The DOI matches its Crossref record; 102 of the 102 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source doesn’t support the claim as written.
In the citing paper
“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
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Additional evidence suggests that the parasympathetic nervous system modulates immune responses at a regional level through both the efferent and afferent fibers of the vagus nerve, enabling it to prevent excessive inflammation”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Tracey, 2009
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
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
Items 301–400 of 998
Jiang, P., Ma, D., Wang, X., Wang, Y., Bi, Y., Jl, Y., Wang, X., & Li, X. (2018) · PubMed Central · doi:10.14348/molcells.2018.2156 · Cited by 54
“According to the definition of cholinergic antiinflammatory pathway, the stimulated α7nAchR could inhibit inflammation reaction by suppressing activation of IKKβ/NF-KB pathway in central and peripheral tissue (Tracey, 2009).”
BackgroundBimonte, S., & Cascella, M. (2017) · Neural Regeneration Research · doi:10.4103/1673-5374.219032 · Cited by 55
“…cognitive dysfunction; BBB: bloods brain barrier; Ach: Ace-tylcholine; LTP: long-term potentiation; NF-k: nuclear factor-κ; CB2R: cannabinoid receptor type 2; PPARγ peroxisome proliferator-activated receptor-γ; HDAC: histone deacetylase. pressed by the cholinergic stimulation (Tracey, 2009).”
Merabet, N., Lucassen, P. J., Crielaard, L., Stronks, K., Quax, R., Sloot, P. M. A., la Fleur, S. E., & Nicolaou, M. (2021) · Frontiers in Neuroendocrinology · doi:10.1016/j.yfrne.2021.100972 · Cited by 77
Woo, J. H., Baik, H. J., Kim, C. H., Chung, R. K., Kim, D. Y., Lee, G. Y., & Chun, E. H. (2015) · Journal of Korean Medical Science · doi:10.3346/jkms.2015.30.10.1503 · Cited by 53
“Cancer surgery can induce an acute inflammatory response, related to local tissue damage and the shedding of malignant cells into the blood and lympha tic circulation despite meticulous surgical manipulation (3).”
BackgroundDifferential modulation of EAE by α9*‐ and β2*‐nicotinic acetylcholine receptors
Simard, A. R., Gan, Y. X., St‐Pierre, S., Kousari, A., Patel, V., Whiteaker, P., Morley, B. J., Lukas, R. J., & Shi, F. (2013) · Immunology and Cell Biology · doi:10.1038/icb.2013.1 · Cited by 53
“Nicotinic acetylcholine receptor (nAChR) signalling is thought to have beneficial, natural, immunosuppressive consequences via what is called the cholinergic anti-inflammatory pathway (reviewed in (1)).”
BackgroundDhawan, S., Palma, G. D., Willemze, R., Hilbers, F., Verseijden, C., Luyer, M., Nuding, S., Wehkamp, J., Souwer, Y., de Jong, E. C., et al. (2016) · American Journal of Physiology - Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00114.2016 · Cited by 48
“THE EFFERENT VAGUS NERVE IS recognized as a negative regulator of immune responses to injury and infection, via its peripheral release of acetylcholine (ACh) (39).”
BackgroundInteraction between the hypothalamus and the immune system
Soto‐Tinoco, E., Guerrero‐Vargas, N. N., & Buijs, R. M. (2016) · Experimental Physiology · doi:10.1113/ep085560 · Cited by 54
“Several studies have used the word ‘reflex’ to indicate the capacity of the autonomic nervous system to respond immediately to an inflammatory stimulus (Tracey, 2009; Martelli et al. 2014).”
MethodZucco, G. M., & Doty, R. L. (2021) · Brain Sciences · doi:10.3390/brainsci12010046 · Cited by 61
Durosier, L. D., Herry, C. L., Cortes, M., Cao, M., Burns, P., Desrochers, A., Fecteau, G., SEELY, A. J. E., & Frasch, M. G. (2015) · Physiological Measurement · doi:10.1088/0967-3334/36/10/2089 · Cited by 52
The α4 Nicotinic Receptor Promotes CD4+ T-Cell Proliferation and a Helper T-Cell Immune Response
Nordman, J. C., Muldoon, P. P., Clark, S. G., Damaj, M. I., & Kabbani, N. (2013) · Molecular Pharmacology · doi:10.1124/mol.113.088484 · Cited by 53
“Studies show that nAChRs play a role in immune function in the spleen (Tracey, 2009).”
