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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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“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
Cites
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“…binds directly to Janus kinase 2 (JAK2) and triggers the JAK2/STAT3 (signal transducer and activator of transcription 3) pathway to interfere with activation of nuclear factor-κB (NF-κB), which is responsible for pro-inflammatory cytokine gene transcription (Tracey 2009; Andersson and Tracey 2012).”
BackgroundAssociation of Short-Term Heart Rate Variability With Breast Tumor Stage
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“The inflammatory response is also modulated by the autonomic nervous system, physiological activation of sympathetic nervous system is in general pro‐inflammatory, while parasympathetic activity is an‐ tiinflammatory (Pongratz & Straub, 2014; Tracey, 2009).”
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“In fact, the inflammatory neural reflex, which has recently been described by Tracey (2009), consists of a sensory afferent arc and an efferent arc, which transmit signals modulating the immune responses.”
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“These receptors are expressed by the CHRNA7 gene located on chromosome 15q14, and its final product is a protein with a molecular weight of 55 kilo Daltons (Tracey, 2009).”
BackgroundThe role of interoception in lifestyle factors: A systematic review
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“One new and stimulating area for consideration comes from the work of Kevin Tracey and colleagues, showing that PNS activation can have an anti-inflammatory effect (Tracey, 2002, 2009).”
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“…activator (STAT3) pathway and cytokine release in the spleen, is fully described by previous studies (Huston et al., 2006; Rosas-Ballina et al., 2008; Tracey, 2009; Huang et al., 2010), few studies described its central anti-inflammatory and antioxidant role. van Gool et al. (2010) suggested that…”
The Neuroimmune Communicatome in Inflammation
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Behavioural Fever Promotes an Inflammatory Reflex Circuit in Ectotherms
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BackgroundInfluentialHeart development and regeneration—a multi‐organ effort
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Activation of α7 nicotinic acetylcholine receptor retards the development of endometriosis
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“In order to modulate splenocyte selection, activation, and downstream signaling, the axon terminals of vagal efferents release acetylcholine (ACh) within the celiac ganglion [27,28].”
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“Therefore, the attenuation of the CAIP signal following vagotomy could potentially exert a direct stimulatory effect on the survival and proliferation of tumor cells sequestered within milky spots.”
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“Since hostility is also related to lower vagal modulation (Sloan et al 1994) and because the vagus has profound antiinflammatory effects (Tracey 2009), one mechanism linking hostility to high MMP levels (in patients with little social support) could include excessive inflammation via reduced vagal…”
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“Then, ACh activates α7-nAChRs in macrophages to inhibit cytokine production and balance the inflammatory response (Tracey 2002, 2009; Wang et al.”
BackgroundPoint-of-care measured serum cholinesterase activity predicts patient outcome following severe burns
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“Support for our hypothesis comes from experimental or clinical reports demonstrating that electrical or pharmacological vagal stimulation inhibits proinflammatory cytokines and improves the prognosis of diseases such as sepsis, haemorrhagic shock, myocardial ischaemia and experimental arthritis (Tracey, 2009).”
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“Neurostimulation of the cholinergic antiinflammatory pathway (NCAP) using VNS may be a feasible means of treating diseases including RA and IBD that are characterized by excessive and dysregulated inflammation (4,5,23).”
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“The magnitude of the inflammatory response is important, as an extreme or insufficient response can be differentially harmful to the individual (see Tracey, 2009, for a review).”
Attenuation of intestinal ischemic injury and shock by physostigmine
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“We now know that a branch of the ENS continuously monitors the gut and provides moment-by-moment communication to/from the brain [3].”
BackgroundModulation of inflammatory response and pain by mind-body therapies as meditation
Moreno, J. J. (2023) · Brain Behavior and Immunity Integrative · doi:10.1016/j.bbii.2023.100036 · Cited by 13
Vagus nerve stimulation blocks vascular permeability following burn in both local and distal sites
Ortiz-Pomales, Y. T., Krzyżaniak, M., Coimbra, R. S. M., Baird, A., & Eliceiri, B. P. (2012) · Burns · doi:10.1016/j.burns.2012.04.004 · Cited by 11
“Direct electrical stimulation of the vagus nerve significantly inhibits cytokine production by innate immune cells in the spleen, liver, gastroinstestinal tract, heart and other tissues that are innervated by the vagus nerve [7].”
