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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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“circuits, including the cholinergic anti-inflammatory pathway, modulating immune responses and the progression of inflammatory diseases.(25) Recent research has newly identified “pulmonary neuroendocrine cells,” secreting neuropeptide c-aminobutyric acid or CGRP to activate ILC2s and sensing exogenous airway signals,…”
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“Kevin Tracey’s (Tracey, 2009) cholinergic anti-inflammatory pathway provides important context to the work reported by Tan et al. (2020).”
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“Composed of an efferent and afferent arc, the vagus nerve can sense cytokines in the periphery and respond through an efferent release of ACh that regulates immune responses and inhibit inflammation.(34) Of note, ACh is not exclusively released by neurons, but can also be biosynthesised by a number of immune cells suc…”
BackgroundNeuroimmune modulation by tryptophan derivatives in neurological and inflammatory disorders
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“Both systems are constantly in communication, overlapping their biochemical language: neurons produce cytokines and express cytokine receptors, while immune cells produce neurotransmitters and express their receptors (Rosas-Ballina and Tracey, 2009).”
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“Early researchers had access to the therapeutic potential of CAP in attenuating systemic inflammation caused by endotoxemia; several studies reported a beneficial effect of CAP in many inflammationmediated diseases (Borovikova et al., 2000; Ghia et al., 2008; Tracey, 2009; Nolan et al., 2012).”
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BackgroundVagus nerve stimulation as immunomodulatory therapy for stroke: A comprehensive review
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Self-citationPost‐stroke immunosuppression: Exploring potential implications beyond infections
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“…similar impact as the electric stimulation of vagus nerve (Andersson and Tracey, 2012; Bonaz et al., 2013; Huston, 2012) and might also involve the activation of the cholinergic antiinflammatory pathway (Tracey, 2002, 2009) through the interconnections between cranial nerves in the nasal cavity.”
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“In recent years, a vagus nerve-mediated cholinergic anti-inflammatory reflex in the spleen was identified, in addition to a neural anti-inflammatory mechanism regulated by glucocorticoid production and the hypothalamic–pituitary–adrenal (HPA) axis [11, 30].”
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“MMT exert an anti-inflammatory effect through decreasing the sympathetic activity and increasing the parasympathetic activity [96,97].”
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“Thus, the activation of α7 nAChRs can suppress peripheral inflammatory activity by inhibiting the production and secretion of cytokines [45,46].”
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“Neuroimmune reflexes could be placed provocatively at this end of the spectrum as they open the possibility of neural memory affecting the immune response (Tracey, 2009).”
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BackgroundInfluentialVagal dysfunction and small intestinal bacterial overgrowth
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“Evidence for the CAR in humans is mostly from observational studies in sepsis, which have demonstrated correlations between lower heart rate variability (a reflection of vagal dysfunction) and elevation of individual cytokines such as IL-6 [70– 72].”
InfluentialCollateral benefits of studying the vagus nerve in bioelectronic medicine
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“…to formulating the concepts of the immunological homunculus (Pavlov et al., 2018; Tracey, 2007), the set point function of the immune responses (Tracey, 2009), the neuroimmune communicatome (Olofsson et al., 2017; Metz & Pavlov, 2018), and innate immune exhaustion in sepsis survivors (Zaghloul…”
González, F. B., Villar, S. R., Pacini, M. F., Bottasso, O. A., & Pérez, A. R. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165642 · Cited by 19
Peng, L., Li, L., He, X., Yu, J., Zeng, Z.-J., Yang, W., Zhang, B., Zhang, T., Cao, H., Huang, S., et al. (2020) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2020.00047 · Cited by 19
“It has been has confirmed that α7R is expressed on many types of cells, such as endothelial cells, fibroblasts, synoviocytes, polymorphonuclear neutrophils, dendritic cells, NK cells, B cells, and T cells (Tracey, 2009).”
BackgroundRibeiro, A. B., Brognara, F., da Silva, J. F., Castania, J. A., Fernandes, P. G., Tostes, R. C., & Salgado, H. C. (2020) · Scientific Reports · doi:10.1038/s41598-020-76194-z · Cited by 19
Indoor unclean fuel cessation linked with adult cognitive performance in China
Cong, X., Zhang, J., Sun, R., & Pu, Y. (2021) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2021.145518 · Cited by 20
Physical inactivity is a disease synonymous for a non-permissive brain disorder
Pruimboom, L. (2011) · Medical Hypotheses · doi:10.1016/j.mehy.2011.07.022 · Cited by 20
Gidron, Y. (2016) · Springer eBooks · doi:10.1007/978-1-4614-6439-6_1602-2 · Cited by 19
Hu, L., Li, D., Ge, C., Liao, H., Wang, Y., & Xu, H. (2019) · Neuroscience · doi:10.1016/j.neuroscience.2019.01.002 · Cited by 18
Noninvasive Low-Frequency Pulsed Focused Ultrasound Therapy for Rheumatoid Arthritis in Mice
Hu, X., Li, F., Zeng, J., Zhou, Z., Wang, Z., Chen, J., Cao, D., Hong, Y., Huang, L., Chen, Y., et al. (2022) · Research · doi:10.34133/research.0013 · Cited by 19
Nicotine, an anti-inflammation molecule
Shi-Ying Cai, J. B. (2014) · Inflammation and Cell Signaling · doi:10.14800/ics.155 · Cited by 18
“Page 4 of 8 the parasympathetic nervous system ([26]); choline; nicotine and experimental therapeutic GTS-21 ([27]).”