BackgroundKul’chyns’kyi, A. B., Kyjenko, V. M., Żukow, W., & Popovych, I. L. (2017) · Open Medicine · doi:10.1515/med-2017-0030 · Cited by 51
“Although there are still some disagreements about specific aspects of neural-immune communications, much evidence to supports the existence of numerous interactions between the central nervous system, the peripheral nervous system (both sympathetic and parasympathetic divisions), and immune systems [2-9].”
BackgroundInfluentialCao, J., Zhang, Y., Li, H., Yan, Z., Liu, X., Hou, X., Chen, W., Hodges, S., Kong, J., & Liu, B. (2021) · Journal of Translational Medicine · doi:10.1186/s12967-021-03024-9 · Cited by 54
Neural regulation of inflammation in the airways and lungs
McGovern, A. E., & Mazzone, S. B. (2013) · Autonomic Neuroscience · doi:10.1016/j.autneu.2013.12.008 · Cited by 51
Neural therapy—A review of the therapeutic use of local anesthetics
Weinschenk, S. W. (2012) · Acupuncture and Related Therapies · doi:10.1016/j.arthe.2012.12.004 · Cited by 51
Septic encephalopathy: when cytokines interact with acetylcholine in the brain
Zhang, Q., Sheng, Z.-Y., & Yao, Y.-M. (2014) · Military Medical Research · doi:10.1186/2054-9369-1-20 · Cited by 53
“so-called “inflammatory reflex arc” [22,39,40].”
BackgroundInnate Immunity and Inflammation Post-Stroke: An α7-Nicotinic Agonist Perspective
Neumann, S., Shields, N. J., Balle, T., Chebib, M., & Clarkson, A. N. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161226141 · Cited by 51
“Interestingly, recent research has shown that the autonomic nervous system also controls inflammation via neural circuits that affect immune cells [6].”
BackgroundZivkovic, A. R., Decker, S., Zirnstein, A. C., Sigl, A., Schmidt, K., Weigand, M. A., Hofer, S., & Brenner, T. (2018) · Mediators of Inflammation · doi:10.1155/2018/1942193 · Cited by 53
Contribution of Baroreceptor Function to Pain Perception and Perioperative Outcomes
Suárez-Roca, H., Klinger, R. Y., Podgoreanu, M. V., Ji, R., Sigurdsson, M. I., Waldron, N. H., Mathew, J. P., & Maixner, W. D. (2018) · Anesthesiology · doi:10.1097/aln.0000000000002510 · Cited by 52
Pavlov, V. A. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2020.107794 · Cited by 50
“…and alternativemedicine therapies, such as meditation, hypnosis, acupuncture, and biofeedback have been shown to alter autonomic regulation towards an increase in vagus nerve activity and to suppress inflammation (Bonaz et al., 2017; Oke & Tracey, 2009; Song et al., 2012; Tracey, 2002).”
Krabs, R. U., Enk, R., Teich, N., & Koelsch, S. (2015) · PLoS ONE · doi:10.1371/journal.pone.0126224 · Cited by 55
“For example, a cholinergic anti-inflammatory pathway has been described, which is a reflex arc that diminishes inflammation via the parasympathetic vagus nerve [87].”
BackgroundAn, G. C., Nieman, G. F., & Yoram Vodovotz, B. (2012) · Annals of Biomedical Engineering · doi:10.1007/s10439-012-0565-9 · Cited by 50
Depressive Symptoms, Social Support, and Risk of Adult Asthma in a Population-Based Cohort Study
Loerbroks, A., Apfelbacher, C., Bosch, J. A., & Stürmer, T. (2010) · Psychosomatic Medicine · doi:10.1097/psy.0b013e3181d2f0f1 · Cited by 50
An Overview of Biofield Devices
Muehsam, D. J., Chevalier, G., Barsotti, T. J., & Gurfein, B. T. (2015) · Global Advances in Health and Medicine · doi:10.7453/gahmj.2015.022.suppl · Cited by 52
Locatelli, G., MATUS, A. M., James, R., Salmoirago‐Blotcher, E., Ausili, D., Vellone, E., & Riegel, B. J. (2023) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2023.105142 · Cited by 58
“Responses include activation of cardiovascular, gastrointestinal, endocrine and immune systems, (Quadt et al., 2018; Tracey, 2009) as well as reactions known as sickness behaviors (Dantzer and Kelley, 2007).”
