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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
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“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]
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“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
From inflammation to sickness and depression: when the immune system subjugates the brain
Dantzer, R., O'Connor, J. C., Freund, G. G., Johnson, R. W., & Kelley, K. W. (2008) · Nature Reviews Neuroscience · doi:10.1038/nrn2297 · Cited by 7,395
Origin and physiological roles of inflammation
Medzhitov, R. (2008) · Nature · doi:10.1038/nature07201 · Cited by 6,618 · cited 1×
“1 ) — that interact with Toll-like receptors (TLRs), which transduce intracellular signals, ultimately leading to the activation of NF-κB and the increased release of pro-inflammatory cytokine”
BackgroundVagus nerve stimulation attenuates the systemic inflammatory response to endotoxin
Borovikova, L. V., Ivanova, S., Zhang, M., Yang, H., Botchkina, G. I., Watkins, L. R., Wang, H., Abumrad, N., Eaton, J. W., & Tracey, K. J. (2000) · Nature · doi:10.1038/35013070 · Cited by 4,211 · cited 1×
“The 'inflammatory reflex' is one example of how action potentials originating in neurons continuously shape immunit”
BackgroundSelf-citationTracey, K. J. (2002) · Nature · doi:10.1038/nature01321 · Cited by 3,728 · cited 1×
“The 'inflammatory reflex' is one example of how action potentials originating in neurons continuously shape immunit”
BackgroundSelf-citationNicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation
Wang, H., Yu, M., Ochani, M., Amella, C. A., Tanovic, M., Susarla, S., Li, J. H., Wang, H., Yang, H., Ulloa, L., et al. (2003) · Nature · doi:10.1038/nature01339 · Cited by 3,228
Self-citationDAMPs, PAMPs and alarmins: all we need to know about danger
Bianchi, M. E. (2007) · Journal of Leukocyte Biology · doi:10.1189/jlb.0306164 · Cited by 2,794
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738 · cited 1×
“These molecules can activate TLRs, mannose receptors and nucleotide-binding oligomerization domain (NOD)-like receptors”
BackgroundThe immune response in atherosclerosis: a double-edged sword
Hansson, G. K., & Libby, P. (2006) · Nature reviews. Immunology · doi:10.1038/nri1882 · Cited by 2,220
Mammalian nicotinic acetylcholine receptors: from structure to function
Albuquerque, E. X., Pereira, E. F. R., Alkondon, M., & Rogers, S. W. (2009) · Physiological Reviews · doi:10.1152/physrev.00015.2008 · Cited by 1,724 · cited 1×
“Acetylcholine, the principal parasympathetic neurotransmitter, interacts with the G protein-coupled muscarinic acetylcholine receptors M1–M5 and nicotinic ligand-gated ion channels (termed neuronal type I–III and muscle type IV”
BackgroundPhysiology and immunology of the cholinergic antiinflammatory pathway
Tracey, K. J. (2007) · Journal of Clinical Investigation · doi:10.1172/jci30555 · Cited by 1,563
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Slavich, G. M., & Irwin, M. R. (2014) · Psychological Bulletin · doi:10.1037/a0035302 · Cited by 2,206
Air pollution: mechanisms of neuroinflammation and CNS disease
Block, M. L., & Calderón‐Garcidueñas, L. (2009) · Trends in Neurosciences · doi:10.1016/j.tins.2009.05.009 · Cited by 1,676
The interplay between the intestinal microbiota and the brain
Collins, S. M., Surette, M., & Bercik, P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2876 · Cited by 1,611
HMGB1 is a therapeutic target for sterile inflammation and infection
Andersson, U., & Tracey, K. J. (2011) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101323 · Cited by 1,437
Self-citationSepsis: pathophysiology and clinical management
Gotts, J. E., & Matthay, M. A. (2016) · BMJ · doi:10.1136/bmj.i1585 · Cited by 1,308
Visceral influences on brain and behavior
Critchley, H. D., & Harrison, N. A. (2013) · Neuron · doi:10.1016/j.neuron.2013.02.008 · Cited by 1,177
“CNS sensing of inflammation, particularly within NTS, also plays a critical role in regulating the magnitude of innate immune response to infection, injury or ischemia (Tracey, 2009).”
Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders
Breit, S., Kupferberg, A., Rogler, G., & Hasler, G. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00044 · Cited by 1,189
“As stated earlier, ACh released at the distal end of VN efferents decreases the production of proinflammatory cytokines, such as TNF-α (188).”
BackgroundInfluentialNeuroinflammation and depression: A review
Troubat, R., Barone, P., Leman, S., Desmidt, T., Cressant, A., Atanasova, B., Brizard, B., El Hage, W., Surget, A., Belzung, C., et al. (2021) · European Journal of Neuroscience · doi:10.1111/ejn.14720 · Cited by 1,107
“Peripheral, circulating inflammatory mediators also affect HPA axis activity, reaching the hypothalamus directly through the endothelium of the circumventricular organs or an altered BBB (Bellavance & Rivest, 2014) or indirectly through afferent fibres from the vagus nerve conveying information about peripheral inflam…”
BackgroundThe 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-citationDopamine controls systemic inflammation through inhibition of NLRP3 inflammasome
Yan, Y., Jiang, W., Liu, L., Wang, X., Ding, C., Tian, Z., & Zhou, R. (2015) · Cell · doi:10.1016/j.cell.2014.11.047 · Cited by 1,014
“Increasing evidence has shown that the immune system can be influenced by the nervous system and neurotransmitters (Olofsson et al., 2012; Tracey, 2009).”
Haroon, E., Raison, C. L., & Miller, A. H. (2012) · Neuropsychopharmacology · doi:10.1038/npp.2011.205 · Cited by 1,000
“For example, treatment of mouse midbrain and striatal synaptosomes with IL-1b and TNF-a was shown to lead to a dose- and time-dependent increase in serotonin reuptake, which was reversed by the p38 antagonist, SB203580 (Zhu et al, 2006).”
BackgroundInfluentialThe 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
Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond
Michopoulos, V., Powers, A., Gillespie, C. F., Ressler, K. J., & Jovanovic, T. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.146 · Cited by 786
“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).”
BackgroundMicroglia and neurodegeneration: The role of systemic inflammation
Cunningham, C. (2013) · Glia · doi:10.1002/glia.22350 · Cited by 769
Neuropathogenesis of Delirium: Review of Current Etiologic Theories and Common Pathways
Maldonado, J. R. (2013) · The American Journal of Geriatric Psychiatry · doi:10.1016/j.jagp.2013.09.005 · Cited by 745
The Adverse Effects of Air Pollution on the Nervous System
Genç, Ş., Zadeoğluları, Z., Fuss, S. H., & Genç, K. (2012) · Journal of Toxicology · doi:10.1155/2012/782462 · Cited by 756
“In addition, circulating cytokines that are released by inflamed peripheral organs or endothelial cells could stimulate peripheral innate immune cells, activate peripheral neuronal afferents, or enter the brain by diffusion and active transport thereby worsening the condition synergistically [27, 28].”
BackgroundStress, Inflammation, and Defense of Homeostasis
Chovatiya, R., & Medzhitov, R. (2014) · Molecular Cell · doi:10.1016/j.molcel.2014.03.030 · Cited by 704
“…nociceptors may monitor and control tissue homeostasis not only at the extremes of infection and injury, but also duringmore common and less dramatic alterations of normal tissue states (Ahern, 2013; Basbaum et al., 2009;Mosser and Edwards, 2008; Nguyen et al., 2011; Pollard, 2009; Tracey, 2009).”
BackgroundSepsis: Current Dogma and New Perspectives
Deutschman, C. S., & Tracey, K. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.04.001 · Cited by 708
“The inflammatory reflex is a prototypical, major efferent neural pathway that modulates TNF release in response to LPS (Figure 2) (Tracey, 2002, 2009; Borovikova et al., 2000).”
BackgroundSelf-citationPrisco, G. D., Cavaliere, V., Annoscia, D., Varricchio, P., Caprio, E., Nazzi, F., Gargiulo, G., & Pennacchio, F. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1314923110 · Cited by 708
“The inflammatory reflex circuit described in mammals is essential to ensure a neural coordination of the defense response to have a sufficient protection while preventing damages deriving from an overzealous reaction (44, 45).”
