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Reflex control of immunity
Open accessAbstract
Inflammation can cause damage and even death. What controls this primitive and potentially lethal innate immune response to injury and infection? Molecular and neurophysiological studies during the past decade have revealed a pivotal answer: immunity is coordinated by neural circuits that operate reflexively. The afferent arc of the reflex consists of nerves that sense injury and infection. This activates efferent neural circuits, including the cholinergic anti-inflammatory pathway, that modulate immune responses and the progression of inflammatory diseases. It might be possible to develop therapeutics that target neural networks for the treatment of inflammatory disorders.
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“Interestingly, evidence suggests that activation of the parasympathetic nervous system also can modulate the activity of the immune system via alterations in vagal release of acetylcholine from T cells (Tracey, 2009).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Tracey, 2009
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“Additional evidence suggests that the parasympathetic nervous system modulates immune responses at a regional level through both the efferent and afferent fibers of the vagus nerve, enabling it to prevent excessive inflammation”
From From stress to inflammation and major depressive disorder: A social signal transduction theory of depression. (2014) · cites this paper as Tracey, 2009
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“For example, motor vagus nerve stimulation attenuates the activation of NFκB following an immune challenge (Tracey, 2009).”
From Inflammation in Fear- and Anxiety-Based Disorders: PTSD, GAD, and Beyond (2017) · cites this paper as Tracey, 2009
In the citing paper
“ACh binds to α-7-nicotinic ACh receptors of those macrophages to inhibit the TNF-α (69).”
From Vagus Nerve as Modulator of the Brain–Gut Axis in Psychiatric and Inflammatory Disorders (2018) · cites this paper as [69]
In the citing paper
“with evidence that vagal activity can modulate immune responses at a regional level through both the efferent and afferent fibers of the vagus nerve, to prevent excessive inflammation”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Tracey, 2009
In the citing paper
“Multiple non-exclusive pathways participate in the activation of the HPA axis upon cerebral or peripheral immune challenges. When an immunogenic insult takes place in the brain, various inflammatory mediators produced locally may trigger the HPA axis.”
From The HPA – Immune Axis and the Immunomodulatory Actions of Glucocorticoids in the Brain (2014) · cites this paper as [21]
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Citations
Cites
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“Stimulation of a7 nicotinic acetylcholine receptor (a7nAChR) on macrophages can inhibit expression of proinflammatory cytokines and prevent tissue damage (9, 10).”
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“First, the present results along with the previous studies suggest that an increase in peripheral pro-inflammatory cytokines might suppress total power of HRV, which might be mediated through their direct effects on the autonomic control areas such as the hypothalamus and/or indirect effects via peripheral afferent ne…”
ResultCausal relationships between the parameters of gas discharge visualization and immunity
Babelyuk, V., Гоженко, А. І., Dubkova, G. I., Żukow, W., Hubyts’kyi, V. Y., Ruzhylo, S., Fedyayeva, S., Kovalchuk, G., & Popovych, I. L. (2021) · Pedagogy and Psychology of Sport · doi:10.12775/pps.2021.07.01.008 · Cited by 9
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“This theory is supported by the observation that humoral and neuronal reflex pathways control the inflammatory process [40,41].”
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“After that, efferent information that modifies the peripheral immune response is sent via the descending pathway [27,28].”
Understanding and managing autonomic dysfunction in persons with multiple sclerosis
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Inflammation as a mediator of stress-related psychiatric disorders
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Weight a minute: The smaller and more immature, the more predictable the autonomic regulation?