BackgroundNeuropathic pain; what we know and what we should do about it
Smith, P. A. (2023) · Frontiers in Pain Research · doi:10.3389/fpain.2023.1220034 · Cited by 51
Topography and extent of pulmonary vagus nerve supply with respect to transthoracic oesophagectomy
Weijs, T. J., Ruurda, J. P. H., Luyer, M. D. P., Nieuwenhuijzen, G. A. P., van Hillegersberg, R., & Bleys, R. L. A. W. (2015) · Journal of Anatomy · doi:10.1111/joa.12366 · Cited by 49
“Furthermore, the vagus nerve plays an important regulatory role in inflammation activated by mechanical or chemical stimulation or via nutrition (Luyer et al. 2005; Tracey, 2009; Lubbers et al. 2010a,b).”
BackgroundWu, Y., You, H., Ma, P., Li, L., Yuan, Y., Li, J., Ye, X., Liu, X., Yao, H., Chen, R., et al. (2013) · PLoS ONE · doi:10.1371/journal.pone.0062827 · Cited by 49
“This in turn activates the efferent arc, which is known as the ‘‘cholinergic antiinflammatory pathway’’ [62].”
BackgroundDarby, M., Schnoeller, C., Vira, A., Culley, F. J., Bobat, S., Logan, E., Kirstein, F., Wess, J., Cunningham, A. F., Brombacher, F., et al. (2015) · PLoS Pathogens · doi:10.1371/journal.ppat.1004636 · Cited by 49
“Cholinergic signalling also influences the immune system, most notably in the cholinergic anti-inflammatory pathway, which results in the α7 nicotinic receptor subunit-dependent inhibition of macrophage TNF-α, IL-1β and IL-6 production [1,2].”
BackgroundDepressive symptoms and immune transcriptional profiles in late adolescents
Chiang, J. J., Cole, S. W., Bower, J. E., Irwin, M. R., Taylor, S. E., Arevalo, J. M. G., & Fuligni, A. J. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.03.004 · Cited by 53
“activity can inhibit NF-κB activity and inflammatory responses (Martelli et al., 2014; Tracey, 2009).”
Human plasma biomarker responses to inhalational general anaesthesia without surgery
Deiner, S. G., Baxter, M. G., Mincer, J. S., Sano, M. C., Hall, J. R., Mohammed, I., O’Bryant, S. E., Zetterberg, H., Blennow, K., & Eckenhoff, R. G. (2020) · British Journal of Anaesthesia · doi:10.1016/j.bja.2020.04.085 · Cited by 49
Vagal nerve activity as a moderator of brain-immune relationships
Ohira, H., Matsunaga, M., Osumi, T., Fukuyama, S., Shinoda, J., Yamada, J., & Gidron, Y. (2013) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2013.04.011 · Cited by 47
“, 1995), expression of receptors for neurotransmitters on immune cells (Levite, 2008; Tracey, 2009) and differential left versus right hemisphere influences on immunity (Davidson et al.”
BackgroundInfluentialMaehara, T., Matsumoto, K., Horiguchi, K., Kondo, M., Iino, S., Horie, S., Murata, T., Tsubone, H., Shimada, S., Ozaki, H., et al. (2014) · British Journal of Pharmacology · doi:10.1111/bph.13006 · Cited by 48
“Thus, stimulation of vagal afferent nerves should ameliorate POI (Tracey, 2009).”
BackgroundRegulation of Carcinogenesis by Sensory Neurons and Neuromediators
Erin, N., Shurin, G. V., Baraldi, J. H., & Shurin, M. R. (2022) · Cancers · doi:10.3390/cancers14092333 · Cited by 50
de Haan, J. J., Hadfoune, M., Lubbers, T., Hodin, C. M. I. M., Lenaerts, K., Ito, A., Verbaeys, I., Skynner, M. J., Cailotto, C., van der Vliet, J., et al. (2013) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00333.2012 · Cited by 47
Lemche, E., Чабан, О., & Lemche, A. V. (2016) · Frontiers in Neuroscience · doi:10.3389/fnins.2016.00142 · Cited by 50
“Increasing the vagal tone there induces a shift from pro-inflammatory T helper cell type 1 (TH1) cytokines such as interferon-γ (IFN-γ) to anti-inflammatory TH2-type cytokines, such as interleukin-10 (IL-10) (Tracey, 2007, 2009; Rosas-Ballina et al., 2008, 2011; Trakhtenberg and Goldberg, 2011).”