BackgroundNeuro-immune Interactions Drive Tissue Programming in Intestinal Macrophages
Gabanyi, I., Muller, P. A., Feighery, L. M., Oliveira, T. Y., Costa‐Pinto, F. A., & Mucida, D. (2016) · Cell · doi:10.1016/j.cell.2015.12.023 · Cited by 673
Neural recording and modulation technologies
Chen, R., Canales, A., & Anikeeva, P. (2017) · Nature Reviews Materials · doi:10.1038/natrevmats.2016.93 · Cited by 655
Sleep health: Reciprocal regulation of sleep and innate immunity
Irwin, M. R., & Opp, M. R. (2017) · Neuropsychopharmacology · doi:10.1038/npp.2016.148 · Cited by 624
“In relation to inflammation, the parasympathetic nervous system is also involved, 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 (Sternberg, 2006; Tracey, 2009).”
BackgroundNeuroimmune mechanisms of depression
Hodes, G. E., Kana, V., Menard, C., Merad, M., & Russo, S. J. (2015) · Nature Neuroscience · doi:10.1038/nn.4113 · Cited by 585
Innate immune responses to trauma
Huber-Lang, M. S., Lambris, J. D., & Ward, P. A. (2018) · Nature Immunology · doi:10.1038/s41590-018-0064-8 · Cited by 618
New insights into the development of lymphoid tissues
van de Pavert, S. A., & Mebius, R. E. (2010) · Nature reviews. Immunology · doi:10.1038/nri2832 · Cited by 616
Resolving postoperative neuroinflammation and cognitive decline
Terrando, N., Eriksson, L. I., Ryu, J. K., Yang, T., Monaco, C. G., Feldmann, M., Fagerlund, M. J., Charo, I. F., Akassoglou, K., & Maze, M. (2011) · Annals of Neurology · doi:10.1002/ana.22664 · Cited by 582
“Stimulation of the cholinergic anti-inflammatory pathway via activation of the a7 nAChR subtype is a pivotal regulator of NF-jB activity.(21,22) We tested whether pharmacologic activation of this receptor could prevent surgery-induced neuroinflammation.”
BackgroundAre bee diseases linked to pesticides? — A brief review
Sánchez‐Bayo, F., Goulson, D., Pennacchio, F., Nazzi, F., Goka, K., & Desneux, N. (2016) · Environment International · doi:10.1016/j.envint.2016.01.009 · Cited by 488
“on immunity (Di Prisco et al., 2013; Tracey, 2009; Tracey, 2011), one could expect a general undermining of the body defences in other”
BackgroundThe Meningeal Lymphatic System: A New Player in Neurophysiology
Da Mesquita, S., Fu, Z., & Kipnis, J. (2018) · Neuron · doi:10.1016/j.neuron.2018.09.022 · Cited by 479
Biology and Genetics of Prions Causing Neurodegeneration
Prusiner, S. B. (2013) · Annual Review of Genetics · doi:10.1146/annurev-genet-110711-155524 · Cited by 455
The neurobiology of interoception in health and disease
Quadt, L., Critchley, H., & Garfinkel, S. N. (2018) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.13915 · Cited by 488
Neural circuits of interoception
Berntson, G. G., & Khalsa, S. S. (2021) · Trends in Neurosciences · doi:10.1016/j.tins.2020.09.011 · Cited by 419
“Future research should be addressed at (i) further elaborating the multisynaptic pathways and circuits connecting the CNS with the internal organs of the body, (ii) clarifying the ascending interoceptive pathways linking the NTS and spinal afferents with higher order regions of the CNS, (iii) understanding how interac…”
BackgroundInfluentialMatteoli, G., Gomez‐Pinilla, P. J., Némethova, A., Giovangiulio, M. D., Cailotto, C., van Bree, S. H., Michel, K., Tracey, K. J., Schemann, M., Boesmans, W., et al. (2013) · Gut · doi:10.1136/gutjnl-2013-304676 · Cited by 448
Self-citationFunctional Innervation of Hepatic iNKT Cells Is Immunosuppressive Following Stroke
Wong, C. H. Y., Jenne, C. N., Lee, W., Léger, C., & Kubes, P. (2011) · Science · doi:10.1126/science.1210301 · Cited by 436
The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain
Bellavance, M.-A., & Rivest, S. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00136 · Cited by 419
“Finally, afferent fibers of the vagus nerve may also signal peripheral inflammation to the brain and thereby activate the HPA response (20, 21).”
