity
Open accessAbstract
Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.
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“Interestingly, evidence suggests that activation of the parasympathetic nervous system also can modulate the activity of the immune system via alterations in vagal release of acetylcholine from T cells (Tracey, 2009).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Tracey, 2009
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In the citing paper
“Additional evidence suggests that the parasympathetic nervous system modulates immune responses at a regional level through both the efferent and afferent fibers of the vagus nerve, enabling it to prevent excessive inflammation”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Tracey, 2009
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“For example, motor vagus nerve stimulation attenuates the activation of NFκB following an immune challenge (Tracey, 2009).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Tracey, 2009
In the citing paper
“ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the TNF-α (69).”
From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [69]
In the citing paper
“with evidence that vagal activity can modulate immune responses at a regional level through both the efferent and afferent fibers of the vagus nerve, to prevent excessive inflammation”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Tracey, 2009
In the citing paper
“Multiple non-exclusive pathways participate in the activation of the HPA axis upon cerebral or peripheral immune challenges. When an immunogenic insult takes place in the brain, various inflammatory mediators produced locally may trigger the HPA axis.”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [21]
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Citations
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“Initial studies into the role of the parasympathetic nervous system in the immune response have characterized the “immunomodulatory reflex,” in which firing of the vagus nerve results in significant reduction of inflammatory markers, including TNF.11 Thus, increased parasympathetic tone appears to have an observable a…”
BackgroundNeuronal Regulation of Pain and Inflammation
Svensson, C. I., & Sorkin, L. S. (2016) · Elsevier eBooks · doi:10.1016/b978-0-323-31696-5.00030-9 · Cited by 2
Asfandiyarova, N. S. (2018) · Immunopathology Allergology Infectology · doi:10.14427/jipai.2018.3.6 · Cited by 2
Fang, C., Chen, C., Shen, K., Yang, W., Muo, C., & Wu, S. (2020) · Scientific Reports · doi:10.1038/s41598-020-78913-y · Cited by 2
Stress, Immune System and the Brain
Bourgognon, J.-M., McColl, A., Suessmilch, M., Krishnadas, R., & Cavanagh, J. (2021) · Cambridge University Press eBooks · doi:10.1017/9781108539623.004 · Cited by 2
Medicinal nicotine in COVID-19 acute respiratory distress syndrome, the new corticosteroid
Ahmad, F. (2022) · World Journal of Critical Care Medicine · doi:10.5492/wjccm.v11.i4.228 · Cited by 2
The role of the main hemodynamic parameters assessing in modern experimental practice
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Lawrence, S., Mueller, B. R., Benn, E. K. T., Kim‐Schulze, S., Kwon, P. M., & Robinson‐Papp, J. (2023) · Journal of Neuroimmune Pharmacology · doi:10.1007/s11481-023-10088-5 · Cited by 2
“…information regarding systemic levels of inflammatory mediators may not efficiently reach the central nervous system (CNS) (Zanos et al. 2018), blunting its modulatory capacity, which might be compounded by loss of the systemic anti-inflammatory capacity of parasympathetic fibers (Tracey 2009).”
Катунина, Е. А., Semenova, A. M., & Katunin, D. A. (2024) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro202412401138 · Cited by 2
Shams, S., Chalmeh, A., Pourjafar, M., & Amirian, A. (2025) · Small Ruminant Research · doi:10.1016/j.smallrumres.2025.107518 · Cited by 2
Autonomic neuropathy is associated with an increase in type-1 cytokines in people living with HIV
Mueller, B. R., Mehta, M., Campbell, M. C., Neupane, N., Cedillo, G., Lee, G., Coyle, K., Qi, J., Chen, Z., George, M. C., et al. (2025) · Clinical Autonomic Research · doi:10.1007/s10286-025-01129-5 · Cited by 2
“Preclinical studies have established that activation of the CAP results in a reduction of inflammatory cytokine release, including interleukin (IL)−6 (IL-6), from splenic macrophages [17, 18].”