BackgroundLiu, Y., Xu, S., Zhang, H., Qian, K., Huang, J., Gu, X., Li, Y., Fan, Y., & Hu, J. (2021) · Cell Death and Disease · doi:10.1038/s41419-021-03726-4 · Cited by 47
Development and characterization of a chronic implant mouse model for vagus nerve stimulation
Mughrabi, I. T., Hickman, J. L., Jayaprakash, N., Thompson, D., Ahmed, U., Papadoyannis, E. S., Chang, Y.-C., Abbas, A., Datta, T., Chang, E. H., et al. (2021) · eLife · doi:10.7554/elife.61270 · Cited by 52
Self-citationHiraki, T., Baker, W. B., & Greenberg, J. H. (2011) · Journal of Neuroscience Research · doi:10.1002/jnr.22812 · Cited by 46
“The cholinergic anti-inflammatory pathway (CAP) is activated by the central cholinergic system in the brain via the efferent fiber of the vagus nerve (Pavlov et al., 2006; Tracey, 2007).”
BackgroundRepeated recall of learned immunosuppression: Evidence from rats and men
Wirth, T., Ober, K., Prager, G., Vogelsang, M., Benson, S., Witzke, O., Kribben, A., Engler, H., & Schedlowski, M. (2011) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2011.05.011 · Cited by 46
“The central nervous system (CNS) and the peripheral immune system are reciprocally exchanging information (Tracey, 2009).”
Brain–immune interactions and the neural basis of disease-avoidant ingestive behaviour
Pacheco‐López, G., & Bermúdez‐Rattoni, F. (2011) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2011.0061 · Cited by 48
van Maanen, M. A., Papke, R. L., Koopman, F. A., Koepke, J., Bevaart, L., Clark, R. B., Lamppu, D., Elbaum, D., LaRosa, G. J., Tak, P. P., et al. (2015) · PLoS ONE · doi:10.1371/journal.pone.0116227 · Cited by 46
“This process was first described by Tracey and colleagues and has been termed “the cholinergic anti-inflammatory pathway” [4,5].”
MethodPeripheral inflammation in neurodegeneration
Träger, U., & Tabrizi, S. J. (2013) · Journal of Molecular Medicine · doi:10.1007/s00109-013-1026-0 · Cited by 47
“Lastly, peripheral inflammation is also translated into the brain via the vagus nerve in the so-called neural reflex which coordinated systemic inflammation by sensing and inhibiting proinflammatory markers [66].”
Closing the brain–heart loop: Towards more holistic models of addiction and addiction recovery
Eddie, D., Bates, M. E., & Buckman, J. F. (2020) · Addiction Biology · doi:10.1111/adb.12958 · Cited by 48
Chronic neural activity recorded within breast tumors
McCallum, G. A., Shiralkar, J., Suciu, D., Covarrubias, G., Yu, J. S., Karathanasis, E., & Durand, D. M. (2020) · Scientific Reports · doi:10.1038/s41598-020-71670-y · Cited by 46
Interoception and Inflammation in Psychiatric Disorders
Savitz, J., & Harrison, N. A. (2018) · Biological Psychiatry: Cognitive Neuroscience and Neuroimaging · doi:10.1016/j.bpsc.2017.12.011 · Cited by 126
“Projections from the solitary nucleus to the vagal dorsal motor nucleus and nucleus ambiguous initiate reflex responses including the inflammatory reflex, which regulate the magnitude of innate immune responses (4).”