InfluentialHoneybee immunity and colony losses
Nazzi, F., Annoscia, D., Caprio, E., Prisco, G. D., & Pennacchio, F. (2014) · Entomologia · doi:10.4081/entomologia.2014.203 · Cited by 11
Altered Neuroendocrine Immune Responses, a Two-Sword Weapon against Traumatic Inflammation
Yang, C., Gao, J., Du, J., Yang, X., & Jiang, J. (2017) · International Journal of Biological Sciences · doi:10.7150/ijbs.21916 · Cited by 11
“Tracey et al named the anti-inflammatory mechanism as cholinergic anti-inflammatory pathway [95, 96].”
BackgroundBovine Endometritis and the Inflammatory Peripheral Cholinergic System
Siqueira, L. C., Favaretto, B., Moraes, B. T., de Freitas, V. O., Bicalho, R. C., Horn, R. C., Bassuíno, D. M., & Wolkmer, P. (2019) · Applied Biochemistry and Biotechnology · doi:10.1007/s12010-019-03157-0 · Cited by 11
“Therefore, ACh partially regulates, through the autonomic nervous system, the release of tumor necrosis factor (TNF), IL-1, and other pro- and anti-inflammatory cytokines from immune cells [22, 25, 29, 52].”
BackgroundSabetian, P., & Yoo, P. B. (2019) · Journal of Neural Engineering · doi:10.1088/1741-2552/ab5551 · Cited by 11
Stress and Physical Inactivity: Two Explosive Ingredients for the Heart in COVID-19 Pandemic Times
Ruberti, O. M., Telles, G. D., & Rodrigues, B. (2021) · Current Cardiology Reviews · doi:10.2174/1573403x17666210126103204 · Cited by 13
“, a breakdown product of soluble fibrin that results from the ordered breakdown of thrombi by the fibrinolytic system) [40].”
BackgroundEffect 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
Melnyk, O., Żukow, W., Hrytsak, M. V., Popovych, D., Zavidnyuk, Y. V., Bilas, V. R., & Popovych, I. L. (2021) · Journal of Education Health and Sport · doi:10.12775/jehs.2021.11.05.038 · Cited by 11
“A priori, effects of mineral waters, by analogy with other natural and reshaped factors, on metabolism and immunity are realized through nervous and hormonal mechanisms [8,10,13-23].”
BackgroundShi, X., Li, J.-C., Han, Y.-Z., Wang, J., Li, Q., Zheng, Y., & Li, W. (2022) · Bosnian Journal of Basic Medical Sciences · doi:10.17305/bjbms.2022.7111 · Cited by 11
“The α7 nicotinic acetylcholine receptor (α7nAChR) has been identified as a unique receptor of the cholinergic anti-inflammatory pathway, which exerts anti-inflammatory effects in a variety of diseases [18].”
Mental Health and Asthma in China: the Guangzhou Biobank Cohort Study
Jiang, C. Q., Loerbroks, A., Lam, K.-B. H., Bosch, J. A., Thomas, G. N., Zhang, W. S., Cheng, K. K., Lam, T. H., & Adab, P. (2012) · International Journal of Behavioral Medicine · doi:10.1007/s12529-012-9222-9 · Cited by 11
Psychophysiological correlates of systemic inflammation in black and white men
Lockwood, K. G., Jennings, J. R., & Matthews, K. A. (2016) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2016.08.013 · Cited by 11
“This research is summarized by Tracey (2002, 2009) cholinergic anti-inflammatory pathway.”
MethodNon-neuronal Cholinergic Muscarinic Acetylcholine Receptors in the Regulation of Immune Function
Mashimo, M., Kawashima, K., & Fujii, T. (2022) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b21-01005 · Cited by 10
Kalava, A., Benyahia, S. A., Calzada, R. T., & Staat, C. M. (2023) · Cureus · doi:10.7759/cureus.40929 · Cited by 10
“The autonomic nervous system plays a role in mediating the immune system to combat infections through the release of catecholamines [9].”
BackgroundUltrasound stimulation of the vagal nerve improves acute septic encephalopathy in mice
Imamura, Y., Matsumoto, H., Imamura, J., Matsumoto, N., Yamakawa, K., Yoshikawa, N., Murakami, Y., Mitani, S., Nakagawa, J., Yamada, T., et al. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1211608 · Cited by 10
“The vagus nerve (VN)—part of the cholinergic anti-inflammatory system—regulates the innate inflammatory response (Tracey, 2009).”