BackgroundMoreira, H. G., Lage, R. L., Martinêz, D. G., Ferreira‐Santos, L., Rondon, M. U. P. B., Negrão, C. E., & Nicolau, J. C. (2017) · Clinical Science · doi:10.1042/cs20170049 · Cited by 19
Choline and Choline alphoscerate Do Not Modulate Inflammatory Processes in the Rat Brain
Tayebati, S. K., Martinelli, I., Moruzzi, M., Amenta, F., & Tomassoni, D. (2017) · Nutrients · doi:10.3390/nu9101084 · Cited by 20
A Brain-Spleen Axis Regulates Humoral Immunity
Zhang, B., Zhong, J., & Gao, Z. (2020) · Neuroscience Bulletin · doi:10.1007/s12264-020-00610-7 · Cited by 18
Fernández-Cabezudo, M. J., George, J. A., Bashir, G. H., Mohamed, Y. A., Al-Mansori, A., Qureshi, M. M., Lorke, D. E., Petroianu, G. A., & al-Ramadi, B. K. (2019) · Frontiers in Immunology · doi:10.3389/fimmu.2019.01038 · Cited by 19
“The cholinergic anti-inflammatory pathway can modulate the inflammatory response to infection and injury and downregulate the production of inflammatory cytokines (24, 67).”
BackgroundSpeer, K. E., Naumovski, N., & McKune, A. J. (2024) · Physiology & Behavior · doi:10.1016/j.physbeh.2024.114576 · Cited by 23
Sloan, R. P., & Cole, S. W. (2021) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2021.08.217 · Cited by 19
“These model system data support the existence of a cholinergic anti-inflammatory reflex (Tracey, 2009).”
MethodResultQian, Z., Yang, H., Li, H., Liu, C., Yang, L., Qu, Z., & Li, X. (2021) · Biomedicines · doi:10.3390/biomedicines9091150 · Cited by 17
Guo, Z.-P., Sörös, P., Zhang, Z.-Q., Yang, M.-H., Liao, D., & Liu, C.-H. (2021) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2021.765106 · Cited by 17
“When pro-inflammatory cytokines are present due to an infection, taVNS can activate afferent vagal neurons through impacting the immune response (139, 140) and also efferent vagal neurons can release acetylcholine through the cholinergic anti-inflammatory pathway and HPA axis (132, 141).”
BackgroundRole of autonomic system imbalance in neurogenic pulmonary oedema
Yang, A., Liu, B., & Inoue, T. (2022) · European Journal of Neuroscience · doi:10.1111/ejn.15648 · Cited by 17
“Previous research has shown that the autonomic nervous system (ANS) can influence inflammatory processes in the body via the inflammatory reflex (Tracey, 2002, 2009).”
BackgroundSittichai, N., Parasin, N., Saokaew, S., Kanchanasurakit, S., Kayod, N., Praikaew, K., Phisalprapa, P., & Prasannarong, M. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.1030568 · Cited by 17
“Increased vagal tone resulting from high levels of PA also reduces pro-inflammatory cytokines (Tracey, 2009).”
BackgroundRegulation of Pro-and Anti-Inflammatory Host Responses
van der Poll, T., van Zoelen, M. A. D., & Wiersinga, W. J. (2011) · Contributions to microbiology · doi:10.1159/000324026 · Cited by 17
Hall, M. P., Ward, J. P., & Cardone, D. A. (2013) · PubMed · Cited by 17
Treatment of chronic inflammatory diseases with implantable medical devices*
Zitnik, R. J. (2011) · Cleveland Clinic Journal of Medicine · doi:10.3949/ccjm.78.s1.05 · Cited by 17
“The vagus nerve mediates an important neural reflex which senses inflammation both peripherally and in the central nervous system, and downregulates the inflammation via efferent neural outflow to the reticuloendothelial system. The efferent arm of this reflex has been termed the ‘cholinergic anti-inflammatory pathway…”
Słoniecka, M., & Danielson, P. (2020) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.15168 · Cited by 17
The promising prognostic value of vagal nerve activity at the initial management of ovarian cancer
Cherifi, F., Lefèvre‐Arbogast, S., Font, J., Abdeddaim, C., Bécourt, S., Penel, N., Coquan, E., Lequesne, J., Gidron, Y., & Joly, F. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.1049970 · Cited by 17
“The autonomic nervous system, particularly the parasympathetic branch, has been shown to be one of the systems which control inflammatory processes (6, 7).”