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“25 It has also been suggested that anti-cholinergic pathways are influencing the vagus nerve in the beginning of infection, leading to reduced vagal activity, and hence lower HRV. 26 Prostaglandin E 2 , another marker of inflammation, correlates with degree of prematurity and amount of desaturation…”
BackgroundSexual Dimorphism of the Neuroendocrine-Immune Complex and its Reactions to Chronic Stress in Rats
Popovych, I. L., Polovynko, І. S., Zajats, L. M., & Melnyk, O. (2018) · Experimental and Clinical Physiology and Biochemistry · doi:10.25040/ecpb2018.03.005 · Cited by 8
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“…is found to promote cancer growth and the development of metastasis (Park et al., 2011; Zhi et al., 2019); however, vagus nerve (VN) stimulation can inhibit excessive sympathetic activity (Saku et al., 2014) inflammation (Tracey, 2009) and increase cellular immunity (Dubeykovskaya et al., 2016).”
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“As investigators continue to explore the influence of vagal tone on limiting destructive hyperinflammation (14, 15), the depression of parasympathetic tone during continuous enteral feeding may be shown to contribute to overall inflammatory risk different from those associated with PN.”
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Regulation of inflammatory responses by the autonomic nervous system
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Cholinergic Machinery as Relevant Target in Acute Lymphoblastic T Leukemia
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“Electrical stimulation of splenic nerve was believed to result in release of ACh into splenic tissue and into the effluent splenic vein, with a subsequent down regulation of the inflammatory cytokines (Tracey, 2009).”
BackgroundInitiating Mechanisms of Surgery-induced Memory Decline: The Role of HMGB1
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Causal relationships between the parameters of gas discharge visualization and phagocytosis
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“Therefore, its presence in this constellation is also fully consistent with the concept of neuro-immunomodulation [11,12,16,23,27,29-32].”
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“The parasympathetic nervous system stimulation (through the vagus nerve) leads to reduced production of proinflammatory cytokines through the release of the neurotransmitter acetylcholine (27, 32).”
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“Miller et al. [2], Morris et al. [3], and Tracey [4] state that this sickness behavior is a set of symptoms that include lassitude, anorexia, social withdrawal, joints and muscle aches, malaise, changes in cognition, depression and isolation.”
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“The vagus reflexively inhibits inflammation by activating the hypothalamic-pituitary-adrenal axis resulting with cortisol secretion [24].”
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“Sympathetic (or adrenergic) and parasympathetic (or cholinergic) [32-35,37] nervous systems on the whole brake inflammation at regional level, through innervation of immune organs.”
BackgroundNeuromodulation in Inflammatory Skin Disease
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“The ‘‘immunomodulatory reflex’’ is a wellcharacterized mechanism that aims to maintain a balanced immune system [1].”
BackgroundRemission of myasthenia gravis following cervical adjustment
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Dynamic causal modelling of immune heterogeneity
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“A series of clinical and experimental studies conducted in recent years have revealed that the Medullary Visceral Zone (MVZ) regulates inflammation and immunity dynamically through the cholinergic anti-inflammatory pathway (CAP) [5].”
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“Similar findings were made in models of lipopolysaccharide-induced inflammatory responses in mouse lung [38] experimental arthritis, ileus and hemorrhagic shock in pre-clinical experimentation [19].”
BackgroundResultAutonomic control of inflammation
Suzuki, K., & Nakai, A. (2016) · Clinical and Experimental Neuroimmunology · doi:10.1111/cen3.12292 · Cited by 7
“The solid molecular basis for immune regulation by the autonomic nervous system was first provided from a series of studies by Tracey et al.(13,14) that led to a concept of “inflammatory reflex” as a neural circuit that contributes to homeostasis of the immune system.”
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Schizophrenia Outside the Brain
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Tumor-Localized Insult Delivered by Photodynamic Therapy and the Breakdown of Tumor Immunotolerance
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“In the afferent arc, nerve sense injury and infection, and in the efferent arc, termed the cholinergic anti-inflammatory pathway, acetylcholine, the main parasympathetic neurotransmitter, exerts a tonic inhibitory role in the immune cells, comprising a reflex that limits proinflammatory responses within a nontoxic ran…”
BackgroundCorneal Sensory Nerve Injury Disrupts Lacrimal Gland Function by Altering Circadian Rhythms in Mice
Li, S., Xie, J., Xiang, J., Yan, R., Liu, J., Fan, Q., Lu, L., Wu, J., Liu, J., Xue, Y., et al. (2025) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.66.4.40 · Cited by 7
Changes in the nitric oxide level in the rat liver as a response to brain injury.