Neuro-Signals from Gut Microbiota: Perspectives for Brain Glioma
D’Alessandro, G., Lauro, C., Quaglio, D., Ghirga, F., Botta, B., Trettel, F., & Limatola, C. (2021) · Cancers · doi:10.3390/cancers13112810 · Cited by 47
Cholinergic neurons trigger epithelial Ca2+ currents to heal the gut
Petsakou, A., Liu, Y., Liu, Y., Comjean, A., Hu, Y., & Perrimon, N. (2023) · Nature · doi:10.1038/s41586-023-06627-y · Cited by 52
Ghrelin as an anti-inflammatory and protective agent in ischemia/reperfusion injury
Raghay, K., Akki, R., Bensaid, D., & Errami, M. (2019) · Peptides · doi:10.1016/j.peptides.2019.170226 · Cited by 45
Zhao, C., Yang, X., Su, E. M., Huang, Y., Li, L., Matthay, M. A., & Su, X. (2017) · Cell Discovery · doi:10.1038/celldisc.2017.9 · Cited by 43
The brain cytokine orchestra in multiple sclerosis: from neuroinflammation to synaptopathology
Amoriello, R., Memo, C., Ballerini, L., & Ballerini, C. (2024) · Molecular Brain · doi:10.1186/s13041-024-01077-7 · Cited by 47
Norman, G. J., Zhang, N., Morris, J. S., Karelina, K., Berntson, G. G., & DeVries, A. C. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1007583107 · Cited by 43
“4D), thereby suggesting that decreased parasympathetic activity may partially mediate increases in cytokine levels following CA/CPR through the “cholinergic anti-inflammatory reflex” (18).”
BackgroundNeuromodulation Applied to Diseases: The Case of HRV Biofeedback
Gitler, A., Vanacker, L., Couck, M., Leeuw, I. D., & Gidron, Y. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11195927 · Cited by 45
“These associations can be explained by the cholinergic anti-inflammatory effects of the vagus [11,12], and the key role inflammation plays in insulin resistance, the hallmark of diabetes [135].”
BackgroundNeurogenic regulation of dendritic cells in the intestine
Nijhuis, L., Olivier, B. J., & de Jonge, W. J. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.06.034 · Cited by 43
Human ghrelin protects animals from renal ischemia-reperfusion injury through the vagus nerve
Rajan, D., Wu, R., Shah, K. G., Jacob, A., Coppa, G. F., & Wang, P. (2011) · Surgery · doi:10.1016/j.surg.2011.06.027 · Cited by 42
Mastocytosis in adulthood and neuropsychiatric disorders
Georgin‐Lavialle, S., Gaillard, R., Moura, D. S., & Hermine, O. (2016) · Translational research · doi:10.1016/j.trsl.2016.03.013 · Cited by 46
The neonicotinoid insecticide Clothianidin adversely affects immune signaling in a human cell line
Prisco, G. D., Iannaccone, M., Ianniello, F., Ferrara, R., Caprio, E., Pennacchio, F., & Capparelli, R. (2017) · Scientific Reports · doi:10.1038/s41598-017-13171-z · Cited by 42
Sex differences in depression: An immunological perspective
Kropp, D. R., & Hodes, G. E. (2023) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2023.02.016 · Cited by 43
“Intracerebral administration of IL-1β or TNF-α also activates the HPA axis resulting in changes in body temperature, social and eating behavior (Dantzer et al., 2008; Tracey, 2009; Watkins & Maier, 2013).”
BackgroundBy what molecular mechanisms do social determinants impact cardiometabolic risk?
Baumer, Y., Pita, M. A., Baez, A. S., Ortiz-Whittingham, L. R., Cintron, M., Rose, R., Gray, V. C., Baah, F. O., & Powell‐Wiley, T. M. (2023) · Clinical Science · doi:10.1042/cs20220304 · Cited by 40
Baker, M. C., Kavanagh, S. T., Cohen, S. B., Matsumoto, A. K., Dikranian, A. H., Tesser, J., Kivitz, A., Alataris, K., & Genovese, M. C. (2023) · Arthritis & Rheumatology · doi:10.1002/art.42637 · Cited by 41
Autonomic nervous system dysfunction and sinonasal symptoms
Yao, A., Wilson, J. A., & Ball, S. L. (2018) · Allergy & Rhinology · doi:10.1177/2152656718764233 · Cited by 41
Wilund, K. R., Rosenblat, M., Chung, H. R., Volkova, N., Kaplan, M., Woods, J. A., & Aviram, M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.09.088 · Cited by 41
“Activation of this receptor inhibits the production of pro-inflammatory cytokines, thereby attenuating the local inflammatory response [2].”
BackgroundNeuro-immune interactions: Exploring the anti-inflammatory role of the vagus nerve.
Liu, L., Lou, S., Fu, D., Ji, P.-F., Xia, P., Shuang, S., Dong, W., Yuan, X.-Y., Wang, J., Xie, K., et al. (2025) · International Immunopharmacology · doi:10.1016/j.intimp.2025.114941 · Cited by 45
White, S. V., Czisch, C. E., Han, M. H., Plant, C. D., Harvey, A. R., & Plant, G. W. (2016) · Stem Cells · doi:10.1002/stem.2364 · Cited by 41
Reed, R. G., & Raison, C. L. (2016) · Springer eBooks · doi:10.1007/978-3-7091-1890-0_5 · Cited by 43
“5.1f ) (Tracey 2002 , 2009 ).”