BackgroundSignalling cognition: The gut microbiota and hypothalamic-pituitary-adrenal axis
Rusch, J. A., Layden, B. T., & Dugas, L. R. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1130689 · Cited by 415
Rheumatoid arthritis and depression: an inflammatory perspective
Nerurkar, L., Siebert, S., McInnes, I. B., & Cavanagh, J. (2018) · The Lancet Psychiatry · doi:10.1016/s2215-0366(18)30255-4 · Cited by 426
Biological mechanisms underlying the role of physical fitness in health and resilience
Silverman, M. N., & Deuster, P. A. (2014) · Interface Focus · doi:10.1098/rsfs.2014.0040 · Cited by 416
“The most important mechanisms relate to modulation of the body’s main stress responsive systems—the HPA axis, the autonomic nervous system and immune system—and interactions among these systems [36–40].”
BackgroundRethinking inflammation: neural circuits in the regulation of immunity
Olofsson, P. S., Rosas‐Ballina, M., Levine, Y. A., & Tracey, K. J. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01138.x · Cited by 393
“A prototypical neural reflex circuit of this kind is the ‘inflammatory reflex’ which includes a sensory arm in the afferent vagus and a motor arm in the efferent vagus nerve (3) (Fig.”
BackgroundSelf-citationMind–body therapies and control of inflammatory biology: A descriptive review
Bower, J. E., & Irwin, M. R. (2016) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2015.06.012 · Cited by 388
“Increases in parasympathetic nervous system activity may also reduce inflammation via the anti-inflammatory cholinergic pathway (Tracey, 2009).”
BackgroundA genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies
Jing, M., Zhang, P., Wang, G., Feng, J., Mesik, L., Zeng, J., Jiang, H., Wang, S., Looby, J. C., Guagliardo, N. A., et al. (2018) · Nature Biotechnology · doi:10.1038/nbt.4184 · Cited by 392
Autonomic Nervous System and Immune System Interactions
Kenney, M., & Ganta, C. K. (2014) · Comprehensive physiology · doi:10.1002/cphy.c130051 · Cited by 441
Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III
Yuan, H., & Silberstein, S. D. (2015) · Headache The Journal of Head and Face Pain · doi:10.1111/head.12649 · Cited by 381
“VN senses inflammation and dampens the inflammatory response by influencing the hypothalamicpituitary-adrenal axis and modulating the autonomic system that controls key immune organs, such as the spleen, adrenal glands, and possibly bone marrow.(27,28) The spleen is the central organ in the inflammatory reflex and the…”
BackgroundInfluentialZannad, F. M., Ferrari, G. M. D., Tuinenburg, A. E., Wright, D. J., Brugada, J., Butter, C., Klein, H., Stolen, C., Meyer, S., Steín, K. M., et al. (2014) · European Heart Journal · doi:10.1093/eurheartj/ehu345 · Cited by 382
Depression in cancer: The many biobehavioral pathways driving tumor progression
Bortolato, B., Hyphantis, T. N., Valpione, S., Perini, G., Maes, M. H. J., Morris, G., Kubera, M., Köhler, C. A., Fernandes, B. S., Stubbs, B., et al. (2016) · Cancer Treatment Reviews · doi:10.1016/j.ctrv.2016.11.004 · Cited by 399
“kappa B (NF-jB), an effect referred to as the ‘‘cholinergic antiinflammatory pathway” [36].”
BackgroundStressful early life experiences and immune dysregulation across the lifespan
Fagundes, C. P., Glaser, R., & Kiecolt-Glaser, J. K. (2013) · Brain, Behavior, and Immunity · doi:10.1016/j.bbi.2012.06.014 · Cited by 371
“On the other hand, higher parasympathetic activity results in lower levels of inflammation via the cholinergic anti-inflammatory pathway that facilitates acetylcholine release (Tracey, 2009).”
BackgroundDiabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease
Vinik, A. I., Erbas, T. A., & CASELLINI, C. M. (2013) · Journal of Diabetes Investigation · doi:10.1111/jdi.12042 · Cited by 385
Targeting Tumor Necrosis Factor Alpha for Alzheimer’s Disease
Decourt, B., Lahiri, D. K., & Sabbagh, M. N. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160930110551 · Cited by 383
Moorman, J. R., Carlo, W. A., Kattwinkel, J., Schelonka, R. L., Porcelli, P. J., Navarrete, C. T., Bancalari, E., Aschner, J. L., Walker, M. W., Perez, J. A. R., et al. (2011) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2011.06.044 · Cited by 369
Kempuraj, D., Thangavel, R., Selvakumar, G. P., Zaheer, S. A., Ahmed, M. E., Raikwar, S. P., Zahoor, H., Saeed, D., Natteru, P., Iyer, S. S., et al. (2017) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2017.00216 · Cited by 382
“Peripheral inflammation is also translated to the brain through the vagus nerve by neural reflex (Tracey, 2009).”
BackgroundOverview and introduction: The blood–brain barrier in health and disease
Abbott, N. J., & Friedman, A. (2012) · Epilepsia · doi:10.1111/j.1528-1167.2012.03696.x · Cited by 378
“Evidence suggests tight direct interactions between the cholinergic and immune systems in both the peripheral and the central nervous systems (Tracey, 2009; Gnatek et al., 2012).”
BackgroundA Path Toward Precision Medicine for Neuroinflammatory Mechanisms in Alzheimer's Disease
Hampel, H., Caraci, F., Cuello, A. C., Caruso, G., Nisticò, R., Corbo, M., Baldacci, F., Toschi, N., Garaci, F., Chiesa, P. A., et al. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.00456 · Cited by 360
Targeting HMGB1 in inflammation
Yang, H., & Tracey, K. J. (2010) · Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms · doi:10.1016/j.bbagrm.2009.11.019 · Cited by 351
Self-citationExercise, inflammation and aging.
(2012) · Europe PMC (PubMed Central) · Cited by 345
Septic-Associated Encephalopathy: a Comprehensive Review
Mazeraud, A., Righy, C., Bouchereau, E., Benghanem, S., Bozza, F. A., & Sharshar, T. (2020) · Neurotherapeutics · doi:10.1007/s13311-020-00862-1 · Cited by 352
“Four broad functions are controlled by the brainstem: brainstem reflexes, sleep–wake cycle, control of vital functions, and modulation of the immune response [88].”
BackgroundCurrent 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
“In particular, VNS was shown to rebalance the working point of autonomic regulation of the immune system into a protective range avoiding pro-inflammatory responses and, on the other hand, avoiding immunosuppression (Tracey, 2009).”
BackgroundPathophysiological and cognitive mechanisms of fatigue in multiple sclerosis
Manjaly, Z., Harrison, N. A., Critchley, H., Tri, C., Stefanics, G., Wenderoth, N., Lutterotti, A., Müller, A. E., & Stephan, K. E. (2019) · Journal of Neurology Neurosurgery & Psychiatry · doi:10.1136/jnnp-2018-320050 · Cited by 358
“84 Additionally, several indirect pathways exist how peripheral inflammation can affect the CNS.”
BackgroundSchedlowski, M., Enck, P., Rief, W., & Bingel, U. (2015) · Pharmacological Reviews · doi:10.1124/pr.114.009423 · Cited by 323
“…there are few studies reporting these effects in humans, and those that do mainly employed insulin as a US measuring blood glucose or insulin levels as a conditioned response (Fehm-Wolfsdorf et al., 1993; Stockhorst et al., 1999, 2004, 2011; Klosterhalfen et al., 2000; reviewed in Wendt et al.,…”
BackgroundTrauma of major surgery: A global problem that is not going away
Dobson, G. P. (2020) · International Journal of Surgery · doi:10.1016/j.ijsu.2020.07.017 · Cited by 316
Anti-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
“Tracey's group reported an anti-inflammatory role of vagal efferents through the cholinergic anti-inflammatory pathway: acetylcholine (Ach) released at the distal end of the vagus nerve, interacts with α-7 nicotinic Ach receptor (α7nAChR) of human macrophages to inhibit the release of proinflammatory cytokines such as…”
BackgroundPsychosocial stress in pregnancy and preterm birth: associations and mechanisms
Shapiro, G. D., Fraser, W., Frasch, M. G., & Séguin, J. (2013) · Journal of Perinatal Medicine · doi:10.1515/jpm-2012-0295 · Cited by 278
“Evidence in support of this pathway comes from suppression of inflammation (decreased production of proinflammatory cytokines with no change in production of anti-inflammatory cytokines) in response to stimulation of the vagus nerve in adult animal models [88].”