Ziaja, M., Pyka, J., Boczkus, B., Płonka, B., & Płonka, P. (2011) · Nitric oxide · doi:10.1016/j.niox.2011.07.004 · Cited by 7
“On the contrary, a reverse effect of brain injury affecting liver metabolism is also possible [8,23,24].”
BackgroundThe gut microbiome in Huntington disease: A review
Patil, R. S., Vyas, S. G., Quazi, W. T., Tembhurnikar, H. J., Milmile, P. S., & Umekar, M. J. (2021) · GSC Biological and Pharmaceutical Sciences · doi:10.30574/gscbps.2021.15.3.0180 · Cited by 6
“the gut can influence the brain via visceral communications, and the brain can control gastrointestinal functions [such as motility, secretion, and mucin synthesis] and immune activities (such as the modulation of cytokine production by mucosal immune system cells) through this complicated network [8].”
BackgroundWang, L., Wang, J., Li, P., Wang, X., Wu, S., & Shi, B. (2021) · Scientific Reports · doi:10.1038/s41598-021-94931-w · Cited by 6
Kamigaichi, A., Aokage, K., Ikeno, T., Wakabayashi, M., Miyoshi, T., Tane, K., Samejima, J., & Tsuboi, M. (2023) · European Journal of Cardio-Thoracic Surgery · doi:10.1093/ejcts/ezad016 · Cited by 6
Association of heartbeat complexity with survival in advanced non-small cell lung cancer patients
Wu, S., Li, G., Chen, M., Zhang, S., Zhou, Y., Shi, B., & Zhang, X. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1113225 · Cited by 6
“, 2017), while vagus nerve activation can inhibit the inflammatory response (Tracey, 2009) and sympathetic nerve activity (Saku et al.”
BackgroundEnlarged cross-sectional area of the left vagus nerve in patients with major depressive disorder
Schreiber, L. S., Wozniak, D., Scheller, E., Böttcher, E., Pelz, J. O., & Schmidt, F. M. (2023) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2023.1237983 · Cited by 6
“We assume, that recurrent depressive episodes might trigger a chronification of vagal dysfunction by overstressing the anti-inflammatory functions of the VNs in the long term (37).”
BackgroundNicotinic stimulation induces Tristetraprolin over-production and attenuates inflammation in muscle
Geyer, B. C., Ben‐Ari, S., Barbash, S., Kilbourne, J., Mor, T. S., & Soreq, H. (2011) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2011.11.001 · Cited by 6
“More recently this so-called cholinergic anti-inflammatory pathway [14] was demonstrated in a mouse model of DMD, where nicotine administration reduced skeletal muscle inflammation by suppressing the expression of cytokine production in infiltrating macrophages [15].”
BackgroundCitocinas y sistema nervioso: relación con crisis convulsivas y epilepsia
Ramírez, S. F. V., Rosales-Rivera, L. Y., Anguiano, A. C. R., & Bitzer-Quintero, O. K. (2013) · Revista de Neurología · doi:10.33588/rn.5704.2013229 · Cited by 6
Murdock, K. W., Stowe, R. P., Peek, M. K., Lawrence, S. L., & Fagundes, C. P. (2017) · Psychosomatic Medicine · doi:10.1097/psy.0000000000000514 · Cited by 6
“Specifically, high parasympathetic activity is associated with reduced inflammation through the cholinergic anti-inflammatory pathway via the release of acetylcholine (37).”