Comorbidities and Postoperative Neurocognitive Disorder
Maze, M., & Feng, X. (2019) · Cambridge University Press eBooks · doi:10.1017/9781316402504.011 · Cited by 2
Adaptive Immune Response in Epilepsy
Orozco-Suárez, S. A., Feria-Romero, I. A., Rayo, D., Diegoprez, J., Fraire, M. I., Sosa, J., Arriaga‐Pizano, L., Alonso, M., Rocha, L., Fagiolino, P. L., et al. (2012) · InTech eBooks · doi:10.5772/36631 · Cited by 2
“For its study, innate immunity is divided into the afferent arm, which identifies or perceives to insult, and the efferent arm, which is how the infection is eradicated (Tracey, 2009).”
Gajewski, M., Maśliński, S., Rzodkiewicz, P., & Wojtecka-Lukasik, E. (2013) · InTech eBooks · doi:10.5772/54506 · Cited by 2
“It should now be possi‐ ble to determine clinically whether these or other approaches activate the cholinergic antiinflammatory pathway [1,2,4].”
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“This effect resulted in decreased production of IL-1 and TNFα, but increased the IL-10 secretion [50,52,55] and was realized via micro RNA-124, activated under alpha7nAChR stimulation.”
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Steinman, L. (2014) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2014.09.013 · Cited by 2
“The work of Tracey, Valentin Pavlov and colleagues shows how the nervous system also mediates diseases caused by pathophysiology in the digestive system and elsewhere (Tracey, 2009; Pavlov and Tracey, 2012).”
BackgroundImmunomodulatory Effec ts of Massage in Skeletal Muscle
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“Thus, immune cells are prone to coordination by evolutionarily ancient neural circuits that operate reflexively [20].”
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“This system may exist also inside cells with no innervation: in embryos, yeasts, plants, and as was shown recently, in lymphocytes [41-45].”
BackgroundVagal Stimulation in Heart Failure: An Anti-inflammatory Intervention?
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Evidence for vagal-immune dysregulation in bipolar disorder
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The BTBR mouse model, cholinergic transmission, and environmental exposure to nitrous oxide
Fluegge, K. (2016) · Psychopharmacology · doi:10.1007/s00213-016-4456-x · Cited by 2
“The α7 receptors are recognized as strongmodulators of inflammation (Tracey 2009), so their significant presence in the bone marrow cells of C57BL/6J mice may be an important constituent underlying the amelioration of social behavior deficits in the BTBR model.”
Background
Metadata
- Authors
- Tracey, K. J.
- Affiliations
- Feinstein Institute for Medical Research (US)
- Corresponding author
- Tracey, Kevin J.
- ORCID
- Tracey, Kevin J.
- Venue
- Nature Reviews Immunology
- Published
- 2009-06
- Volume
- 9
- Issue
- 6
- Pages
- 418-428
- ISSN
- 1474-1733 (ISSN-L)
- 1474-1741
- PMC
- PMC4535331
- OpenAlex
- W2029051866
- Cited by
- 1,154
- References
- 102
- Citations by year
- 2026: 55 · 2025: 61 · 2024: 49 · 2023: 66 · 2022: 71 · 2021: 77 · 2020: 73 · 2019: 71 · 2018: 66 · 2017: 71 · 2016: 80 · 2015: 75 · 2014: 70 · 2013: 81 · 2012: 68
- FWCI
- 4.87
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature reviews. Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Feinstein Institutes for Medical Research
- National Institute of General Medical Sciences (R01GM057226)
- Topics
- Life Sciences › Neuroscience › Neurology › Vagus Nerve Stimulation Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Rate Variability and Autonomic Control
- Keywords
- cholinergic anti-inflammatory pathway, acetylcholine, inflammatory cytokines, neural circuits, innate immunity, neuroimmune regulation, inflammatory diseases
- MeSH terms
- Animals, Cardiovascular Physiological Phenomena, Catecholamines, Efferent Pathways, Homeostasis, Humans, Hypertension, Immunity, Innate, Inflammation, Receptors, Cholinergic, Reflex, Neuroimmunomodulation
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