Reflex control of immunity

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.

[1]  M. Rand,et al.  Acetylcholine and the sympathetic innervation of the spleen , 1961, The Journal of physiology.

[2]  F. Leaders,et al.  THE CHOLINERGIC COMPONENT IN THE SYMPATHETIC INNERVATION TO THE SPLEEN. , 1965, The Journal of pharmacology and experimental therapeutics.

[3]  C. Dinarello Production of endogenous pyrogen. , 1979, Federation proceedings.

[4]  C. Brooks,et al.  Functional significance of coactivation of vagal and sympathetic cardiac nerves. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[5]  B. Beutler,et al.  Tumor necrosis factor (cachectin) is an endogenous pyrogen and induces production of interleukin 1 , 1986, The Journal of experimental medicine.

[6]  S. Felten,et al.  Origin of noradrenergic innervation of the spleen in rats , 1989, Brain, Behavior, and Immunity.

[7]  T. Fahey,et al.  Metabolic effects of cachectin/tumor necrosis factor are modified by site of production. Cachectin/tumor necrosis factor-secreting tumor in skeletal muscle induces chronic cachexia, while implantation in brain induces predominantly acute anorexia. , 1990, The Journal of clinical investigation.

[8]  S. Felten,et al.  Acetylcholinesterase Staining and Choline Acetyltransferase Activity in the Young Adult Rat Spleen: Lack of Evidence for Cholinergic Innervation , 1993, Brain, Behavior, and Immunity.

[9]  G. Sundkvist,et al.  Autonomic vagal nerve dysfunction in patients with ulcerative colitis. , 1993, Scandinavian journal of gastroenterology.

[10]  H. Berthoud,et al.  Characterization of vagal innervation to the rat celiac, suprarenal and mesenteric ganglia. , 1993, Journal of the autonomic nervous system.

[11]  S. Kunkel,et al.  Endogenous norepinephrine regulates tumor necrosis factor-alpha production from macrophages in vitro. , 1994, Journal of immunology.

[12]  K. Bulloch,et al.  Characterization of choline O-acetyltransferase (ChAT) in the BALB/C mouse spleen. , 1994, The International journal of neuroscience.

[13]  S. Maier,et al.  Blockade of cytokine induced conditioned taste aversion by subdiaphragmatic vagotomy: further evidence for vagal mediation of immune-brain communication , 1995, Neuroscience Letters.

[14]  Steven F. Maier,et al.  Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication , 1995, Neuroscience Letters.

[15]  A. Niijima,et al.  The afferent discharges from sensors for interleukin 1 beta in the hepatoportal system in the anesthetized rat. , 1996, Journal of the autonomic nervous system.

[16]  H. Berthoud,et al.  Interaction between parasympathetic and sympathetic nerves in prevertebral ganglia: Morphological evidence for vagal efferent innervation of ganglion cells in the rat , 1996, Microscopy research and technique.

[17]  E. Ginzler,et al.  Heart rate variability in patients with systemic lupus erythematosus , 1996, Lupus.

[18]  S. Maier,et al.  Vagal Paraganglia Bind Biotinylated Interleukin-1 Receptor Antagonist: A Possible Mechanism for Immune-to-Brain Communication , 1997, Brain Research Bulletin.

[19]  S. Watanabe,et al.  Inhibition of tumor necrosis factor-alpha and interleukin-1-beta production by beta-adrenoceptor agonists from lipopolysaccharide-stimulated human peripheral blood mononuclear cells. , 1997, Pharmacology.

[20]  W. Mckenna,et al.  Reduction in heart rate variability in patients with systemic lupus erythematosus. , 1997, The Journal of rheumatology.

[21]  S. Maier,et al.  Interleukin-1β in Immune Cells of the Abdominal Vagus Nerve: a Link between the Immune and Nervous Systems? , 1999, The Journal of Neuroscience.

[22]  P Bailey,et al.  Double Edged Sword , 2002 .

[23]  W. Scott,et al.  Heart rate variability after acute traumatic brain injury in children , 2000, Critical care medicine.