BackgroundYang, I. H., Corwin, E. J., Brennan, P. A., Jordan, S., Murphy, J. R., & Dunlop, A. L. (2015) · Nursing Research · doi:10.1097/nnr.0000000000000133 · Cited by 310
“All rights reserved. reducing the production of proinflammatory cytokines, including tumor necrosis factor-alpha (Pavlov, Wang, Czura, Friedman, & Tracey, 2003; Tracey, 2009; Vijayaraghavan et al., 2013).”
BackgroundThe vagal innervation of the gut and immune homeostasis
Matteoli, G., & Boeckxstaens, G. E. (2013) · Gut · doi:10.1136/gutjnl-2012-302550 · Cited by 276
Inflammatory mediators in human epilepsy: A systematic review and meta-analysis
de Vries, E. E., van den Munckhof, B., Braun, K. P. J., van Royen‐Kerkhof, A., de Jager, W., & Jansen, F. E. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.02.007 · Cited by 271
Lagraauw, H. M., Kuiper, J., & Bot, I. (2015) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2015.08.007 · Cited by 289
Inflammatory Response in Dry Eye
Yamaguchi, T. (2018) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.17-23651 · Cited by 270
Neuronal regulation of immunity: why, how and where?
Schiller, M., Ben-Shaanan, T. L., & Rolls, A. (2020) · Nature reviews. Immunology · doi:10.1038/s41577-020-0387-1 · Cited by 284
Sepsis-associated encephalopathy: A vicious cycle of immunosuppression
Ren, C., Yao, R.-Q., Zhang, H., Feng, Y.-W., & Yao, Y.-M. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-1701-3 · Cited by 259
α7-Cholinergic Receptor Mediates Vagal Induction of Splenic Norepinephrine
Vida, G., Peña, G., Deitch, E. A., & Ulloa, L. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.1003722 · Cited by 262
Pavlov, V. A., & Tracey, K. J. (2015) · Immunologic Research · doi:10.1007/s12026-015-8718-1 · Cited by 254
Self-citationInhibitors of Acetylcholinesterase and Butyrylcholinesterase Meet Immunity
Pohanka, M. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15069809 · Cited by 252
“CNS is involved in the regulation of innate immunity [15–24].”
BackgroundPro-cognitive properties of T cells
Kipnis, J., Gadani, S., & Derecki, N. C. (2012) · Nature Reviews Immunology · doi:10.1038/nri3280 · Cited by 246
Peripheral gating of pain signals by endogenous lipid mediators
Piomelli, D., & Sasso, O. (2014) · Nature Neuroscience · doi:10.1038/nn.3612 · Cited by 240
Neuroimmune cardiovascular interfaces control atherosclerosis
Mohanta, S. K., Peng, L., Li, Y., Lu, S., Sun, T., Carnevale, L., Perrotta, M., Ma, Z., Förstera, B., Stanic, K., et al. (2022) · Nature · doi:10.1038/s41586-022-04673-6 · Cited by 249
The self in context: brain systems linking mental and physical health
Koban, L., Gianaros, P. J., Hedy Kober, A., & Wager, T. D. (2021) · Nature reviews. Neuroscience · doi:10.1038/s41583-021-00446-8 · Cited by 258
The Pathophysiology of Sepsis-Associated AKI
Kuwabara, S., Goggins, E. S., & Okusa, M. D. (2022) · Clinical Journal of the American Society of Nephrology · doi:10.2215/cjn.00850122 · Cited by 236
Brommer, B., Engel, O., Kopp, M. A., Watzlawick, R., Müller, S., Prüß, H., Chen, Y., DeVivo, M. J., Finkenstaedt, F. W., Dirnagl, U., et al. (2016) · Brain · doi:10.1093/brain/awv375 · Cited by 231
“Fourth, brain stem derived innervation of the vagus nerve, which also attributes to immune modulatory effects (Tracey, 2009), remains unaffected.”
