The vagus nerve as a modulator of intestinal inflammation - TI Pharma

More documents

Recommendations

Info

Chapter 8 macrophage types (chapter 5). Further analysis of potential α7 nAChR protein in these macrophages is hampered by the fact that commercially available α7 nAChR antisera seem not specific and stain an 57kD protein in brain homogenates from wildtype as well as α7 nAChR -/- mice31. In line, nicotine reduced TNF production in α7 WT, as well as in α7 KO mice (chapter 4). Accordingly, we observed that α7 specific agonists were less effective in reducing pro-inflammatory cytokine production as compared to nicotine (chapter 5). Altogether, these observations imply that the acetylcholine and nicotine effects on peritoneal macrophage cytokine production should not be exclusively attributed to nAChR α7 activation, but maybe also due to activation of alternative nAChR subtypes. Therefore, the use of selective agonists targeting other nAChRs than the α7 receptor could be successful, especially specific agonists of the nAChRα4β2, which is required for cholinergic activation of phagocytosis. In addition to the use of specific cholinergic agonists, vagus nerve stimulation itself could be a potential therapeutic asset in the treatment of patients with inflammatory diseases. Interestingly, in patients with drug-resistant epilepsy and depression, vagus nerve stimulation is already in use as a new adjunctive therapy. Furthermore, highfat enteral nutrition, sensed in the gastrointestinal tract, has shown to activate the parasympathetic nervous system. However, as the vagus nerve does not innervate the distal colon and rectum, the areas usually affected in IBD patients, vagus nerve stimulation may not be the first therapeutic choice in targeting IBD. Nevertheless, vagus nerve activity can regulate disease in animal models5, possibly clarified by the role of the spleen in exerting the anti-inflammatory effect of vagus nerve signaling 32,33 . The finding that nicotine inhibits activation of immune cells, together with the observation that vagus nerve signaling or specific nAChR agonists attenuate disease in several inflammatory animal models, implies that therapeutic agents modifying cholinergic signalling might be beneficial in humans. However, one should keep in mind that targeting the cholinergic anti-inflammatory pathway in humans could be less straightforward than originally thought, as there might be an individual variation in response to future therapeutic agents modifying the cholinergic anti-inflammatory pathway in humans. Overall, in this thesis, we further identified the working mechanism of the ‘cholinergic anti-inflammatory pathway ’ to alleviate specific targeting of this pathway, in order to increase the translational potential. Our data may aid in the development of therapeutic strategies to modify the cholinergic anti-inflammatory pathway, in order to treat various inflammatory conditions. 138
REFERENCE LIST Summary and conclusions 1. Borovikova LV, Ivanova S, Zhang M, Yang H, Botchkina GI, Watkins LR, Wang H, Abumrad N, Eaton JW, Tracey KJ. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 2000;405:458-462. 2. Bernik TR, Friedman SG, Ochani M, DiRaimo R, Susarla S, Czura CJ, Tracey KJ. Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion. J Vasc Surg 2002;36:1231-1236. 3. Guarini S, Altavilla D, Cainazzo MM, Giuliani D, Bigiani A, Marini H, Squadrito G, Minutoli L, Bertolini A, Marini R, Adamo EB, Venuti FS, Squadrito F. Efferent vagal fibre stimulation blunts nuclear factor-kappaB activation and protects against hypovolemic hemorrhagic shock. Circulation 2003;107:1189-1194. 4. van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, van der PT. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis. J Infect Dis 2005;191:2138-2148. 5. Ghia JE, Blennerhassett P, Kumar-Ondiveeran H, Verdu EF, Collins SM. The vagus nerve: a tonic inhibitory influence associated with inflammatory bowel disease in a murine model. Gastroenterology 2006;131:1122-1130. 6. van Maanen MA, Lebre MC, van der Poll T, Larosa GJ, Elbaum D, Vervoordeldonk MJ, Tak PP. Stimulation of nicotinic acetylcholine receptors attenuates collagen-induced arthritis in mice. Arthritis Rheum 2009;60:114-122. 7. Altschuler SM, Ferenci DA, Lynn RB, Miselis RR. Representation of the cecum in the lateral dorsal motor nucleus of the vagus nerve and commissural subnucleus of the nucleus tractus solitarii in rat. J Comp Neurol 1991;304:261-274. 8. Altschuler SM, Escardo J, Lynn RB, Miselis RR. The central organization of the vagus nerve innervating the colon of the rat. Gastroenterology 1993;104:502-509. 9. Wang H, Yu M, Ochani M, Amella CA, Tanovic M, Susarla S, Li JH, Wang H, Yang H, Ulloa L, Al Abed Y, Czura CJ, Tracey KJ. