The vagal innervation of the gut and immune homeostasis

Gut

Volumn 62, Issue 8, 2013, Pages 1214-1222

  Matteoli, Gianluca ^a   Boeckxstaens, Guy E ^a,b  

^a UNIVERSITY OF LEUVEN   (Belgium)

^b UNIVERSITY HOSPITALS LEUVEN   (Belgium)

Author keywords

[No Author keywords available]

Indexed keywords

ACETYLCHOLINE; AR R17779; BUNGAROTOXIN RECEPTOR; ENDOTOXIN; GSK 1345038 A; GSK1345038A; INTERLEUKIN 1ALPHA; INTERLEUKIN 6; MITOGEN ACTIVATED PROTEIN KINASE P38; NEOSTIGMINE; NICOTINE; NICOTINIC AGENT; PHYSOSTIGMINE; SPIRO[1 AZABICYCLO[2.2.2]OCTANE 3,2' THIAZOLIDINE] 2' ONE; TUMOR NECROSIS FACTOR; UNCLASSIFIED DRUG;

ANTIINFLAMMATORY ACTIVITY; ARTICLE; CHOLINERGIC SYSTEM; COLITIS; CROHN DISEASE; CYTOKINE PRODUCTION; EFFERENT NERVE; ENTERITIS; GASTROINTESTINAL TRACT; HOMEOSTASIS; HUMAN; IMMUNE RESPONSE; IMMUNE SYSTEM; IMMUNOCOMPETENT CELL; INTESTINE INNERVATION; NERVOUS SYSTEM; NONHUMAN; PANCREATITIS; POSTOPERATIVE COMPLICATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN INTERACTION; SENSORY NERVE; SMOKING; SPLEEN FUNCTION; ULCERATIVE COLITIS; VAGUS NERVE; VAGUS NERVE STIMULATION; VAGUS TONE;

ENTERIC NERVOUS SYSTEM; GASTROINTESTINAL IMMUNE RESPONSE; GUT IMMUNOLOGY; NEUROIMMUNOLOGY;

ACETYLCHOLINE; HOMEOSTASIS; HUMANS; ILEUS; IMMUNITY, MUCOSAL; INFLAMMATION; INFLAMMATORY BOWEL DISEASES; INTESTINES; NEUROIMMUNOMODULATION; SIGNAL TRANSDUCTION; VAGUS NERVE;

EID: 84880267231     PISSN: 00175749     EISSN: 14683288     Source Type: Journal    
DOI: 10.1136/gutjnl-2012-302550     Document Type: Article

References (122)