BackgroundLevine, Y. A., Faltys, M. A., & Zitnik, R. J. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-805353-9.00126-1 · Cited by 6
Ernstgård, L., Bottai, M., Johanson, G., & Sjögren, B. (2019) · Occupational and Environmental Medicine · doi:10.1136/oemed-2018-105537 · Cited by 6
Gut Microbiome-Brain Communications Regulate Host Physiology and Behavior
Serre, C. B. D. L. (2015) · Journal of Nutritional Health & Food Science · doi:10.15226/jnhfs.2015.00141 · Cited by 6
“Information from the GI tract and the intestinal microbiota can reach the peripheral and Central Nervous System (CNS), concurrently the brain is able to influence GI functions such as motility and secretion but also immune responses and cytokine production [36,37].”
BackgroundOvchinnikov, D. A., Amosov, D. D., Vorobyov, E. A., Garnyuk, V., Beltyukov, P. P., Grebennik, V. K., Гордеев, М. Л., & Barantsevich, E. R. (2017) · S S Korsakov Journal of Neurology and Psychiatry · doi:10.17116/jnevro2017117415-10 · Cited by 6
Heart Rate Characteristic Monitoring—HeRO or Villain?
Groves, A. M., & Edwards, A. D. (2011) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2011.08.049 · Cited by 6
An implant for long-term cervical vagus nerve stimulation in micePreprint
Mughrabi, I. T., Hickman, J. L., Jayaprakash, N., Papadoyannis, E. S., Abbas, A., Chang, Y.-C., Lee, S., Datta, T., Chang, E. H., Zanos, T. P., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.06.20.160473 · Cited by 5
“The relatively recent discovery that the VN modulates the inflammatory response [19-22] might broaden the range of future indications for VNS, as inflammation is implicated in many common chronic diseases, such as type 2 diabetes, obesity, and atherosclerosis [23-26].”
BackgroundVagotomy and the incidence of rheumatoid arthritis and osteoarthritis: a Danish register-based study
Baker, M. C., Nagy, D., Tamang, S. R., Horváth–Puhó, E., & Sørensen, H. T. (2025) · Arthritis Research & Therapy · doi:10.1186/s13075-025-03567-y · Cited by 5
“Vagus nerve stimulation typically has anti-inflammatory effects by triggering acetylcholine release in the spleen, thus inhibiting proinflammatory cytokine production by macrophages [4–8].”
Courties, A., Tuffet, S., Cormier, G., Roux, C. H., Ornetti, P., Pers, Y., Gottenberg, J., Lespessailles, É., Chapurlat, R. D., Arniaud, D., et al. (2025) · The Lancet Rheumatology · doi:10.1016/s2665-9913(25)00226-7 · Cited by 6
Intestinal interoception: A nexus of environment-body-brain interactions
Salvador, A. F. M., Golynker, I., Betley, J. N., & Thaiss, C. A. (2026) · Neuron · doi:10.1016/j.neuron.2025.11.026 · Cited by 6
Pathogen recognition by sensory neurons: hypotheses on the specificity of sensory neuron signaling
Millet, A., & Jendzjowsky, N. G. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1184000 · Cited by 5
“Prominent examples of the effects of these neuroimmune cell units are the cholinergic anti-inflammatory pathway (24, 25) or sympathetic influence on lymphopoiesis (26, 27).”
BackgroundPedersen, M. V., Renberg, A. F. V., Christensen, J. K., Andersen, H. B., Andelius, T. C. K., Kyng, K. J., Andersen, M. J., & Henriksen, T. B. (2024) · Pediatric Research · doi:10.1038/s41390-024-03394-y · Cited by 5
COVID-19: impatto sulla salute mentale e supporto psicosociale
Cantelmi, T., Lambiase, E., Pensavalli, M., Laselva, P., & Cecchetti, S. (2021) · MODELLI DELLA MENTE · doi:10.3280/mdm1-2020oa10908 · Cited by 6
Multilevel analysis: Integrating multiple levels of neurobehavioral systems
Berntson, G. G., & Norman, G. J. (2021) · Social Neuroscience · doi:10.1080/17470919.2021.1874513 · Cited by 5
Galantamine ameliorates experimental pancreatitis
Thompson, D., Tsaava, T., Rishi, A., George, S. J., Hepler, T. D., Hide, D., Pavlov, V. A., Brines, M. L., Chavan, S. S., & Tracey, K. J. (2023) · Molecular Medicine · doi:10.1186/s10020-023-00746-y · Cited by 5
“This efferent arc of the inflammatory reflex is referred to as the cholinergic anti-inflammatory pathway (CAP) (Tracey 2009).”