BackgroundCostantini, T. W., Dang, X., Yurchyshyna, M. V., Coimbra, R. S. M., Eliceiri, B. P., & Baird, A. (2015) · Molecular Medicine · doi:10.2119/molmed.2015.00018 · Cited by 40
The Role of the Vagus Nerve: Modulation of the Inflammatory Reaction in Murine Polymicrobial Sepsis
Keßler, W., Diedrich, S., Menges, P., Ebker, T., Nielson, M., Partecke, L. I., Traeger, T., Cziupka, K., van der Linde, J., Puls, R., et al. (2012) · Mediators of Inflammation · doi:10.1155/2012/467620 · Cited by 40
Joe, Y., Kim, H. J., Kim, S., Chung, J., Ko, M. S., Lee, W. H., Chang, K. C., Park, J. W., & Chung, H. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.204859 · Cited by 39
Yousef, M. I., Khalil, D. K. A. M., & Abdou, H. M. (2018) · Toxicology Reports · doi:10.1016/j.toxrep.2018.04.006 · Cited by 39
“linergic anti-inflammatory pathway that induces acetylcholine release [43].”
BackgroundSiniavin, A. E., Streltsova, M. A., Kudryavtsev, D. S., Shelukhina, I. V., Utkin, Y. N., & Tsetlin, V. I. (2020) · Biomolecules · doi:10.3390/biom10040507 · Cited by 39
“It has been earlier shown that the vagus nerve stimulation ca reduce inflam ation both i t peripheral lymphoid organs a d in the brain [39,40].”
BackgroundPeripheral Focused Ultrasound Neuromodulation (pFUS)
Cotero, V. E., Miwa, H., Graf, J. F., Ashe, J. M., Loghin, E., Carlo, D. D., & Puleo, C. (2020) · Journal of Neuroscience Methods · doi:10.1016/j.jneumeth.2020.108721 · Cited by 39
Shabani, S. (2021) · Environmental Science and Pollution Research · doi:10.1007/s11356-020-11620-3 · Cited by 40
“Then, these circulating cytokines affect peripheral innate immune cells (Tracey 2009), activate peripheral neuronal afferents, and finally transmit to the cerebral tissue via diffusion to influence the CNS (Dantzer et al. 2008).”
BackgroundGhrelin as a Novel Therapy for Radiation Combined Injury
Jacob, A., Shah, K. G., Wu, R., & Wang, P. (2010) · Molecular Medicine · doi:10.2119/molmed.2009.00154 · Cited by 39
BDNF in Neuropathic Pain; the Culprit that Cannot be Apprehended
Smith, P. A. (2024) · Neuroscience · doi:10.1016/j.neuroscience.2024.02.020 · Cited by 40
Islas-Weinstein, L., Revuelta, A., & Hernández‐Pando, R. (2015) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.12792 · Cited by 38
Contribution of vascular cell-derived cytokines to innate and inflammatory pathways in atherogenesis
Loppnow, H., Buerke, M., Werdan, K., & Rose‐John, S. (2010) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2010.01245.x · Cited by 39
“Cholinergic regulation through the vagal inflammatory reflex [136] may influence this situation by keeping inflammation under control; however, after down-regulation of vagal activity the cytokine inhibition may fade and inflammation may increase.”
BackgroundImmune Cells Exploit a Neural Circuit to Enter the CNS
Tracey, K. J. (2012) · Cell · doi:10.1016/j.cell.2012.01.025 · Cited by 38
Self-citationSmith, R. S., Alkozei, A., Killgore, W. D. S., & Lane, R. D. (2017) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2017.09.011 · Cited by 39
“In particular, because the parasympathetic nervous system modulates immune responses through the vagus nerve in a manner that reduces inflammation (Sternberg, 2006; Tracey, 2009), low HRV in depression is likely related to higher levels of inflammation, and specifically to reduced parasympathetic immune modulation (e.”