1. Steinman L. Elaborate interactions between the immune and nervous systems. Nat Immunol 2004;5:575-81.
2. Sternberg EM. Neural regulation of innate immunity: a coordinated nonspecific host response to pathogens. Nat Rev Immunol 2006;6:318-28.
3. Silverman MN, Pearce BD, Biron CA, et al. Immune modulation of the hypothalamic-pituitary-adrenal (HPA) axis during viral infection. Viral Immunol 2005;18:41-78.
4. Haddad JJ, Saade NE, Safieh-Garabedian B. Cytokines and neuro-immune-endocrine interactions: a role for the hypothalamic-pituitary- adrenal revolving axis. J Neuroimmunol 2002;133:1-19.
5. Bellinger DL, Millar BA, Perez S, et al. Sympathetic modulation of immunity: relevance to disease. Cell Immunol 2008;252:27-56.
6. Borovikova LV, Ivanova S, Zhang M, et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458-62.
7. Tracey KJ. The inflammatory reflex. Nature 2002;420:853-9.
8. Tracey KJ. Reflex control of immunity. Nat Rev Immunol 2009;9:418-28.
9. Lomax AE, Sharkey KA, Furness JB. The participation of the sympathetic innervation of the gastrointestinal tract in disease states. Neurogastroenterol Motil 2010;22:7-18.
10. Boisse L, Chisholm SP, Lukewich MK, et al. Clinical and experimental evidence of sympathetic neural dysfunction during inflammatory bowel disease. Clin Exp Pharmacol Physiol 2009;36:1026-33.
11. Straub RH, Wiest R, Strauch UG, et al. The role of the sympathetic nervous system in intestinal inflammation. Gut 2006;55:1640-9.
12. Borovikova LV, Ivanova S, Nardi D, et al. Role of vagus nerve signaling in CNI-1493-mediated suppression of acute inflammation. Auton Neurosci 2000;85:141-7.
13. Wang H, Yu M, Ochani M, et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384-8.
14. Buijs RM, van d V, Garidou ML, et al. Spleen vagal denervation inhibits the production of antibodies to circulating antigens. PLoS One 2008;3:e3152.
15. Hansen MK, O'Connor KA, Goehler LE, et al. The contribution of the vagus nerve in interleukin-1beta-induced fever is dependent on dose. Am J Physiol Regul Integr Comp Physiol 2001;280:R929-34.
16. Marquette C, Linard C, Galonnier M, et al. IL-1beta, TNFalpha and IL-6 induction in the rat brain after partial-body irradiation: role of vagal afferents. Int J Radiat Biol 2003;79:777-85.
17. Goehler LE, Relton JK, Dripps D, et al. Vagal paraganglia bind biotinylated interleukin-1 receptor antagonist: a possible mechanism for immune-to-brain communication. Brain Res Bull 1997;43:357-64.
18. Watkins LR, Goehler LE, Relton JK, et al. Blockade of interleukin-1 induced hyperthermia by subdiaphragmatic vagotomy: evidence for vagal mediation of immune-brain communication. Neurosci Lett 1995;183:27-31.
19. Goehler LE, Gaykema RP, Opitz N, et al. Activation in vagal afferents and central autonomic pathways: early responses to intestinal infection with Campylobacter jejuni. Brain Behav Immun 2005;19:334-44.
20. Cailotto C, Costes LM, van der Vliet J, et al. Neuroanatomical evidence demonstrating the existence of the vagal anti-inflammatory reflex in the intestine. Neurogastroenterol Motil 2012;24:191-3.
21. Luyer MD, Buurman WA, Hadfoune M, et al. Pretreatment with high-fat enteral nutrition reduces endotoxin and tumor necrosis factor-alpha and preserves gut barrier function early after hemorrhagic shock. Shock 2004;21:65-71.
22. Luyer MD, Greve JW, Hadfoune M, et al. Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. J Exp Med 2005;202: 1023-9.
23. Lubbers T, de Haan JJ, Luyer MD, et al. Cholecystokinin/Cholecystokinin-1 receptor-mediated peripheral activation of the afferent vagus by enteral nutrients attenuates inflammation in rats. Ann Surg 2010;252:376-82.
24. Neuhuber WL, Kressel M, Stark A, et al. Vagal efferent and afferent innervation of the rat esophagus as demonstrated by anterograde DiI and DiA tracing: focus on myenteric ganglia. J Auton Nerv Syst 1998;70:92-102.
25. Bautista TG, Sun QJ, Zhao WJ, et al. Cholinergic inputs to laryngeal motoneurons functionally identified in vivo in rat: a combined electrophysiological and microscopic study. J Comp Neurol 2010;518:4903-16.