BackgroundJi, H., Zhang, Y., Liu, Y., Shen, X., GAO, F. G., Nguyen, T., Busuttil, R. W., Waschek, J. A., & Kupiec‐Weglinski, J. W. (2013) · Liver Transplantation · doi:10.1002/lt.23681 · Cited by 17
“Then, the regional neural-hormonal-stress response may amplify the local inflammation immune cascade to eliminate pathogens,(6-9) restore host homeostasis, and return to a resting state.(10) Vasoactive intestinal peptide (VIP), which has 28 amino acids, was first isolated from the gastrointestinal tract as a vasodilat…”
Leong, J., Zhou, M., Jacob, A., & Wang, P. (2010) · Life Sciences · doi:10.1016/j.lfs.2010.03.009 · Cited by 17
“Nonetheless, the spleen has a major role in the anti-inflammatory effects produced by the cholinergic system (Tracey 2009).”
Backgroundde Cuba, M. B., Machado, M. P. R., Farnesi-de-Assunção, T. S., Alves, A. C., Martins, L. A., de Oliveira, L. F., Capitelli, C. S., Leite, C. F., da Silva, M. V., Machado, J. R., et al. (2014) · Mediators of Inflammation · doi:10.1155/2014/475946 · Cited by 17
“Taking into account the concepts described above, new therapies based on manipulations of vagal neuroimmunomodulation of the heart may be beneficial for treating heart diseases in general and chronic chagasic cardiomyopathy in particular [17, 23].”
Heart Rate Variability Predicts Cell Death and Inflammatory Responses to Global Cerebral Ischemia
Norman, G. J., Karelina, K., Berntson, G. G., Morris, J. S., Zhang, N., & DeVries, A. C. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00131 · Cited by 17
“Ischemic brain injury resulting from CA is thought to exacerbate negative health status through a broad spectrum of mechanisms that include a diminished capacity to coordinate hormonal and autonomic processes important for metabolic, immune, and cardiovascular regulation (Micieli and Cavallini, 2008; Neigh et al., 200…”
BackgroundZivkovic, A. R., Schmidt, K., Stein, T., Münzberg, M., Brenner, T., Weigand, M. A., Kleinschmidt, S., & Hofer, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-46995-y · Cited by 17
Grander, W., Müllauer, K., Koller, B., Tilg, H., & Dünser, M. W. (2013) · Clinical Research in Cardiology · doi:10.1007/s00392-013-0571-4 · Cited by 17
“Given the tight interaction between the immune and autonomic nervous system [3], a heart rate [90 bpm serves as one of four characteristics defining the systemic inflammatory response”
BackgroundLei, W., Zhao, C., Sun, J., Jin, Y., & Duan, Z. (2022) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2022.112733 · Cited by 16
Yoga Therapy in Functional Dyspepsia. A Narrative Review
Setia, G., Bhavanani, A. B., Ramanathan, M., Ananthakrishnan, N., Vinoth, V., Prabu, B. S. M., & Subramanian, B. (2023) · Journal of Gastrointestinal and Liver Diseases · doi:10.15403/jgld-4867 · Cited by 19
Kassis, E. B., Murn, M., Dzierba, A. L., Serra, A. L., Garcia, I., Minus, E., Padilla, C., Sarge, T., Banner‐Goodspeed, V., Matthay, M. A., et al. (2024) · Critical Care · doi:10.1186/s13054-024-04920-4 · Cited by 16
Delirium from the gliocentric perspective
Sfera, A., Osorio, C. P., Price, A. I., Gradini, R., & Cummings, M. A. (2015) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2015.00171 · Cited by 15
“Acethylcholine (ACh) signaling was suggested to engender a potent cholinergic antiinflammatory shield (CAIS), protecting against peripheral and central inflammation (Tracey, 2009).”
BackgroundTreatment of chronic inflammatory diseases with implantable medical devices
Zitnik, R. J. (2011) · Annals of the Rheumatic Diseases · doi:10.1136/ard.2010.138677 · Cited by 16
Presidential Address 2011: Autonomic modes of control and health
Berntson, G. G. (2018) · Psychophysiology · doi:10.1111/psyp.13306 · Cited by 16
A basic solution to activate the cholinergic anti-inflammatory pathway via the mesothelium?
Mannon, E. C., Sun, J., Wilson, K., Brands, M. W., Quinones, P. M., Baban, B., & O'Connor, P. M. (2019) · Pharmacological Research · doi:10.1016/j.phrs.2019.01.007 · Cited by 16
“The inflammatory reflex, first proposed by Tracey et al is a parasympathetic neural circuit that is activated in response to inflammation, containing both afferent and efferent arms [1,5].”
Influential
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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