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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
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The Prevention and Treatment of Delirium in Elderly Patients Following Hip Fracture Surgery
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“The activation of the inflammatory cascade is associated with release of proinflammatory cytokines into the blood stream as well as recruitment of immune cells (Parrish et al., 2008, Porhomayon et al., 2014; Tracey, 2009).”
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“, 2012), and with the concept of a cholinergic anti-inflammatory system (Tracey, 2009), which is postulated to suppress inflammatory and immune responses by integrating signaling in the immune and nervous systems.”
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“The afferent arc consists of nerves that sense the injury and infection, and this in turn activates a cholinergic anti-inflammatory pathway that modulates the response and is the potential target for future therapies of diabetes (73, 74).”
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“thought that the tonic activity of the vagus nerve is essential for maintaining immune homeostasis [15].”
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Ponsford, M., Pecoraro, A., & Jolles, S. R. A. (2019) · Current Opinion in Allergy and Clinical Immunology · doi:10.1097/aci.0000000000000592 · Cited by 30
“Interplay between neuronal and immune systems has long been recognized [41] and has led to novel therapeutic avenues [42–44].”
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Fleckenstein, J., Neuberger, E. W. I., Bormuth, P., Comes, F., Schneider, A., Banzer, W. B., Fischer, L., & Simon, P. D. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.697335 · Cited by 35
“For this reason, it is logical that the ANS is also involved in pain, inflammation, and immune processes in a “coordinating” way and plays an important role in microcirculation (Elenkov et al., 2000; Tracey, 2002, 2009; Jänig, 2006; Schaible et al., 2011; Janig, 2014).”
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“This cholinergic anti-inflammatory pathway has been proposed to be part of a vago-vagal immune reflex inwhich signals arising from the gut activate vagal afferents, which in turn activate the descending cholinergic anti-inflammatory pathway (Tracey, 2009).”
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“The efferent arc of this reflex has been shown to modulate animal models of sepsis and autoimmunity, and it is mediated by cholinergic neurotransmission (6).”
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“It is a proinflammatory cytokine secreted by activated monocytes, macrophages, endothelial cells, adipocytes, fibroblasts and T-helper-2 cells, typically after stimulation by interleukin-1 or TNF-α.”
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“The inflammatory response is regulated via the vagus nerve and vagus nerve stimulation has been shown to be effective in many inflammatory models (10,11).”
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“The regulation was called the reflex-like antiinflammatory pathway and later the term cholinergic pathway was coined [93].”
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Thinking outside the brain for cognitive improvement: Is peripheral immunomodulation on the way?
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“The peripheral immune system is also under the feedback regulation of neural circuits thatoperate reflexively (Tracey, 2009).”
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“In contrast, increased activation of the vagal nerve correlated with antiinflammatory signaling (Thayer, 2009; Tracey, 2009).”
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“IL-6, as a kind of pro-inflammatory factor, can serve as an indicator for early diagnosis of tissue injury (Tracey, 2009), and its level can reflect the damage to tissues; stress response to the surgical trauma can lead to the excessive expression of IL-6 (Ramlawi et al.”
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“Lack of vagal immune function is compensated by an increase of peripheral PGE2 concentration According to mechanisms suggested by Tracey (2009), a high plasma IL-6 level is associated with low activity of vagus nerve [54].”
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Cardiorespiratory Fitness, Inflammation, and the Incident Risk of Pneumonia
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Vagus nerve stimulation using a miniaturized wirelessly powered stimulator in pigs
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Towards systems immunology of critical illness at scale: from single cell ‘omics to digital twins
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“However, it was shown that acetylcholine, the alpha-7 subunit of the nicotinergic acetylcholine receptor and the lymphocytes in the spleen are essential components of the anti-inflammatory reflex [13].”
Cholinergic agonists reduce blood pressure in a mouse model of systemic lupus erythematosus
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“Recent evidence suggests that the immune system and nervous system act together to regulate inflammation (Steinman 2004; Tracey 2009; Sundman and Olofsson 2014).”
BackgroundCorrêa, F. I., Souza, P. H. L., Uehara, L., Ritti‐Dias, R. M., da Silva, G. O., Segheto, W., Pacheco‐Barrios, K., Fregni, F., & Corrêa, J. C. F. (2022) · Life · doi:10.3390/life12101644 · Cited by 28
“Tracey [24] introduced the CAP concept and showed that the alpha7 subunit of the nicotinic acetylcholine receptor is required for inhibition of Tumor Necrosis Factor release from macrophages.”
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Regulation of IL-17 Family Members by Adrenal Hormones During Experimental Sepsis in Mice
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“org control of immunity.(33) Catecholamines regulate lymphocyte functions including an inhibition of proliferation and cytotoxicity of CD4þ and CD8þ cells.”