26. Berthoud HR, Carlson NR, Powley TL. Topography of efferent vagal innervation of the rat gastrointestinal tract. Am J Physiol 1991;260(1 Pt 2):R200-7.
27. Schemann M, Grundy D. Electrophysiological identification of vagally innervated enteric neurons in guinea pig stomach. Am J Physiol 1992;263(5 Pt 1):G709-18.
28. Hudson LC. Horseradish peroxidase study of the location of extrinsic efferent and afferent neurons innervating the colon of dogs. Am J Vet Res 1990;51:1875-81.
29. Vizzard MA, Brisson M, de Groat WC. Transneuronal labeling of neurons in the adult rat central nervous system following inoculation of pseudorabies virus into the colon. Cell Tissue Res 2000;299:9-26.
30. Dorofeeva AA, Panteleev SS, Makarov FN. Involvement of the sacral parasympathetic nucleus in the innervation of the descending colon and rectum in cats. Neurosci Behav Physiol 2009;39:207-10.
31. Berthoud HR, Jedrzejewska A, Powley TL. Simultaneous labeling of vagal innervation of the gut and afferent projections from the visceral forebrain with dil injected into the dorsal vagal complex in the rat. J Comp Neurol 1990;301:65-79.
32. Huston JM, Ochani M, Rosas-Ballina M, et al. Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis. J Exp Med 2006;203:1623-8.
33. Huston JM, Wang H, Ochani M, et al. Splenectomy protects against sepsis lethality and reduces serum HMGB1 levels. J Immunol 2008;181:3535-9.
34. Qin S, Wang H, Yuan R, et al. Role of HMGB1 in apoptosis-mediated sepsis lethality. J Exp Med 2006;203:1637-42.
35. Rosas-Ballina M, Olofsson PS, Ochani M, et al. Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science 2011;334:98-101.
36. Abraham C, Medzhitov R. Interactions between the host innate immune system and microbes in inflammatory bowel disease. Gastroenterology 2011;140:1729-37.
37. O'Mahony C, van der Kleij H, Bienenstock J, et al. Loss of vagal anti-inflammatory effect: in vivo visualization and adoptive transfer. Am J Physiol Regul Integr Comp Physiol 2009;297:R1118-26.
38. Ghia JE, Blennerhassett P, Collins SM. Impaired parasympathetic function increases susceptibility to inflammatory bowel disease in a mouse model of depression. J Clin Invest 2008;118:2209-18.
39. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, et al. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006;131:1122-30.
40. Ghia JE, Blennerhassett P, Deng Y, et al. Reactivation of inflammatory bowel disease in a mouse model of depression. Gastroenterology 2009;136:2280-8.
41. Ghia JE, Park AJ, Blennerhassett P, et al. Adoptive transfer of macrophage from mice with depression-like behavior enhances susceptibility to colitis. Inflamm Bowel Dis 2011;17:1474-89.
42. Choi KM, Gibbons SJ, Nguyen TV, et al. Heme oxygenase-1 protects interstitial cells of Cajal from oxidative stress and reverses diabetic gastroparesis. Gastroenterology 2008;135:2055-64.
43. Choi KM, Kashyap PC, Dutta N, et al. CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice. Gastroenterology 2010;138:2399-409.
44. Wehner S, Behrendt FF, Lyutenski BN, et al. Inhibition of macrophage function prevents intestinal inflammation and postoperative ileus in rodents. Gut 2007;56:176-85.
45. Kalff JC, Schraut WH, Simmons RL, et al. Surgical manipulation of the gut elicits an intestinal muscularis inflammatory response resulting in postsurgical ileus. Ann Surg 1998;228:652-63.
46. Boeckxstaens GE, de Jonge WJ. Neuroimmune mechanisms in postoperative ileus. Gut 2009;58:1300-11.
47. De Winter BY, van NL, De Man JG, et al. Role of oxidative stress in the pathogenesis of septic ileus in mice. Neurogastroenterol Motil 2005;17:251-61.
48. Eskandari MK, Kalff JC, Billiar TR, et al. Lipopolysaccharide activates the muscularis macrophage network and suppresses circular smooth muscle activity. Am J Physiol 1997;273(3 Pt 1):G727-34.
49. Eskandari MK, Kalff JC, Billiar TR, et al. LPS-induced muscularis macrophage nitric oxide suppresses rat jejunal circular muscle activity. Am J Physiol 1999;277(2 Pt 1):G478-86.
50. Turler A, Schwarz NT, Turler E, et al. MCP-1 causes leukocyte recruitment and subsequently endotoxemic ileus in rat. Am J Physiol Gastrointest Liver Physiol 2002;282:G145-55.