[24]  K. Tracey,et al.  Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin , 2000, Nature.

[25]  R. Gilmartin,et al.  Prospective Long‐Term Study of Vagus Nerve Stimulation for the Treatment of Refractory Seizures , 2000, Epilepsia.

[26]  H. Shibasaki,et al.  α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity* , 2001, The Journal of Biological Chemistry.

[27]  S. Maier,et al.  The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose. , 2001, American journal of physiology. Regulatory, integrative and comparative physiology.

[28]  R. Straub,et al.  Norepinephrine, the β-Adrenergic Receptor, and Immunity , 2002, Brain, Behavior, and Immunity.

[29]  Carl Nathan,et al.  Points of control in inflammation , 2002, Nature.

[30]  Sachin Shah,et al.  Heart rate variability in emergency department patients with sepsis. , 2002, Academic emergency medicine : official journal of the Society for Academic Emergency Medicine.

[31]  K. Tracey,et al.  Pharmacological Stimulation of the Cholinergic Antiinflammatory Pathway , 2002, The Journal of experimental medicine.

[32]  R. Fitzgerald,et al.  Muscarinic modulation of hypoxia-induced release of catecholamines from the cat carotid body , 2002, Brain Research.

[33]  S. Wonnacott,et al.  Nicotine activates the extracellular signal‐regulated kinase 1/2 via the α7 nicotinic acetylcholine receptor and protein kinase A, in SH‐SY5Y cells and hippocampal neurones , 2002, Journal of neurochemistry.

[34]  Kevin J. Tracey,et al.  The inflammatory reflex , 2002, Nature.

[35]  B. Polat,et al.  Heart rate variability in patients with rheumatoid arthritis , 2004, Rheumatology International.

[36]  Eduardo R Migliaro,et al.  Heart rate variability as early marker of multiple organ dysfunction syndrome in septic patients. , 2003, Journal of critical care.

[37]  K. Kawashima,et al.  The lymphocytic cholinergic system and its contribution to the regulation of immune activity. , 2003, Life sciences.

[38]  C. V. van Koppen,et al.  Regulation of muscarinic acetylcholine receptor signaling. , 2003, Pharmacology & therapeutics.

[39]  L. Minutoli,et al.  Efferent Vagal Fibre Stimulation Blunts Nuclear Factor-&kgr;B Activation and Protects Against Hypovolemic Hemorrhagic Shock , 2003, Circulation.

[40]  Kevin J. Tracey,et al.  Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation , 2002, Nature.

[41]  F. Homo-Delarche,et al.  Is innervation an early target in autoimmune diabetes? , 2003, Trends in immunology.

[42]  J. Neubauer,et al.  Oxygen-sensing neurons in the central nervous system. , 2004, Journal of applied physiology.

[43]  Lawrence Steinman,et al.  Elaborate interactions between the immune and nervous systems , 2004, Nature Immunology.

[44]  K. Kawashima,et al.  Expression of non-neuronal acetylcholine in lymphocytes and its contribution to the regulation of immune function. , 2004, Frontiers in bioscience : a journal and virtual library.

[45]  P. Sanberg,et al.  Cholinergic modulation of microglial activation by α7 nicotinic receptors , 2004 .

[46]  K. Tracey,et al.  Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis , 2004, Nature Medicine.

[47]  H. Berthoud,et al.  Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway , 2005, Nature Immunology.

[48]  Mark P. Mattson,et al.  NF-κB in the Survival and Plasticity of Neurons , 2005, Neurochemical Research.

[49]  Erik A. Yuill,et al.  Interleukin-1β depolarizes magnocellular neurons in the paraventricular nucleus of the hypothalamus through prostaglandin-mediated activation of a non selective cationic conductance , 2005, Regulatory Peptides.

[50]  J. Schwartz,et al.  Cardiac autonomic changes associated with fish oil vs soy oil supplementation in the elderly. , 2005, Chest.