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation. Nature 2003;421:384-388. 10. Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ, Miller EJ, Tracey KJ, Al Abed Y. Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis. Crit Care Med 2007;35:1139-1144. 11. Parrish WR, Rosas-Ballina M, Gallowitsch-Puerta M, Ochani M, Ochani K, Yang LH, Hudson L, Lin X, Patel N, Johnson SM, Chavan S, Goldstein RS, Czura CJ, Miller EJ, Al Abed Y, Tracey KJ, Pavlov VA. Modulation of TNF release by choline requires alpha7 subunit nicotinic acetylcholine receptormediated signaling. Mol Med 2008;14:567-574. 12. De Jonge WJ, Ulloa L. The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 2007;151:915-929. 13. Wang H, Liao H, Ochani M, Justiniani M, Lin X, Yang L, Al Abed Y, Wang H, Metz C, Miller EJ, Tracey KJ, Ulloa L. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nat Med 2004;10:1216-1221. 14. Takeda K, Clausen BE, Kaisho T, Tsujimura T, Terada N, Forster I, Akira S. Enhanced Th1 activity and development of chronic enterocolitis in mice devoid of Stat3 in macrophages and neutrophils. Immunity 1999;10:39-49. 15. Levy DE, Lee CK. What does Stat3 do? J Clin Invest 2002;109:1143-1148. 16. Prasad M, Matthews JB. Deflating postoperative ileus. Gastroenterology 1999;117:489-492. 17. De Jonge WJ, van den Wijngaard RM, The FO, ter Beek ML, Bennink RJ, Tytgat GN, Buijs RM, Reitsma PH, van Deventer SJ, Boeckxstaens GE. Postoperative ileus is maintained by intestinal immune infiltrates that activate inhibitory neural pathways in mice. Gastroenterology 2003;125:1137-1147. 139
Page 1 and 2:
The vagus nerve as a modulator ofin
Page 3 and 4:
The vagus nerve as a modulator of i
Page 5 and 6:
Promotiecommissie Promotores: Prof.
Page 7 and 8:
Table of contents Chapter 1 Introdu
Page 9 and 10:
Introduction and outline The aim of
Page 11 and 12:
Introduction and outline Hence, the
Page 13 and 14:
Introduction and outline 18. van de
Page 15 and 16:
Chapter 2 ABSTRACT The cholinergic
Page 17 and 18:
Chapter 2 neurotransmitter ACh with
Page 19 and 20:
Chapter 2 THE VAGUS NERVE AND CHOLI
Page 21 and 22:
Chapter 2 nicotine treatment impair
Page 23 and 24:
Chapter 2 Figure 1. Hypothetical sc
Page 25 and 26:
Chapter 2 unclear whether this hybr
Page 27 and 28:
Chapter 2 reduction of NF-κB activ
Page 29 and 30:
Chapter 2 CONCLUDING REMARKS The hy
Page 31 and 32:
Chapter 2 34 17. The FO, Boeckxstae
Page 33 and 34:
Chapter 2 55. Moser N, Mechawar N,
Page 35 and 36:
Chapter 2 93. Shafique S, Dalsing M
Page 37 and 38:
Chapter 3 ABSTRACT Acetylcholine re
Page 39 and 40:
Chapter 3 by bowel manipulation 12
Page 41 and 42:
Chapter 3 for preparation of whole
Page 43 and 44:
Chapter 3 Figure 1. Nicotine attenu
Page 45 and 46:
Chapter 3 Figure 2. Inhibition of m
Page 47 and 48:
Chapter 3 macrophage cell lysates s
Page 49 and 50: Chapter 3 reports 2 . We next incub
Page 51 and 52: Chapter 3 Figure 5. Perioperative e
Page 53 and 54: Chapter 3 Figure 7. Stimulation of
Page 55 and 56: Chapter 3 Activation of the STAT3 c
Page 57 and 58: Chapter 3 REFERENCE LIST 60 1. Trac
Page 59 and 60: 4 CHAPTER Deciphering STAT3 signali
Page 61 and 62: INTRODUCTION Deciphering STAT3 sign
Page 63 and 64: Deciphering STAT3 signaling in chol
Page 69 and 70: DISCUSSION Deciphering STAT3 signal
Page 71 and 72: REFERENCES Deciphering STAT3 signal
Page 73 and 74: Chapter 5 ABSTRACT Background and A
Page 75 and 76: Chapter 5 METHODS Reagents and anti
Page 77 and 78: Chapter 5 described previously 6 .
Page 79 and 80: Chapter 5 Figure 1 Cholinergic agon
Page 81 and 82: Chapter 5 Figure 3 Cholinergic agon
Page 83 and 84: Chapter 5 we analyzed whether nicot
Page 85 and 86: Chapter 5 Zymosan induced formation
Page 87 and 88: Chapter 5 marker CD11 c (Fig. 7E),
Page 89 and 90: Chapter 5 Our data demonstrate that
Page 91 and 92: Chapter 5 REFERENCE LIST 96 1. Boro
Page 93 and 94: Thesis E.P.M. van der Zanden The va
Page 95 and 96: Summary and conclusions The goal of
Page 97 and 98: Summary and conclusions whether the
Page 99: Summary and conclusions exposure co
Page 103 and 104: Nederlandse samenvatting
Page 105 and 106: Chapter 7 van STAT3 in de ‘cholin
Page 107 and 108: Chapter 7 De bevinding dat nicotine
Page 109 and 110: Chapter 7 macrofagen aan te tonen (
Page 111 and 112: Chapter 7 18. Yu Z, Zhang W, Kone B
Page 113 and 114: Shizuo Akira Department of Host Def
Page 115 and 116: List of publications
Page 117 and 118: Dankwoord
Page 119 and 120: om de ene keer olijfolie te drinken
Page 121: Curriculum Vitae Curriculum Vitae E
show all

The vagus nerve as a modulator of intestinal inflammation - TI Pharma

Create successful ePaper yourself

Delete template?

Save as template?