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

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Mast cells The vagus nerve a modulator of intestinal inflammation Although best known for their role in allergy, mast cells play an important immune protective role as well, being intimately involved in wound healing and defense against pathogens. Mast cells express the nAChR α3, α5, α7, α9 and α10 75.76 and appear to make intimate contact with afferent vagus fibers in the small intestinal mucosa 75 . In human mucosal mast cells, ACh inhibits histamine release. However, this seems to be species specific, since in rats ACh stimulates mast cell degranulation 77,78 . Host sensitization status may also affect the response of mast cells to ACh, as sensitization to a specific allergen makes rat mast cells more sensitive to ACh-induced histamine release 78 . In conclusion, cholinergic activation has broad effects on immune cell function. In animal models of intestinal inflammation, vagus nerve signaling may attenuate inflammation activity not exclusively via inhibition of macrophages but also other immune cells, such as dendritic cells and mast cells can be affected. NICOTINIC ACETYLCHOLINE RECEPTOR SUBCELLULAR SIGNALING The exact intracellular mechanism via which ACh exerts its effects on immune cells has been investigated in several studies. Most studies in immune cells focus on activation and subcellular signaling of the α7 nAChR. nAChR α7 receptor signaling on neuronal cells is mediated by ion channel fluxes due to ACh binding 3 , although the α7 nAChR can also activate alternative signaling pathways. In rat microglia, nicotine exposure elicits a transient increase in intracellulair Ca 2+ levels 79 . This increase in intracellular Ca 2+ may involve phosphoinositide 3-kinases (PI3K) and phospho-lipase C (PLC) activation and subsequent Ca 2+ release from intracellular Ca 2+ stores 79 , which can finally lead to Ca 2+ depletion and cell deactivation. However, unpublished data from our group indicate that no intracellular Ca 2+ flux was observed after nicotine exposure in mouse peritoneal macrophages, although nAChR signaling was present (experiments performed at David Greaves’ laboratory, Oxford University). Some studies link nAChR α7 to PI3K activation, possibly via phosphorylation of Akt 62,80 and activation of Janus Kinase 2 (Jak2) 81 . In line with this observation , nAChR α7 activation in macrophages leads to recruitment and phosphorylation of Jak2 and subsequent activation of the Signal Transducer and Activator of Transcription 3 (STAT3) protein 82 . STAT3 is a negative regulator of inflammation, contributing to the anti-inflammatory effects of IL-10 82 . STAT3 does not inhibit transcription of pro-inflammatory cytokines directly 82 . Presumably, other signaling pathways are involved. Studies in macrophages indicate that nAChR α7 activation reduces NF-kB activation, resulting in decreased pro-inflammatory cytokine production 40 . This 29
Chapter 2 reduction of NF-κB activation can be explained via induced STAT3 phosphorylation, as phosphorylated STAT3 has been shown to interact with NF-κB p65 83 and thus inhibit p65 translocation to the nucleus, resulting in inhibition of NF-κB transcriptional activity. In monocytes and various other cell types, nicotine induces expression of COX-2 and the synthesis of one of its major products, prostaglandine E2 (PGE 2 ). PGE2 is able to elicit an increase in cyclic AMP levels and protein kinase A (PKA) activity, leading to reduced adhesion molecule expression, cytokine production and lymphocyte proliferation 84 . Other studies show modulation of mitogen activated protein kinases (MAPK), which are involved in various cellular activities, upon AChR activation 63 . In conclusion, nAChR α7 activation triggers various signaling mechanisms that most likely interact with each other to achieve immunomodulatory effects. However, the precise mechanism requires further investigation. CLINICAL IMPLICATIONS OF THE ANTI-INFLAMMATORY PROPERTIES OF VAGUS NERVE SIGNALING The finding that nicotine inhibits activation of immune cells, together with the observation that vagus nerve signaling or specific nAChR α7 agonists attenuate disease in several inflammatory animal models, implies that therapeutic agents modifying cholinergic signalling might be beneficial in humans. Cigarette smoking is an important environmental factor in inflammatory bowel disease (IBD), but most strikingly smoking has differential effects in ulcerative colitis (UC) and Crohn’s disease (CD). While smoking increases the risk of developing CD and worsens its course, epidemiological studies of smokers in UC point out that smoking appears to have a protective effect in the development of this disease and reduces its severity 85 . The exact explanation for this discrepancy is far from clear, but it certainly adds to the current belief that UC and Crohn’s disease are two different disease entities. About 90% of UC patients are non-smokers. Patients with a history of smoking acquire their disease after they have stopped smoking 44 . Patients who smoke intermittently often experience improvement in their colitis symptoms during the periods when smoking 86,87 . In ex-smokers, onset is nearly always after quitting smoking. However, clinical trials using nicotine for the treatment of UC have provided different results. Transdermal nicotine appears to be superior to placebo for the induction of remission in patients with UC, but no significant advantage for transdermal nicotine therapy compared to standard medical therapy was found. Moreover, adverse events associated with transdermal nicotine are significant which will limit its use in patients 88 . However, to avoid side effects caused by nicotine, more specific nAChR agonists are designed. Partial selective nAChR α7 and α4β2 agonists are already being 30
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: Chapter 2 unclear whether this hybr
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
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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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