[51]  D. Bertrand,et al.  α7 Neuronal Nicotinic Acetylcholine Receptors Are Negatively Regulated by Tyrosine Phosphorylation and Src-Family Kinases , 2005, The Journal of Neuroscience.

[52]  S. Maier,et al.  Immune regulation of central nervous system functions: from sickness responses to pathological pain , 2005, Journal of internal medicine.

[53]  R A L Dampney,et al.  LONG‐TERM REGULATION OF ARTERIAL BLOOD PRESSURE BY HYPOTHALAMIC NUCLEI: SOME CRITICAL QUESTIONS , 2005, Clinical and experimental pharmacology & physiology.

[54]  T. van der Poll,et al.  The Cholinergic Anti-inflammatory Pathway Regulates the Host Response during Septic Peritonitis , 2022 .

[55]  K. Tracey,et al.  Cholinergic stimulation blocks endothelial cell activation and leukocyte recruitment during inflammation , 2005, The Journal of experimental medicine.

[56]  U. Rosenschein,et al.  Exercise training modulates cytokines activity in coronary heart disease patients. , 2005, International journal of cardiology.

[57]  Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. , 2006, The Journal of experimental medicine.

[58]  M. Kurokawa,et al.  Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I‐κB phosphorylation and nuclear factor‐κB transcriptional activity through nicotinic acetylcholine receptor α7 , 2006 .

[59]  T. Bártfai,et al.  MyD88-dependent and -independent signaling by IL-1 in neurons probed by bifunctional Toll/IL-1 receptor domain/BB-loop mimetics. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[60]  T. van der Poll,et al.  The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. , 2006, Gastroenterology.

[61]  Peter Libby,et al.  The immune response in atherosclerosis: a double-edged sword , 2006, Nature Reviews Immunology.

[62]  P. Moore,et al.  Role of substance P in hydrogen sulfide-induced pulmonary inflammation in mice. , 2006, American journal of physiology. Lung cellular and molecular physiology.

[63]  S. Collins,et al.  The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. , 2006, Gastroenterology.

[64]  Christopher J Czura,et al.  Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[65]  M. Eren,et al.  Heart Rate Variability in Patients with Systemic Sarcoidosis , 2006, Annals of noninvasive electrocardiology : the official journal of the International Society for Holter and Noninvasive Electrocardiology, Inc.

[66]  Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis , 2006, The Journal of Experimental Medicine.

[67]  B. Fernhall,et al.  Effects of lifestyle modifications on C-reactive protein: contribution of weight loss and improved aerobic capacity. , 2006, Metabolism: clinical and experimental.

[68]  E. Sternberg Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens , 2006, Nature Reviews Immunology.

[69]  A. Rebuzzi,et al.  Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. , 2006, The American journal of cardiology.

[70]  Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis , 2006 .

[71]  C. Hama,et al.  Microglial α7 nicotinic acetylcholine receptors drive a phospholipase C/IP3 pathway and modulate the cell activation toward a neuroprotective role , 2006, Journal of neuroscience research.

[72]  Richard M. Eglen,et al.  Muscarinic acetylcholine receptors: mutant mice provide new insights for drug development , 2007, Nature Reviews Drug Discovery.

[73]  Julian F. Thayer,et al.  The role of vagal function in the risk for cardiovascular disease and mortality , 2007, Biological Psychology.

[74]  M. Bianchi DAMPs, PAMPs and alarmins: all we need to know about danger , 2007, Journal of leukocyte biology.

[75]  J. Blalock,et al.  Conceptual development of the immune system as a sixth sense , 2007, Brain, Behavior, and Immunity.

[76]  S. Collins,et al.  Vagus nerve integrity and experimental colitis. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[77]  S. Collins,et al.  The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. , 2007, American journal of physiology. Gastrointestinal and liver physiology.

[78]  V. Pavlov,et al.  Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis * , 2007, Critical care medicine.

[79]  V. Pavlov,et al.  Selective &agr;7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis* , 2007, Critical care medicine.

[80]  K. Tracey Physiology and immunology of the cholinergic antiinflammatory pathway. , 2007, The Journal of clinical investigation.