BackgroundInfluentialCirillo, G., Negrete-Diaz, F., Yucumá, D., Virtuoso, A., Korai, S. A., Luca, C. D., Kaniušas, E., Papa, M., & Panetsos, F. (2022) · Cells · doi:10.3390/cells11244103 · Cited by 40
“Inflammatory mediators, in turn, activate VN fiber endings, which generate postsynaptic excitatory potentials into STN neurons according to a somatotopic pattern [32,153].”
BackgroundCardiac Autonomic Nerve Stimulation in the Treatment of Heart Failure
Kobayashi, M., MASSIELLO, A. L., Karimov, J. H., Wagoner, D. R. V., & Fukamachi, K. (2013) · The Annals of Thoracic Surgery · doi:10.1016/j.athoracsur.2012.12.060 · Cited by 38
“The pathophysiologic effects of a decrease in parasympathetic tone may reflect the vagus nerve’s role as the efferent arm of the “cholinergic antiinflammatory pathway” [25].”
BackgroundTargeting Anti-Inflammatory Treatment Can Ameliorate Injury-Induced Neuropathic Pain
Iwatsuki, K., Arai, T., Ota, H., Kato, S., Natsume, T., Kurimoto, S., Yamamoto, M., & Hirata, H. (2013) · PLoS ONE · doi:10.1371/journal.pone.0057721 · Cited by 38
“The release and activity of TNF-a and other potentially damaging cytokines are controlled at multiple levels to prevent unrestrained collateral tissue damage that can disable, or even kill, the host [43].”
BackgroundPredictors of response to acetylcholinesterase inhibitors in dementia: A systematic review
Pozzi, F. E., Conti, E., Appollonio, I., Ferrarese, C., & Tremolizzo, L. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2022.998224 · Cited by 36
“The efferent vagus nerve transmits signals to the spleen that eventually result in the synthesis and release of ACh, whose binding to α7-nAChR on peripheral macrophage leads to the inhibition of cytokine production (Tracey, 2009).”
BackgroundJaiswal, C., & Singh, A. K. (2024) · Environmental Pollution · doi:10.1016/j.envpol.2024.125275 · Cited by 37
McLarnon, S. R., Baban, B., Tucker, M. A., Seaton, A. J., Chang, K. C., Mannon, E. C., Sun, J., Patel, B., Wilson, K., Musall, J. B., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1701605 · Cited by 37
“The cholinergic anti-inflammatory pathway has been reported to be the efferent arm of the anti-inflammatory reflex (15), which acts via vagal efferents to promote M2 macrophage polarization in the spleen and limit activation of the innate immune system, thereby preventing damage caused by excessive cytokine production…”
BackgroundWhy are bleeding trauma patients still dying? Towards a systems hypothesis of trauma
Dobson, G. P., Morris, J. L., & Letson, H. L. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.990903 · Cited by 34
“…towards parasympathetic dominance would rebalance the system to reduce immune dysregulation and inflammation and improve end-organ functions (Tracey, 2009; Huston and Tracey, 2011; Lombardi and Stein, 2011; Reyes del Paso et al., 2013; Olshansky, 2016; Sykora et al., 2016; Johansson et…”
BackgroundDoenlen, R., Krügel, U., Wirth, T., Riether, C., Engler, A., Prager, G., Engler, H., Schedlowski, M., & Pacheco‐López, G. (2010) · Proceedings of the Royal Society B Biological Sciences · doi:10.1098/rspb.2010.2040 · Cited by 36
Tesser, J., Crowley, A., Box, E. J., June, J. P., Wickersham, P., Valenzuela, G. J., GAYLIS, N. B., Lam, G., Pacheco, L. A., Ridley, D., et al. (2025) · Nature Medicine · doi:10.1038/s41591-025-04114-7 · Cited by 35
“Actively stimulating the vagus nerve can engage the inflammatory reflex, resulting in acetylcholine release and specific agonism of α7 nicotinic acetylcholine receptors on immune cells 6,7 .”
Systemic and Central Immunity in Alzheimer's Disease: Therapeutic Implications
Butchart, J., & Holmes, C. (2011) · CNS Neuroscience & Therapeutics · doi:10.1111/j.1755-5949.2011.00245.x · Cited by 36
“Thus, manipulation of the inflammatory reflex has a number of potential applications in AD but no direct interventions have, as yet, been realized [192].”