BackgroundInfluentialSelf-citationde Melo, B. P., da Silva, J. A. M., Rodrigues, M. A., Palmeira, J. D. F., Amato, A. A., Argañaraz, G. A., & Argañaraz, E. R. (2025) · Viruses · doi:10.3390/v17050619 · Cited by 5
“The CAP is activated by the binding of acetylcholine (Ach) to nicotinic receptors present in the cell membrane [195].”
Kaniušas, E., Kampusch, S., & Széles, J. C. (2015) · IEEE Sensors Applications Symposium (SAS) · doi:10.1109/sas.2015.7133566 · Cited by 5
“In addition to dominant anti-inflammatory effects [3], our group has demonstrated modulation of the (efferent) sympathetic control of vascular tone, which is highly beneficial in the treatment of vascular disorders [5], [12], [14].”
Cerejeira, R., Fernandes, S., & Moura, C. P. (2015) · Auris Nasus Larynx · doi:10.1016/j.anl.2015.08.011 · Cited by 5
“IL-10 and transforming growth factor-beta (TGFbeta)), thereby attenuating the local inflammatory response [4,5].”
BackgroundInfluentialVNS for Treatment of Inflammatory Joint Diseases
Levine, Y. A., Simon, J., Koopman, F. A., Faltys, M. A., Zitnik, R. J., & Tak, P. P. (2017) · Springer eBooks · doi:10.1007/978-3-319-28612-9_2 · Cited by 5
Chen, S., Huang, S., Yu, S., Han, Z., Gao, L., Shen, Z., & Kang, M. (2019) · Journal of Thoracic Disease · doi:10.21037/jtd.2019.01.15 · Cited by 5
“In many studies, it was reported that the pulmonary vagus nerve branches play an important role in the cough reflex, sputum excretion and immune defense of pulmonary inflammation after surgery (20-22).”
BackgroundDoes hypothalamic serotonin govern septic inflammation via the splanchnic anti-inflammatory reflex?
Rummel, C. D. (2019) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2019.06.023 · Cited by 5
Schick, B., Barth, E., Mayer, B., Weber, C.-L., Hagemeyer, T., & Schönfeldt‐Lecuona, C. (2021) · BMJ Open · doi:10.1136/bmjopen-2021-050501 · Cited by 5
Leonard, S. S., & Benfante, R. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106783 · Cited by 5
Vagal nerve stimulation for the treatment of autism
Derakhshan, N. (2015) · Mental Illness · doi:10.4081/mi.2015.5788 · Cited by 5
Heart rate variability is reduced during acute uncomplicated diverticulitis
Huang, C., Alamili, M., Rosenberg, J., & Gögenür, I. (2015) · Journal of Critical Care · doi:10.1016/j.jcrc.2015.12.006 · Cited by 5
“Recent data suggest that vagal outflow regulates the systemic inflammatory response during inflammation and infection [25].”
Lafon, M. (2013) · Elsevier eBooks · doi:10.1016/b978-0-12-396547-9.00010-9 · Cited by 5
Immune Mechanisms of Hypertension
Ryan, M. J. (2013) · Colloquium Series on Integrated Systems Physiology From Molecule to Function · doi:10.4199/c00092ed1v01y201309isp046 · Cited by 5
Aspects of corneal transplant immunology
Zarei-Ghanavati, M., & Liu, C. (2017) · Journal of Ophthalmic and Vision Research · doi:10.4103/jovr.jovr_115_17 · Cited by 5
“One such study highlighted the regulatory functions of the peripheral nervous system in immunological reactions.[4] It has been shown that dendritic cell (DC) density correlates with decreasing corneal nerves.”
Background
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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