51. de Jonge WJ, Van Der Zanden EP, The FO, et al. Stimulation of the vagus nerve attenuates macrophage activation by activating the Jak2-STAT3 signaling pathway. Nat Immunol 2005;6:844-51.
52. de Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 2007;151:915-29.
53. Matteoli G, Gomez-Pinilla PJ, Di Giovangiulio M, et al. Intestinal resident macrophages expressing alpha 7nAChr mediate the anti-inflammatory effect of vagus nerve stimulation in postoperative ileus. Gastroenterology 2012; 142(5, Suppl 1), S-125.
54. Cailotto C, Gomez Pinilla PJ, van der Vliet J, et al. Immunohistochemical Study Evaluating the Vagal Innervation of Intestinal Resident Macrophages. Gastroenterology 2012;140(5 Suppl 1):S-370.
55. Volpi C, Fazio F, Fallarino F. Targeting metabotropic glutamate receptors in neuroimmune communication. Neuropharmacology 2012;63:501-6.
56. Lukacs-Kornek V, Malhotra D, Fletcher AL, et al. Regulated release of nitric oxide by nonhematopoietic stroma controls expansion of the activated T cell pool in lymph nodes. Nat Immunol 2011;12:1096-104.
57. Franco R, Pacheco R, Lluis C, et al. The emergence of neurotransmitters as immune modulators. Trends Immunol 2007;28:400-7.
58. Van Der Zanden EP, Snoek SA, Heinsbroek SE, et al. Vagus nerve activity augments intestinal macrophage phagocytosis via nicotinic acetylcholine receptor alpha4beta2. Gastroenterology 2009;137:1029-39.
59. Giebelen IA, Le MA, van den Pangaart PS, et al. Deficiency of alpha7 cholinergic receptors facilitates bacterial clearance in Escherichia coli peritonitis. J Infect Dis 2008;198:750-7.
60. Boland C, Collet V, Laterre E, et al. Electrical vagus nerve stimulation and nicotine effects in peritonitis-induced acute lung injury in rats. Inflammation 2011;34:29-35.
61. van Westerloo DJ, Giebelen IA, Florquin S, et al. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J Infect Dis 2005;191:2138-48.
62. Snoek SA, Verstege MI, Van Der Zanden EP, et al. Selective alpha7 nicotinic acetylcholine receptor agonists worsen disease in experimental colitis. Br J Pharmacol 2010;160:322-33.
63. Pavlov VA. Cholinergic modulation of inflammation. Int J Clin Exp Med 2008;1:203-12.
64. Bencherif M, Lippiello PM, Lucas R, et al. Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol Life Sci 2011;68:931-49.
65. Rutgeerts P, Vermeire S, Van AG. Biological therapies for inflammatory bowel diseases. Gastroenterology 2009;136:1182-97.
66. Danese S, Colombel JF, Reinisch W, et al. Review article: infliximab for Crohn's disease treatment-shifting therapeutic strategies after 10 years of clinical experience. Aliment Pharmacol Ther 2011;33:857-69.
67. Van AG, Vermeire S, Rutgeerts P. Management of acute severe ulcerative colitis. Gut 2011;60:130-3.
68. Miceli PC, Jacobson K. Cholinergic pathways modulate experimental dinitrobenzene sulfonic acid colitis in rats. Auton Neurosci 2003;105:16-24.
69. Orr-Urtreger A, Kedmi M, Rosner S, et al. Increased severity of experimental colitis in alpha 5 nicotinic acetylcholine receptor subunit-deficient mice. Neuroreport 2005;16:1123-7.
70. Cosnes J, Carbonnel F, Beaugerie L, et al. Effects of cigarette smoking on the long-term course of Crohn's disease. Gastroenterology 1996;110:424-31.
71. Yamamoto T. Factors affecting recurrence after surgery for Crohn's disease. World J Gastroenterol 2005;11:3971-9.
72. Nos P, Domenech E. Management of Crohn's disease in smokers: is an alternative approach necessary? World J Gastroenterol 2011;17:3567-74.
73. Bastida G, Beltran B. Ulcerative colitis in smokers, non-smokers and ex-smokers. World J Gastroenterol 2011;17:2740-7.
74. Gheorghe C, Pascu O, Gheorghe L, et al. Epidemiology of inflammatory bowel disease in adults who refer to gastroenterology care in Romania: a multicentre study. Eur J Gastroenterol Hepatol 2004;16:1153-9.
75. Hoie O, Wolters F, Riis L, et al. Ulcerative colitis: patient characteristics may predict 10-yr disease recurrence in a European-wide population-based cohort. Am J Gastroenterol 2007;102:1692-701.
76. Motley RJ, Rhodes J, Ford GA, et al. Time relationships between cessation of smoking and onset of ulcerative colitis. Digestion 1987;37:125-7.