BackgroundRETRACTED: Protective effects of ghrelin on cisplatin-induced nephrotoxicity in mice
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InfluentialNeuroendocrine Modulation of IL-27 in Macrophages
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BackgroundClinical overview of diabetes mellitus as a risk factor for cardiovascular death
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Impact of Anesthetics on Immune Functions in a Rat Model of Vagus Nerve Stimulation
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“Low-frequency vagus nerve stimulation (VNS) has been successful for the treatment of different animal models of inflammation such as septic shock, pancreatitis, ischaemiareperfusion, postoperative ileus, and arthritis (see Tracey for review [1]).”
BackgroundInhibitors of C5 complement enhance vaccinia virus oncolysis
Magge, D. R., Guo, Z. S., O’Malley, M. E., Francis, L., Ravindranathan, R., & Bartlett, D. L. (2013) · Cancer Gene Therapy · doi:10.1038/cgt.2013.26 · Cited by 28
Mapping the immunological homunculus
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“Recent advances at the intersection of these fields have provided direct evidence that neural circuits reflexively control the onset and resolution of inflammation, and previously undescribed molecular mechanisms have been defined (3).”
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“Lower resting HRV has been linked to stress, anxiety, depression, reduced immune response, and all-cause mortality (1, 21, 67, 78, 81).”
BackgroundCholinergic Receptors Modulate Immune Complex–Induced Inflammation In Vitro and In Vivo
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“(1), consists of an afferent sensory neural arc that detects molecular products of injury, infection, and ischemia, and an efferent neural”
BackgroundHanes, W. M., Olofsson, P. S., Kwan, K., Hudson, L., Chavan, S. S., Pavlov, V. A., & Tracey, K. J. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00142 · Cited by 27
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“Studies have shown that para-sympathetic activation releases ACh, which binds to the α7 nicotinic ACh receptor (α7nAChR) to promote anti-tumor immune responses, such as increasing CD8 + T cell infiltration and suppressing the pro-tumorigenic phenotype of tumor-associated macrophages (TAMs) [152].”
Ancient Neurons Regulate Immunity
Tracey, K. J. (2011) · Science · doi:10.1126/science.1206353 · Cited by 27
Self-citationXue, N., Delgado-Martínez, I., Sun, J., Cheng, Y., & Liu, C. (2018) · Biosensors and Bioelectronics · doi:10.1016/j.bios.2018.04.043 · Cited by 27
Higher risk of herpes zoster in stroke patients
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“On one hand, the autonomic nervous system controls inflammation through neural circuits that affect immune cells [33].”
BackgroundNeural Regulation of Interactions Between Group 2 Innate Lymphoid Cells and Pulmonary Immune Cells
Chen, W., Shu, Q., & Fan, J. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.576929 · Cited by 28
Sex Differences in Vagus Nerve Stimulation Effects on Rat Cardiovascular and Immune Systems
Yaghouby, F., Jang, K. W., Hoang, U., Asgari, S., & Vasudevan, S. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.560668 · Cited by 27
“The sensory vagal pathway, incorporating afferent nerve bundles from mainly the left cervical vagus nerve, communicates with the nucleus tractus solitarius (NTS) in the brainstem via cardiac and immunological signals (Tracey, 2009).”
BackgroundJakob, M. O., Kofoed-Branzk, M., Deshpande, D., Murugan, S., & Klose, C. S. N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.679055 · Cited by 28
Machado, M. P. R., Rocha, A. M., de Oliveira, L. F., de Cuba, M. B., Loss, I. D. O., Castellano, L. R. C., da Silva, M. V., Machado, J. R., Nascentes, G. A. N., de Paiva, L. H., et al. (2012) · Experimental Physiology · doi:10.1113/expphysiol.2012.066431 · Cited by 27
“Considering the anti-inflammatory role played by both the sympathetic (Elenkov & Chrousos, 1999) and the vagal parasympathetic nervous systems (Tracey, 2009) in shifting the Th1–Th2 balance of the immune response towards a predominantly Th2 anti-inflammatory response, deliberate changes in the…”
BackgroundInfluentialUddin, M. J., Joe, Y., Zheng, M., Blackshear, P. J., Ryter, S. W., Park, J. W., & Chung, H. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.09.027 · Cited by 28
“The cholinergic nervous system controls the inflammatory response to prevent excessive inflammation [1,2].”
BackgroundLiu, H. L., Garzoni, L., Herry, C. L., Durosier, L. D., Cao, M., Burns, P., Fecteau, G., Desrochers, A., Patey, N., SEELY, A. J. E., et al. (2016) · Pediatric Critical Care Medicine · doi:10.1097/pcc.0000000000000643 · Cited by 27
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“It has been suggested that exercise, controlled breathing, relaxation therapies and fish-oil increase the activity of the vagus nerve and decrease production of TNFα and IL-6 [164].”
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“After elimination of invasion, the neural system modulates local immune response towards host homeostasis [13].”
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“When pain is transmitted centrally, activation of the hypothalamus and sympathetic nervous system results in a rise in plasma cortisol, catecholamines, acetylcholine, and peptides with subsequent depression of both innate (Natural Killer (NK) cells [a subgroup of cytotoxic lymphocytes], monocytes, macrophages, and den…”
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“Furthermore, these results are in line with the known anti-inflammatory functions of this important cranial nerve [9].”