[81]  K. Tracey,et al.  Aerobic exercise attenuates inducible TNF production in humans. , 2007, Journal of applied physiology.

[82]  S. Manuck,et al.  Stimulated Production of Proinflammatory Cytokines Covaries Inversely With Heart Rate Variability , 2007, Psychosomatic medicine.

[83]  G. Ahern,et al.  Vagus nerve stimulation therapy in depression and epilepsy: therapeutic parameter settings , 2007, Acta neurologica Scandinavica.

[84]  T. Yoshino,et al.  The immunosuppressive effects of nicotine during human mixed lymphocyte reaction. , 2007, European journal of pharmacology.

[85]  濱野 亮輔 Stimulation of α7 nicotinic acetylcholine receptor inhibits CD14 and the Toll-like receptor 4 expression in human monocytes , 2007 .

[86]  T. Seeman,et al.  RR Interval Variability Is Inversely Related to Inflammatory Markers: The CARDIA Study , 2007, Molecular medicine.

[87]  R. Langley,et al.  T Cells Express α7-Nicotinic Acetylcholine Receptor Subunits That Require a Functional TCR and Leukocyte-Specific Protein Tyrosine Kinase for Nicotine-Induced Ca2+ Response1 , 2007, The Journal of Immunology.

[88]  C. Orengo,et al.  From Structure to Function , 2021, Models of the Mind.

[89]  M. Sugimachi,et al.  Vagal stimulation suppresses ischemia-induced myocardial interstitial myoglobin release. , 2008, Life sciences.

[90]  Kevin J. Tracey,et al.  Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia , 2008, Proceedings of the National Academy of Sciences.

[91]  J. Dimsdale,et al.  The relationship between heart rate variability and inflammatory markers in cardiovascular diseases , 2008, Psychoneuroendocrinology.

[92]  S. Collins,et al.  Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. , 2008, The Journal of clinical investigation.

[93]  R. Medzhitov Origin and physiological roles of inflammation , 2008, Nature.

[94]  R. Dantzer,et al.  From inflammation to sickness and depression: when the immune system subjugates the brain , 2008, Nature Reviews Neuroscience.

[95]  H. Besedovsky,et al.  Sympathetic Nervous System-Immune Interactions in Autoimmune Lymphoproliferative Diseases , 2008, Neuroimmunomodulation.

[96]  Valentin A. Pavlov,et al.  Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling , 2008, Molecular medicine.

[97]  P. Zhang,et al.  Inhibition of the development of collagen-induced arthritis in Wistar rats through vagus nerve suspension: a 3-month observation , 2008, Inflammation Research.

[98]  A. Boulares,et al.  Serotonin 5-Hydroxytryptamine2A Receptor Activation Suppresses Tumor Necrosis Factor-α-Induced Inflammation with Extraordinary Potency , 2008, Journal of Pharmacology and Experimental Therapeutics.

[99]  R. Straub,et al.  Neuronally released sympathetic neurotransmitters stimulate splenic interferon-gamma secretion from T cells in early type II collagen-induced arthritis. , 2008, Arthritis and rheumatism.

[100]  J. Dimsdale,et al.  Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects , 2008, Brain, Behavior, and Immunity.

[101]  Jeffery L. Carter,et al.  Sympathetic modulation of immunity: relevance to disease. , 2008, Cellular immunology.

[102]  J. Thayer,et al.  Heart rate variability, overnight urinary norepinephrine and C‐reactive protein: evidence for the cholinergic anti‐inflammatory pathway in healthy human adults , 2009, Journal of internal medicine.

[103]  E. Albuquerque,et al.  Mammalian nicotinic acetylcholine receptors: from structure to function. , 2009, Physiological reviews.

[104]  T. van der Poll,et al.  Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. , 2009, Arthritis and rheumatism.

[105]  C. Lewis,et al.  The CARDIA Study , 2009 .

[106]  V. Pavlov,et al.  Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway , 2009, Brain, Behavior, and Immunity.