BackgroundFood for thought: The role of nutrition in the microbiota-gut–brain axis
Oriach, C. S., Robertson, R. C., Stanton, C., Cryan, J. F., & Dinan, T. G. (2016) · Clinical Nutrition Experimental · doi:10.1016/j.yclnex.2016.01.003 · Cited by 240
“Through this complex network the gut can influence the brain via visceral messages, and conversely, the brain is able to influence gastrointestinal functions (like motility, secretion and mucin production) and immune functions, such as the modulation of cytokine production by cells of the mucosal immune system [40].”
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
“The answer stems from studies addressing the role of neural networks, which revealed that signals originating in the brain, and conveyed as action potentials transmitted in the vagus nerve, regulate cytokine production by the innate immune system (Tracey, 2009).”
BackgroundSelf-citationImpact of ICU-acquired weakness on post-ICU physical functioning: a follow-up study
Wieske, L., Dettling-Ihnenfeldt, D. S., Verhamme, C., Nollet, F., van Schaik, I. N., Schultz, M. J., Horn, J., & van der Schaaf, M. (2015) · Critical Care · doi:10.1186/s13054-015-0937-2 · Cited by 243
“Alternatively, an increased risk of developing infections may be the result of immune dysfunction secondary to autonomic dysfunction that may accompany ICU-AW [28,29].”
Neuroimmune crosstalk in the central nervous system and its significance for neurological diseases
Tian, L., Ma, L., Kaarela, T., & Li, Z. (2012) · Journal of Neuroinflammation · doi:10.1186/1742-2094-9-155 · Cited by 224
“Membrane proteins TLRs, RAGE, LFA-1, MAC-1, CRs, FcRβ [16-19,21,25,45-47] CD45, CD91, CD200R, CD172a [18,48]; CX3CR1 [49]; TREM-2 [50]; FasL, Fas [38,39]”
BackgroundInfluentialAutonomic regulation of cellular immune function
Bellinger, D. L., & Lorton, D. (2014) · Autonomic Neuroscience · doi:10.1016/j.autneu.2014.01.006 · Cited by 217
Noninvasive sub-organ ultrasound stimulation for targeted neuromodulation
Cotero, V. E., Fan, Y., Tsaava, T., Kressel, A. M., Hancu, I., Fitzgerald, P. B., Wallace, K. D., Kaanumalle, S., Graf, J. F., Rigby, W., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-08750-9 · Cited by 214
Self-citationVIP and PACAP : neuropeptide modulators of CNS inflammation, injury, and repair
Waschek, J. A. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12181 · Cited by 221
“NA then acts on MF in these organs to release ACh, which in turn acts in an autocrine or paracrine manner on immune cells that express a7 nicotinic receptors to alter their function (Rosas-Ballina and Tracey, 2009; Tracey, 2009; Thayer and Sternberg, 2010).”
BackgroundHao, J., Liu, R., Piao, W., Zhou, Q., Vollmer, T. L., Campagnolo, D. I., Xiang, R., Cava, A. L., Kaer, L. V., & Shi, F. (2010) · The Journal of Experimental Medicine · doi:10.1084/jem.20092749 · Cited by 222
“These factors might include CNS Ags, signals generated from neuronal cells (Tracey, 2009), and CNSderived APCs.”
BackgroundThe immunology of neurodegeneration
Czirr, E., & Wyss‐Coray, T. (2012) · Journal of Clinical Investigation · doi:10.1172/jci58656 · Cited by 218
“…tissues may signal to the brain through at least four different routes: active transport across the BBB, signaling at the luminal side of the BBB and propagation of secondary factors into the CNS, diffusion via circumventricular organs, and signaling via peripheral nerves such as the vagus (64–66).”
