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

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Chapter 1 The immune system of the gut faces the challenge of discriminating between self and non-self in order to elicit a proper response against pathogens, but must at the same time tolerate mutual beneficial organisms and food antigens. Antigen presenting cells such as macrophages and dendritic cells are thought to be crucial in maintaining this balance. Intestinal macrophages are the first phagocytic cells of the immune system to interact with microorganisms that have breached the epithelium. Smythies et al showed that human resident intestinal macrophages are rather phagocytes than cytokine producers 13 . Therefore, in chapter 5, we examined whether the antiinflammatory potential of vagus nerve activity in intestinal inflammation solely rests on reduced macrophage cytokine production, or if other important macrophage functions such as endocytosis and phagocytosis are affected. Furthermore, we examined the nicotinic acetylcholine receptor type and signaling pathways involved in these processes. Finally, we studied the effects of vagal signaling on phagocytosis and uptake in vivo. In chapter 6, we tried to analyze how vagus nerve activity can modulate immune cells in vivo. In chapter 3, we showed that cholinergic nerve fibers are in close anatomical apposition to macrophages in the small intestine. However, since the halflife of acetylcholine is very short, one may question if acetylcholine that is released at the vagal termini actually reaches the immune cells in a quantity that could explain the in vitro effects. We hypothesized that, next to the direct anti-inflammatory effects of vagus nerve derived acetylcholine on nAChR on tissue macrophages, vagus nerve stimulation could affect immune cells via post-ganglionic mechanisms that lead to the release of alternative neurotransmitters, such as neuropeptides. Vasoactive intestinal polypeptide (VIP) and substance P (SP) are neuropeptides that are abundantly expressed in the gut, and elicit important immunomodulatory functions in the intestine 14-16 . Therefore, in chapter 6, we investigated whether vagus nerve released acetylcholine negatively regulates macrophage reactivity directly, or by modulating the responses to co-released VIP or SP. All previous data were conducted in cell lines, mouse macrophages and experimental mouse models. Data from human studies considering cholinergic immunomodulation are limited. Is has been long known that cigarette smoking is an important environmental factor in ulcerative colitis, as smoking appears to have a protective effect in the development of disease and reduces its severity 17 . However, clinical trials of nicotine treatment in ulcerative colitis have shown variable outcomes 18 . As previous data suggest that nicotinic receptor α7 may specifically participate in the inflammatory response of monocytes 12 , in chapter 7, we evaluated whether smoking, or repeated nicotine exposure affected nAChR α7 monocyte expression, and whether this renders human monocytes more susceptible to cholinergic immune-modulation. Luyer et al demonstrated in a hemorrhagic shock rat model, that high fat enteral nutrition could inhibit the inflammatory response by way of efferent vagal fibers 19 . 12
Introduction and outline Hence, the second aim of chapter 7 was to establish the effect of oral olive oil diet on human whole blood LPS-induced cytokine production. 13
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Page 7 and 8: Table of contents Chapter 1 Introdu
Page 9: Introduction and outline The aim of
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
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Page 53 and 54: Chapter 3 Figure 7. Stimulation of
Page 55 and 56: Chapter 3 Activation of the STAT3 c
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INTRODUCTION Deciphering STAT3 sign
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Deciphering STAT3 signaling in chol
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DISCUSSION Deciphering STAT3 signal
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REFERENCES Deciphering STAT3 signal
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Chapter 5 ABSTRACT Background and A
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Chapter 5 METHODS Reagents and anti
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Chapter 5 described previously 6 .
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Chapter 5 Figure 1 Cholinergic agon
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Chapter 5 Figure 3 Cholinergic agon
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Chapter 5 we analyzed whether nicot
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Chapter 5 Zymosan induced formation
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Chapter 5 marker CD11 c (Fig. 7E),
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Chapter 5 Our data demonstrate that
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Chapter 5 REFERENCE LIST 96 1. Boro
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Thesis E.P.M. van der Zanden The va
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Summary and conclusions The goal of
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Summary and conclusions whether the
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Summary and conclusions exposure co
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REFERENCE LIST Summary and conclusi
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Nederlandse samenvatting
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Chapter 7 van STAT3 in de ‘cholin
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Chapter 7 De bevinding dat nicotine
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Chapter 7 macrofagen aan te tonen (
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Chapter 7 18. Yu Z, Zhang W, Kone B
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Shizuo Akira Department of Host Def
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List of publications
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Dankwoord
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om de ene keer olijfolie te drinken
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Curriculum Vitae Curriculum Vitae E
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The vagus nerve as a modulator of intestinal inflammation - TI Pharma

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