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

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Vagal anti-inflammatory pathway mediated via JAK2-STAT3 activation Supplementary Figure 1 Vagal nerve stimulation reduces recruitment of inflammatory infiltrates to the intestinal muscularis by activating peripheral nicotinic acetylcholine receptors. MPO activity measured in intestinal muscularis tissue homogenates isolated 24 h after surgery with IM. VNS with 5V, but not 1V, -stimulus prevents the increased muscularis MPO activity elicited by IM. Asterisks indicate significant differences in MPO activity in intestinal muscularis tissue from L control and IM VNS5V determined by one-way ANOVA followed by Dunnett’s multiple comparison test. Data represent mean ± SEM of 10-15 mice (a). MPO-activity containing cells were stained in whole mount preparations of intestinal muscularis (b and c) prepared 24 hrs post-operatively . Mice underwent IM with sham VNS (IM Sham), or IM combined with VNS using 1, or 5 V pulses (IM VNS1V, and IM VNS5V) (b). Mice were pretreated with hexamethonium (100μM; Hexa) or vehicle and underwent Laparotomy (L) with VNS (L VNS5V) or IM with VNS5V (e). MPO-positive cells were counted in five consecutive microscopic fields of whole mount preparations of the indicated groups. Asterisks indicate significant differences (P
Chapter 3 Figure 5. Perioperative electrical stimulation of the left cervical vagus nerve prevents gastroparesis 24 h after surgery with intestinal manipulation in mice. Gastric emptying curves of a semi-liquid ‘test meal’ are for mice that underwent surgery with intestinal manipulation (filled circles), control laparotomy surgery (gray triangles), stimulation of the vagus nerve plus control laparotomy surgery (gray diamonds) or stimulation of the vagus nerve plus surgery with intestinal manipulation (filled squares). Values are means +/-s.e.m.; n = 8−10. * , P < 0.05 for gastric retention at 60 min, surgery with intestinal manipulation versus surgery with intestinal manipulation plus stimulation of the vagus nerve (Mann-Whitney U test). most probably granulocytes and monocytes recruited to the peritoneal compartment as a result of tissue trauma inflicted by the intestinal manipulation procedure. However, when stimulation of the vagus nerve was applied, we noted phosphorylated STAT3− positive nuclei in cells between longitudinal and circular muscle layers surrounding the myenteric plexus. To identify the cellular source of the phosphorylated STAT3− positive nuclei, we labeled tissue phagocytes in vivo by pretreating mice with Alexa 546−labeled dextran particles (molecular weight, 10,000). This procedure labels F4/80 antigen−positive macrophages populating the intestinal muscularis 25 . Most of phosphorylated STAT3−positive nuclei in intestinal tissue of mice that had undergone stimulation of the vagus nerve localized together with cells that had taken up Alexa 546−labeled dextran particles, indicating that these phosphorylated STAT3−positive nuclei represented macrophages (Fig. 7c). These observations corroborate our in vitro findings on the function of STAT3 in the cholinergic inhibition of tissue macrophages and are in line with our proposed function of the network of resident intestinal macrophages 26 as the inflammatory cells targeted by stimulation of the vagus nerve. To further demonstrate that the cholinergic anti-inflammatory pathway critically depends on STAT3 activation in vivo, we studied the inflammatory response to intestinal manipulation in mice specifically deficient in STAT3 in their myeloid cell lineage (called ‘LysM-Stat3 fl/- ’ mice here). LysM-Stat3 fl/- mice lack STAT3 in their macrophages and granulocytes 6 . In Stat3 fl/+ control mice as well as in LysM- Stat3 fl/- mice, intestinal manipulation led to increased peritoneal IL-6 (Fig. 8a) as well as massive inflammatory infiltrates in the manipulated muscularis tissue (Fig. 54
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: Chapter 3 reports 2 . We next incub
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 and 100: Summary and conclusions exposure co
Page 101 and 102:
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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