Antidepressant therapies inhibit inflammation and microglial M1-polarization
Kalkman, H. O., & Feuerbach, D. (2016) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2016.04.001 · Cited by 212
Liu, 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
Sun, 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
The Cholinergic System and Inflammation: Common Pathways in Delirium Pathophysiology
Cerejeira, J., Nogueira, V., Luís, P., Vaz‐Serra, A., & Mukaetova‐Ladinska, E. B. (2012) · Journal of the American Geriatrics Society · doi:10.1111/j.1532-5415.2011.03883.x · Cited by 207
“In addition, the CNS modulates the innate immune response through the cholinergic output of the vagus nerve.(3) It has recently been reported that individuals with delirium had lower plasma levels of cholinesterase activity than controls even before surgery, suggesting that lower plasma levels of cholinesterase activi…”
BackgroundInfluentialBrain Ischemia Suppresses Immunity in the Periphery and Brain via Different Neurogenic Innervations
Liu, Q., Jin, W.-N., Liu, Y., Shi, K., Sun, H., Zhang, F., Zhang, C., Gonzales, R. J., Sheth, K. N., Cava, A. L., et al. (2017) · Immunity · doi:10.1016/j.immuni.2017.02.015 · Cited by 209
“Acute ischemic brain injury swiftly activates the sympathetic, parasympathetic, and HPA axis pathways, leading to the release of norepinephrine (NE), ACh, and glucocorticoids (GCs) (Meisel et al., 2005; Prass et al., 2003; Rosas-Ballina and Tracey, 2009; Wong et al., 2011).”
Loneliness Promotes Inflammation During Acute Stress
Jaremka, L. M., Fagundes, C. P., Peng, J., Bennett, J. M., Glaser, R., Malarkey, W. B., & Kiecolt-Glaser, J. K. (2013) · Psychological Science · doi:10.1177/0956797612464059 · Cited by 255
“Furthermore, parasympathetic activity can reduce inflammation via the cholinergic anti-inflammatory pathway that induces acetylcholine release (Tracey, 2009).”
BackgroundKong, J., Fang, J., Park, J., Li, S., & Rong, P. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00020 · Cited by 197
“Neural anatomy has shown that the auricular branch of the vagus nerve (ABVN) projects to the nucleus tractus solitari (NTS), which is further connected with other brain regions, such as the locus coeruleus, parabrachial nucleus, hypothalamus, thalamus, amygdala, hippocampus, anterior cingulate cortex (ACC), anterior i…”
BackgroundInfluentialNeural 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
“N IH -PA Author M anuscript N IH -PA Author M anuscript N IH -PA Author M anuscript alpha 7 nicotinic receptors that inhibit NF kappa B and thus cytokine synthesis and release (Rosas-Ballina and Tracey, 2009).”
BackgroundThe crosstalk between autonomic nervous system and blood vessels.
Sheng, Y., & Zhu, L. (2018) · PubMed Central · Cited by 196
Crosstalk between the nociceptive and immune systems in host defence and disease
McMahon, S. B., Russa, F. L., & Bennett, D. (2015) · Nature reviews. Neuroscience · doi:10.1038/nrn3946 · Cited by 196
The neuroinflammatory response of postoperative cognitive decline
Vacas, S., Degos, V., Feng, X., & Maze, M. (2013) · British Medical Bulletin · doi:10.1093/bmb/ldt006 · Cited by 195
Midgut microbiota and host immunocompetence underlie Bacillus thuringiensis killing mechanism
Caccia, S., Lelio, I. D., Storia, A. L., Marinelli, A., Varricchio, P., Franzetti, E., Banyuls, N., Tettamanti, G., Casartelli, M., Giordana, B., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1521741113 · Cited by 190
Beyond neurotransmission: acetylcholine in immunity and inflammation
Cox, M. A., Bassi, C., Saunders, M. E., Nechanitzky, R., Morgado‐Palacin, I., Zheng, C., & Mak, T. W. (2019) · Journal of Internal Medicine · doi:10.1111/joim.13006 · Cited by 192
Modulatory effects of α7 nAChRs on the immune system and its relevance for CNS disorders
Kalkman, H. O., & Feuerbach, D. (2016) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-016-2175-4 · Cited by 191
“Vagus nerve stimulation, which reduces inflammation [23, 66, 69, 122], has been approved for treatment of drugresistant depression in humans [123].”
BackgroundInfluentialCholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity
Halder, N., & Lal, G. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.660342 · Cited by 190
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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