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

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The vagus nerve a modulator of intestinal inflammation VAGUS MODULATION OF IMMUNE RESPONSES The innate immune system is pivotal in the first response to invading pathogens or tissue trauma. When challenged, the host needs an adequate inflammatory reaction but also needs to prevent collateral damage to tissues due to excessive systemic spread of inflammation and release of inflammatory mediators. Hence, regulation of the acute inflammatory response is important, and regulatory mechanisms are required to accomplish this. Decades ago, the sympathetic nervous system was already identified as a ‘hard-wired’ counter-regulatory mechanism that can locally regulate immune responses 1 . Besides the sympathetic nervous system, the parasympathetic nervous system, comprised by the vagus nerve (the largest nerve in the body) is increasingly recognized as a potent player in neuro-immune inflammation. The vagus nerve, in addition to its classically assigned function of controlling heart rate, hormone secretion, gastrointestinal peristalsis, and digestion, may also be involved in control of immune responses to commensal flora and dietary components. The vagus nerve is a mixed nerve composed of 90% afferent and 10% efferent fibers. The afferent vagus system is known to regulate the inflammatory response via activation of the hypothalamic pituitary adrenal axis. However, more recent evidence reveals that efferent vagus nerve cholinergic activity exerts quite potent immuno-modulatory potential as well 2 . The vagus nerve transmits signals by releasing acetylcholine (ACh), its principal neurotransmitter, at its peripheral nerve endings. ACh activates nicotinic acetylcholine receptors (nAChRs), ligand-gated ion channels on neuronal cells 3 . In this function, ACh is historically referred to as a neurotransmitter. Immune cells that have been shown to be especially sensitive to modulation by vagus nerve activity are macrophages (the main class of innate immune cells) 2 . Macrophages express nAChRs and potently respond to ACh. This was corroborated by our observation of close anatomical association between cholinergic nerve fibers and enteric macrophages 4 . These data suggest that the classical neurotransmitter ACh also functions as neuroimmune cytokine, providing a molecular basis for the purported “neuro-immune axis” between the brain and immune system. The initial experiments to show the role of the parasympathetic nervous system in the regulation of the innate immune response were performed in a rat model of experimental sepsis 2 . In these experiments is was shown that surgical dissection of the vagus nerve enhanced pro-inflammatory cytokine production and accelerated the development of septic shock, whereas electrical stimulation of the efferent vagus nerve prevented systemic inflammation and reduced lethality 2 . Subsequently, in several studies it was demonstrated that activation of the cholinergic nervous system ameliorated disease in animal models of ischemia–reperfusion injury 5 , hemorrhagic shock 6 , and experimental arthritis 7 , pancreatitis 8 , peritonitis 9 and DSS-colitis 10 . It is hypothesized that the vagus nerve exerts anti-inflammatory effects through the interaction of its principal 19
Chapter 2 neurotransmitter ACh with acetylcholine receptors expressed on macrophages. The group of Tracey 2 have originally showed that in vitro, ACh inhibited the endotoxininduced release of pro-inflammatory cytokines in human macrophages 2 . Since ACh signals through nicotinic or muscarinic receptors, selective agonists and antagonists have been used to identify the receptors involved in the immunomodulatory effects of ACh. Nicotine was as efficient as ACh in inhibiting pro-inflammatory cytokine production in macrophages, indicating that the anti-inflammatory effects of ACh on immune cells are mediated through nicotinic receptors, rather than muscarinic receptors. nAChR are pentameric ligand-gated ion channels that can consist of a large number of different subunits (α1-α9, α8, β1-β4, γ , δ and ε) 11 and it is reported that the nAChR α7 subtype, which is expressed on immune cells, is essential in mediating the anti-inflammatory effect of ACh 12 . From the pioneering work of Tracey 13 it is postulated that the cholinergic antiinflammatory pathway may act as part of a anti-inflammatory reflex arch, in which the presence of proinflammatory cytokines in the periphery activates vagus afferents, resulting in a vagus efferent firing subsequently leading to an attenuation of cytokine release from macrophages via nAChR α7. On the other hand, recent data indicate that the efferent arm of the cholinergic anti-inflammatory pathway may, at least in part be mediated via post-ganglionic events 14 . Here we review the recent reports on the possible pathways via which vagus nerve activity can exert its anti-inflammatory effects, with specific focus on intestinal disease. Moreover, the role of nAChR expressed on macrophages as well as other immune cells in intestinal and peritoneal tissue in the immunomodulatory effects of cholinergic signaling are highlighted. VAGUS NERVE SIGNALING IN INTESTINAL INFLAMMATION Neuronal tracing studies reveal that efferent vagus nerve fibers innervate the small intestine and proximal colon of the gastro-intestinal (GI) tract 15,16 , leaving the possibility that cholinergic activity may modulate immune cells residing in, or recruited to, the densely innervated bowel wall. Therefore, vagus nerve stimulation, or the use of applied cholinergic agonists targeting distinct nAChR subtypes, has been studied extensively as a novel approach to treat intestinal inflammatory disease in several animal models. One of the GI-disorders in which vagus nerve stimulation has been shown to ameliorate disease is post-operative ileus (POI) 4,17 . POI is a commonly occurring postoperative complication that results from manipulation of the bowel during abdominal surgery, and is characterized by a transient hypomotility of the GI tract. With ~22 million surgical procedures being performed annually in the US (data derived from hospital discharge records between 1980 and 1993 18 ), and with all of these procedures 20
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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: Chapter 2 ABSTRACT The cholinergic
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 65 and 66: Deciphering STAT3 signaling in chol
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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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