77. Galitovskiy V, Qian J, Chernyavsky AI, et al. Cytokine-induced alterations of alpha7 nicotinic receptor in colonic CD4 T cells mediate dichotomous response to nicotine in murine models of Th1/Th17- versus Th2-mediated colitis. J Immunol 2011;187:2677-87.
78. Nikfar S, Ehteshami-Ashar S, Rahimi R, et al. Systematic review and meta-analysis of the efficacy and tolerability of nicotine preparations in active ulcerative colitis. Clin Ther 2010;32:2304-15.
79. Ingram JR, Thomas GA, Rhodes J, et al. A randomized trial of nicotine enemas for active ulcerative colitis. Clin Gastroenterol Hepatol 2005;3:1107-14.
80. McGrath J, McDonald JW, Macdonald JK. Transdermal nicotine for induction of remission in ulcerative colitis. Cochrane Database Syst Rev 2004;(4):CD004722.
81. Bai A, Guo Y, Lu N. The effect of the cholinergic anti-inflammatory pathway on experimental colitis. Scand J Immunol 2007;66:538-45.
82. Kalff JC, Buchholz BM, Eskandari MK, et al. Biphasic response to gut manipulation and temporal correlation of cellular infiltrates and muscle dysfunction in rat. Surgery 1999;126:498-509.
83. The FO, Boeckxstaens GE, Snoek SA, et al. Activation of the cholinergic anti-inflammatory pathway ameliorates postoperative ileus in mice. Gastroenterology 2007;133:1219-28.
84. Lubbers T, Luyer MD, de Haan JJ, et al. Lipid-rich enteral nutrition reduces postoperative ileus in rats via activation of cholecystokinin-receptors. Ann Surg 2009;249:481-7.
85. The F, Cailotto C, van d V, et al. Central activation of the cholinergic anti-inflammatory pathway reduces surgical inflammation in experimental post-operative ileus. Br J Pharmacol 2011;163:1007-16.
86. Clark JA, Coopersmith CM. Intestinal crosstalk: a new paradigm for understanding the gut as the "motor" of critical illness. Shock 2007;28:384-93.
87. MacFie J, O'Boyle C, Mitchell CJ, et al. Gut origin of sepsis: a prospective study investigating associations between bacterial translocation, gastric microflora, and septic morbidity. Gut 1999;45:223-8.
88. Costantini TW, Krzyzaniak M, Cheadle GA, et al. Targeting alpha-7 nicotinic acetylcholine receptor in the enteric nervous system: a cholinergic agonist prevents gut barrier failure after severe burn injury. Am J Pathol 2012;181:478-86.
89. Krzyzaniak M, Peterson C, Loomis W, et al. Postinjury vagal nerve stimulation protects against intestinal epithelial barrier breakdown. J Trauma 2011; 70:1168-75.
90. van Westerloo DJ, Giebelen IA, Florquin S, et al. The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology 2006;130:1822-30.
91. Hiramoto T, Chida Y, Sonoda J, et al. The hepatic vagus nerve attenuates Fas-induced apoptosis in the mouse liver via alpha7 nicotinic acetylcholine receptor. Gastroenterology 2008;134:2122-31.
92. Guinet E, Yoshida K, Nouri-Shirazi M. Nicotinic environment affects the differentiation and functional maturation of monocytes derived dendritic cells (DCs). Immunol Lett 2004;95:45-55.
93. Wessler I, Kirkpatrick CJ. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br J Pharmacol 2008;154:1558-71.
94. De Rosa MJ, Dionisio L, Agriello E, et al. Alpha 7 nicotinic acetylcholine receptor modulates lymphocyte activation. Life Sci 2009;85:444-9.
95. Westman M, Engstrom M, Catrina AI, et al. Cell specific synovial expression of nicotinic alpha 7 acetylcholine receptor in rheumatoid arthritis and psoriatic arthritis. Scand J Immunol 2009;70:136-40.
96. Takahashi HK, Liu K, Wake H, et al. Effect of nicotine on advanced glycation end product-induced immune response in human monocytes. J Pharmacol Exp Ther 2010;332:1013-21.
97. Ghia JE, Blennerhassett P, El-Sharkawy RT, et al. The protective effect of the vagus nerve in a murine model of chronic relapsing colitis. Am J Physiol Gastrointest Liver Physiol 2007;293:G711-18.
98. Huston JM, Tracey KJ. The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy. J Intern Med 2011;269:45-53.
99. Sloan RP, McCreath H, Tracey KJ, et al. RR interval variability is inversely related to inflammatory markers: the CARDIA study. Mol Med 2007;13:178-84.