BackgroundThornton, T., Mills, D. E., & Bliss, E. (2023) · Life Sciences · doi:10.1016/j.lfs.2023.122337 · Cited by 10
Azam, M. A., Weinrib, A., Slepian, P. M., Rosenbloom, B. N., Waisman, A. S., Clarke, H. A., & Katz, J. D. (2024) · Frontiers in Pain Research · doi:10.3389/fpain.2024.1354015 · Cited by 10
Chan, E., & Mani, A. R. (2025) · Physiological Reports · doi:10.14814/phy2.70230 · Cited by 12
“This pathway leverages the vagus nerve's capacity to reduce the production of pro-inflammatory cytokines through activation of α 7 - nicotinic cholinergic receptors, thereby attenuating inflammatory responses without compromising overall immune function (Pavlov & Tracey, 2017; Tracey, 2009).”
InfluentialLindblom, R. P. F., Ström, M., Heinig, M., Nimer, F. A., Aeinehband, S., Berg, A., Dominguez, C. A., Vijayaraghavan, S., Zhang, X., Harnesk, K., et al. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1301233 · Cited by 10
“Apart from its role as a neurotransmitter, ACh also exerts effects on glial activation status and attenuates neuroinflammation by modulating TNF-a pathways (46) through”
BackgroundImpaired vagus-mediated immunosuppression in microsomal prostaglandin E synthase-1 deficient mice
Maître, E. L., Revathikumar, P., Idborg, H., Raouf, J., Korotkova, M., Jakobsson, P., & Lampa, J. (2015) · Prostaglandins & Other Lipid Mediators · doi:10.1016/j.prostaglandins.2015.05.006 · 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
“The afferent vagal nerve conveys inflammatory signaling to the brain, while vagal efferent signaling leads to inhibition of inflammation [3,4].”
BackgroundVagal Nerve Activity Predicts Prognosis in Diffused Large B-Cell Lymphoma and Multiple Myeloma
Atar, O., Ram, R., Avivi, I. M., Amit, O., Vitkon, R., Luttwak, E., On, Y. B., & Gidron, Y. (2023) · Journal of Clinical Medicine · doi:10.3390/jcm12030908 · Cited by 10
“First, by translation of peripheral IL-1 signals to acetylcholine, which activates the hypothalamic–pituitary–adrenal axis, resulting in cortisol, which inhibits inflammation [44].”
BackgroundYang, L., Li, W., Xie, Y., Ma, S., Zhou, X., Huang, X., & Tan, S. (2023) · BMC Neurology · doi:10.1186/s12883-023-03162-1 · Cited by 11
Lv, Z., Fan, H., Gao, M., Zhang, X., Li, G., Fan, Y., Ning, Z., & Guo, Y. (2024) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2024.131136 · Cited by 10
Das nichtentzugsbedingte Delir
Haußmann, R., Bauer, M., & Donix, M. (2015) · Der Nervenarzt · doi:10.1007/s00115-015-0027-3 · Cited by 10
Wu, S., Fang, C., Chen, W. T., & Muo, C. (2016) · Medicine · doi:10.1097/md.0000000000005651 · Cited by 10
Fang, C., Tseng, C., Wu, S., Chen, W. T., & Muo, C. (2017) · World Journal of Surgery · doi:10.1007/s00268-017-4127-z · Cited by 10
Esmolol indirectly stimulates vagal nerve activity in endotoxemic pigs
Aboab, J., Mayaud, L., Sebille, V., de Oliveira, R., Jourdain, M., & Annane, D. (2018) · Intensive Care Medicine Experimental · doi:10.1186/s40635-018-0178-1 · Cited by 10
PNU-282987 Attenuates Intestinal Epithelial Barrier Dysfunction in LPS-Induced Endotoxemia
Zhang, Y., Zhou, F., Wang, Z., Li, Z., & Li, J. (2020) · Inflammation · doi:10.1007/s10753-019-01096-w · Cited by 10
“α7 nicotinic acetylcholine receptor(α7nAchR) is a critical regulator of cholinergic anti-inflammatory actions in several diseases [9, 10].”
BackgroundGalvin, V., Cheek, D. J., Zhang, Y., Collins, G., & Gaskin, D. (2023) · Local and Regional Anesthesia · doi:10.2147/lra.s402197 · Cited by 10
Pain and the Placebo/Nocebo Effect
Pollo, A., & Benedetti, F. (2011) · Springer eBooks · doi:10.1007/978-1-4419-1651-8_20 · Cited by 10
Communication entre cerveau et intestin
Bonaz, B. L. (2010) · La Revue de Médecine Interne · doi:10.1016/j.revmed.2009.09.035 · Cited by 14
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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