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

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The vagus nerve a modulator of intestinal inflammation mainly synapses with neurons of the enteric nervous system, it is very likely that the cholinergic terminals shown in proximity of macrophages may belong to enteric rather than vagus nerve fibers. In this regard, recent data indicate that the spleen may play a role in effectuating the anti-inflammatory effects of vagus nerve activity, as electrical stimulation of the vagus nerve fails to attenuate serum TNF levels in splenectomized mice treated with endotoxin 49 . This implies that the parasympathetic nervous system may regulate systemic inflammation by modulating immune cells in the spleen. Huston et al. show that vagus nerve stimulation fails to regulate splenic TNF production in α7nAChR-deficient mice, and splenocytes from α7 KO mice do not respond to in vitro stimulation with ACh 49 . In another study it was demonstrated that nerve endings are in close apposition to macrophages in the spleen, but interestingly, these nerve fibers, found in apposition to the TNF-secreting macrophages are catecholaminergic, not cholinergic 14 . The authors propose that ACh released by the vagus nerve does not reach the spleen directly, but acts on α7 nAChR at the level of the ganglia of the celiacsuperior mesenteric ganglion to modulate splenic nerve function 14 . Hence, the vagus nerve via this ganglion, modulates adrenergic input to the spleen (via the n. splenicus), resulting in the release of catecholamines that stimulate adrenergic receptors on splenic macrophages and attenuate LPS-induced TNF production 14 Whether or not the vagus nerve innervates the spleen directly, or indirectly, is currently under debate. Rosas-Ballinas et al. 14 base their conclusion that the spleen does not receive direct vagus nerve input on the observation that ACh, choline acetyltransferase and the vescicular ACh transporter, are absent from splenic nerve terminals. Although this conclusion may seem justified, Buijs et al 50 show that the absence of the classically assigned vagus neurotransmitter ACh, or the ACh metabolizing enzymes in the spleen, does not directly imply the lack of direct input from the vagus. Indeed, they demonstrate that in rats, the spleen is directly innervated by the vagus nerve 50 . Their results corroborate earlier observations regarding parasympathetic innervation of the liver. In parallel, ACh metabolizing enzymes are absent from the liver, although this organ has shown to be vagusly innervated 51-53 . Given the recently purported role of the spleen in mediating the anti-inflammatory effect of vagus nerve activity, the question arises as to what is the role of macrophage nAChR α7 residing in the peritoneal or intestinal compartment is in this process. The interesting recent data on the role of the spleen in vagus nerve immune modulation put the role of nAChR α7 receptors on macrophages in a new perspective: although in vitro nicotine modulates macrophages function via nAChR α7, the in vivo effects of vagus nerve stimulation may rely on nAChR α7 on neurons rather than macrophages. Further research is required to assess the physiological mechanism by which the vagus nerve can modulate immune responses and whether this modulation is indeed the result of direct affects of ACh exposure to immune cells or whether vagus innervation of primary or secondary lymphoid organs plays a role (Figure 1). 25
Chapter 2 Figure 1. Hypothetical scheme of the mechanism via which vagus nerve activity can modulate immune cells in vivo. Vagal efferent fibres, that originate in the brainstem, release acetylcholine upon physiological or electrical stimulation. Vagal nerve stimulation may affect immune cells via direct release of acetylcholine, or via post-ganglionic mechanisms involving alternative neurotransmitters. This activates a connecting interneuron, resulting in the release of acetylcholine or other neurotransmitters, such as neuropeptides or catecholamines. Acetylcholine can act on nAChR which are broadly expressed on different types of immune cells, such as tissue macrophages. Possibly, neuropeptides and catecholamines acting on their specific receptors may be important as well. Receptor activation can lead to reduced pro-inflammatory cytokine production, abrogated microbial killing and enhanced phagocytosis. This skews immune cells to a more anergic phenotype, which can be beneficial in disorders that are characterized by an aberrant immune response. WHICH nAChR IS INVOLVED IN THE VAGUS MODULATION OF IMMUNE CELLS? The anti-inflammatory effects of nAChR activation on macrophages have previously been solely attributed to activation of the nAChR α7 12 . However, some reports indicate that vagus activity may also convey its anti-inflammatory effect via distinct nAChRs expressed in macrophages. Mastunaga et al 41 and others 54 have shown expression of α4β2, but not α7 nAChR in alveolar macrophages. Likewise, we have failed to detect α7 nAChR transcripts in certain mouse macrophages types (unpublished 2008). 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 -/- mice 55 . Most previous studies, including our own 4 , have ascribed the effects of ACh and nicotine on peritoneal macrophage cytokine production solely to activation of 26
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: Chapter 2 nicotine treatment impair
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
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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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