BackgroundGerő, D., Szoleczky, P., Módis, K., Pribis, J. P., Al‐Abed, Y., Yang, H., Chevan, S., Billiar, T. R., Tracey, K. J., & Szabó, C. (2013) · PLoS ONE · doi:10.1371/journal.pone.0065994 · Cited by 35
Self-citationMalmsten, L., Vijayaraghavan, S., Hovatta, O., Marutle, A., & Darreh‐Shori, T. (2014) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.12343 · Cited by 35
“Cholinergic signalling in the peripheral circulation exerts a well-established immune-regulatory effect on systemic inflammatory responses via the action of ACh putatively on the a7 nAChRs present on immune cells [37, 47].”
BackgroundSeeley, E. J., Barry, S. S., Narala, S., Matthay, M. A., & Wolters, P. J. (2013) · The Journal of Immunology · doi:10.4049/jimmunol.1300027 · Cited by 36
“This research has culminated in the recognition of a parasympathetic anti-inflammatory reflex that helps to maintain immunologic homeostasis after acute inflammation (4, 5).”
BackgroundCoelho‐Júnior, H. J., Gambassi, B. B., Diniz, T. A., Fernandes, I. M. D. C., Caperuto, É. C., Uchida, M. C., Lira, F. S., & Rodrigues, B. (2016) · Mediators of Inflammation · doi:10.1155/2016/3957958 · Cited by 37
Welch, M. G., Anwar, M., Chang, C. Y., Gross, K. J., Ruggiero, D. A., Tamir, H., & Gershon, M. D. (2010) · Neurogastroenterology & Motility · doi:10.1111/j.1365-2982.2010.01477.x · Cited by 35
Kumar, R., Långström, B., & Darreh‐Shori, T. (2016) · Scientific Reports · doi:10.1038/srep31247 · Cited by 35
Hunt, V. L., Tsai, I. J., Selkirk, M. E., & Viney, M. (2016) · Parasitology · doi:10.1017/s0031182016001554 · Cited by 35
“ACh is also involved in inflammatory immune responses (Wang et al., 2003; Tracey, 2009) and has recently been shown to act as a co-stimulatory signalling molecule for CD4+ T cell activation and cytokine production in mice during N.”
BackgroundPeterson, D., Poppel, M. D. V., Boling, W., Santos, P. M., Schwalb, J. M., Eisenberg, H. M., Mehta, A. D., Spader, H. S., Botros, J., Vrionis, F. D., et al. (2024) · Bioelectronic Medicine · doi:10.1186/s42234-023-00138-x · Cited by 37
“These signals are transmitted across the celiac plexus, through the splenic nerve and to the spleen, directly affecting neurotransmitter-sensitive immunocytes (Tracey 2009).”
BackgroundBeckmann, J., Schubert, J., Morhenn, H.-G., Grau, V., Schnettler, R., & Lips, K. S. (2014) · Cell and Tissue Research · doi:10.1007/s00441-014-2036-0 · Cited by 34
“However, the role of the α7 nicotinic receptor, which is known to function in the antiinflammatory cholinergic pathway (Tracey 2009), is still being discussed controversially in this regard (van Maanen et al.”
BackgroundMondal, B., Choudhury, S., Banerjee, R., Roy, A., Chatterjee, K., Basu, P., Singh, R., Halder, S., Shubham, S., Baker, S. N., et al. (2021) · npj Parkinson s Disease · doi:10.1038/s41531-021-00190-x · Cited by 34
RetractedThe clinical importance of the anti-inflammatory vagovagal reflex
Boeckxstaens, G. E. (2013) · Handbook of clinical neurology · doi:10.1016/b978-0-444-53491-0.00011-0 · Cited by 34
“This mechanism protects against the lethal effects of cytokines by restraining the magnitude of a potentially fatal peripheral immune response (Borovikova et al., 2000a; Tracey, 2002, 2009).”
BackgroundBehavioral Symptoms after Breast Cancer Treatment: A Biobehavioral Approach
Fagundes, C. P., LeRoy, A. S., & Karuga, M. (2015) · Journal of Personalized Medicine · doi:10.3390/jpm5030280 · Cited by 34
“When acetylcholine interacts with the macrophage’s alpha-7 nicotinic receptor, it inhibits proinflammatory cytokine production [87].”
BackgroundCirculating T cell subsets are altered in individuals with chronic spinal cord injury
Monahan, R., Stein, A., Gibbs, K., Bank, M. A., & Bloom, O. (2015) · Immunologic Research · doi:10.1007/s12026-015-8698-1 · Cited by 34
“nervous system regulates immune system function [10, 11].”
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