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Pathways of neuro-immune communication: past and present time, clinical application
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“In innate immunity, nAChRs and their agonists are mainly involved in an attenuation of inflammation (Borovikova et al., 2000; Kox et al., 2009; Tracey, 2009; Simard et al., 2013; StPierre et al., 2016; Fujii et al., 2017a; Pavlov et al., 2018; Godin et al., 2020).”
BackgroundThe immune phenotype of perinatal anxiety
Sherer, M. L., Voegtline, K., Park, H.-S., Miller, K. N., Shuffrey, L. C., Klein, S. L., & Osborne, L. M. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.09.005 · Cited by 28
Chemical Sensitivity: Pathophysiology or Pathopsychology?
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“Peripheral-to-central communication In the last few decades, a large body of knowledge has been accumulated regarding bidirectional communication between the immune system and the brain (for review see [1–7], for historical overview of the discoveries see [8]).”
Li, H., Zhang, Z., Zhan, J., He, X., Song, X., & Wang, Y. (2012) · Journal of Cardiovascular Pharmacology · doi:10.1097/fjc.0b013e31824c86c3 · Cited by 24
“CAP is a physiologic mechanism through which efferent signals in vagus nerve could modulate inflammatory status.(3) Previous researches have demonstrated that vagus nerve stimulation and some acetylcholine receptor agonists exert protective effects against MIRI in vivo and in vitro.”
BackgroundHerry, C. L., Cortes, M., Wu, H., Durosier, L. D., Cao, M., Burns, P., Desrochers, A., Fecteau, G., SEELY, A. J. E., & Frasch, M. G. (2016) · PLoS ONE · doi:10.1371/journal.pone.0153515 · Cited by 26
“[4–6] CAP activity is reflected in fetal heart rate (FHR) variability (fHRV).[7] [8] [9] HRV measures can be derived from various signalanalytical domains such as statistical, informational, invariant or energetic.”
BackgroundDelgado‐Vélez, M., Báez-Pagán, C. A., Gerena, Y., Quesada, O., Santiago‐Pérez, L. I., Capó-Vélez, C. M., Wojna, V., Meléndez, L. M., León‐Rivera, R., Silva, W., et al. (2015) · Clinical & Translational Immunology · doi:10.1038/cti.2015.31 · Cited by 26
The vagal immune reflex: a blessing from above
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“anti-inflammatory cytokines such as IL-10 and transforming growth factor b, the vagal immune reflex functions as a crucial mechanism keeping the set point of immune homeostasis at non-toxic levels [ 22 ].”
Backgroundde Theije, C. G. M., van den Elsen, L. W. J., Willemsen, L. E. M., Milosevic, V., Korte-Bouws, G. A. H., da Silva, S. L., Broersen, L. M., Korte, S. M., Olivier, B., Garssen, J., et al. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.11.001 · Cited by 26
“Inflammatory signalling molecules such as cytokines, neuropeptides, and serotonin (5hydroxytryptamine; 5-HT) can directly and indirectly activate afferent nerves, which signal to the brain to activate the HPA-axis or the cholinergic anti-inflammatory pathway (Van Der Zanden et al., 2009; Tracey, 2009).”
Ortiz, G., Chao, C., Jamali, A., Seyed‐Razavi, Y., Kenyon, B. M., Harris, D. L., Zoukhri, D., & Hamrah, P. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01713 · Cited by 25
“Recently, several studies have shown that the peripheral nervous system (PNS), in addition to mediating communication between the central nervous system and peripheral tissues, also controls innate immune responses via non-specific responses to pathogens (69, 70).”
BackgroundAn aberrant parasympathetic response: a new perspective linking chronic stress and itch
Kim, H. S., & Yosipovitch, G. (2012) · Experimental Dermatology · doi:10.1111/exd.12070 · Cited by 25
Successful Therapy of Vulvodynia with Local Anesthetics: A Case Report
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Alcohol and hepatocyte-Kupffer cell interaction (Review)
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Integrating Body and Brain Systems in Addiction Neuroscience
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Demodex canis regulates cholinergic system mediated immunosuppressive pathways in canine demodicosis
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“ACh plays an important role in neuronal stimulation and is also important as a mediator in inflammatory process (Tracey, 2009).”
BackgroundReduced serum cholinesterase activity indicates splenic modulation of the sterile inflammation
Zivkovic, A. R., Tourelle, K. M., Brenner, T., Weigand, M. A., Hofer, S., & Schmidt, K. (2017) · Journal of Surgical Research · doi:10.1016/j.jss.2017.07.024 · Cited by 25
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“The vagal stimulation, in general, modulates nociceptive processing [13] and inflammation [14], as well as serotonergic, noradrenergic, and endorphiner-”
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Extracellular Activities of Aminoacyl-tRNA Synthetases: New Mediators for Cell–Cell Communication
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Biofeedback in the treatment of heart disease
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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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