100. von KR, Nelesen RA, Mills PJ, et al. Relationship between heart rate variability, interleukin-6, and soluble tissue factor in healthy subjects. Brain Behav Immun 2008;22:461-8.
101. Haarala A, Kahonen M, Eklund C, et al. Heart rate variability is independently associated with C-reactive protein but not with Serum amyloid A. The Cardiovascular Risk in Young Finns Study. Eur J Clin Invest 2011;41:951-7.
102. Weber CS, Thayer JF, Rudat M, et al. Low vagal tone is associated with impaired post stress recovery of cardiovascular, endocrine, and immune markers. Eur J Appl Physiol 2010;109:201-11.
103. Marsland AL, Gianaros PJ, Prather AA, et al. Stimulated production of proinflammatory cytokines covaries inversely with heart rate variability. Psychosom Med 2007;69:709-16.
104. Goldstein RS, Bruchfeld A, Yang L, et al. Cholinergic anti-inflammatory pathway activity and High Mobility Group Box-1 (HMGB1) serum levels in patients with rheumatoid arthritis. Mol Med 2007;13:210-15.
105. Haensel A, Mills PJ, Nelesen RA, et al. The relationship between heart rate variability and inflammatory markers in cardiovascular diseases. Psychoneuroendocrinology 2008;33:1305-12.
106. Lanza GA, Sgueglia GA, Cianflone D, et al. Relation of heart rate variability to serum levels of C-reactive protein in patients with unstable angina pectoris. Am J Cardiol 2006;97:1702-6.
107. Kox M, Pompe JC, Pickkers P, et al. Increased vagal tone accounts for the observed immune paralysis in patients with traumatic brain injury. Neurology 2008;70:480-5.
108. Holguin F, Tellez-Rojo MM, Lazo M, et al. Cardiac autonomic changes associated with fish oil vs soy oil supplementation in the elderly. Chest 2005;127: 1102-7.
109. Goldhammer E, Tanchilevitch A, Maor I, et al. Exercise training modulates cytokines activity in coronary heart disease patients. Int J Cardiol 2005;100: 93-9.
110. Toyohara J, Hashimoto K. Alpha7 nicotinic receptor agonists: potential therapeutic drugs for treatment of cognitive impairments in Schizophrenia and Alzheimer's disease. Open Med Chem J 2010;4:37-56.
111. Wallace TL, Ballard TM, Pouzet B, et al. Drug targets for cognitive enhancement in neuropsychiatric disorders. Pharmacol Biochem Behav 2011;99:130-45.
112. Tregellas JR, Tanabe J, Rojas DC, et al. Effects of an alpha 7-nicotinic agonist on default network activity in schizophrenia. Biol Psychiatry 2011;69:7-11.
113. Thomsen MS, Hansen HH, Timmerman DB, et al. Cognitive improvement by activation of alpha7 nicotinic acetylcholine receptors: from animal models to human pathophysiology. Curr Pharm Des 2010;16:323-43.
114. Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry 2006;63:630-8.
115. Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, et al. The selective alpha7 agonist GTS-21 attenuates cytokine production in human whole blood and human monocytes activated by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med 2009;15:195-202.
116. Kox M, van Velzen JF, Pompe JC, et al. GTS-21 inhibits pro-inflammatory cytokine release independent of the Toll-like receptor stimulated via a transcriptional mechanism involving JAK2 activation. Biochem Pharmacol 2009;78:863-72.
117. Kox M, Pompe JC, Gordinou de Gouberville MC, et al. Effects of the alpha7 nicotinic acetylcholine receptor agonist GTS-21 on the innate immune response in humans. Shock 2011;36:5-11.
118. Barone L, Colicchio G, Policicchio D, et al. Effect of vagal nerve stimulation on systemic inflammation and cardiac autonomic function in patients with refractory epilepsy. Neuroimmunomodulation 2007;14:331-6.
119. Majoie HJ, Rijkers K, Berfelo MW, et al. Vagus nerve stimulation in refractory epilepsy: effects on pro- and anti-inflammatory cytokines in peripheral blood. Neuroimmunomodulation 2011;18:52-6.
120. De HV, Bogaert S, Bracke KR, et al. Effects of vagus nerve stimulation on pro- and anti-inflammatory cytokine induction in patients with refractory epilepsy. J Neuroimmunol 2009;214:104-8.
121. Vadivelu S, McCarty M, Chavan S, et al. 110 Modulation of the inflammatory response: a potential novel use for vagus nerve stimulation. Neurosurgery 2012;71:E546.
122. Pabst O, Mowat AM. Oral tolerance to food protein. Mucosal Immunol 2012;5:232-9.