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

More documents

Recommendations

Info

Vagal anti-inflammatory pathway mediated via JAK2-STAT3 activation Figure 8. Stimulation of the vagus nerve fails to reduce inflammation in LysM-Stat3 fl/- mice. IL-6 was measured in peritoneal lavage fluid (a) and myeloperoxidase-positive inflammatory infiltrates were quantified in muscularis tissues (b) of Stat3 fl/+ control mice (filled bars) or LysM-Stat3 fl/- mice (open bars) treated with control laparotomy surgery (L sham), intestinal manipulation (IM sham) or intestinal manipulation plus stimulation of the vagus nerve (IM VNS). (a) Peritoneal lavage fluid was collected 3 h after the procedures. (b) Infiltrates were quantified in whole-mount preparations 24 h after the surgical procedures. Data are mean +/-s.e.m.; n = 3−4. * , P < 0.05, compared with the respective control laparotomy surgery group (Mann-Whitney U test). 8b). Notably, however, stimulation of the vagus nerve reduced peritoneal IL-6 and intestinal inflammation in Stat3 fl/+ control mice but failed to do so in LysM-Stat3 fl/- mice. These data support the critical function of STAT3 activation in the cholinergic anti-inflammatory pathway in vivo. DISCUSSION The cholinergic anti-inflammatory pathway represents a physiological system for controlling macrophage activation and inflammation in sepsis models 1 . Its working mechanism ultimately involves the prevention of NF-ĸB p65 activity 3 after α7 nAChR activation 4 , but the exact cellular mechanism has remained unclear. Here we have demonstrated that nicotine acts on macrophages via the recruitment of Jak2 to the α7 nAChR and activation of Jak2, thereby initiating the anti-inflammatory STAT3 and SOCS3 signaling cascade. Notably, recruitment of Jak2 to the α7 nAChR subunit has also been described in neuronal PC12 cells exposed to nicotine, as part of a neuroprotective mechanism against β-amyloid-induced apoptosis 20 . Our results in resident peritoneal macrophages were consistent with our in vivo data, as we found activation of STAT3 in intestinal macrophages in response to stimulation of the vagus nerve in mice, which indicates activation of STAT3 induced by acetylcholine derived from vagal efferents. 57
Chapter 3 Activation of the STAT3 cascade after nAChR ligation is fully consistent with the observed inhibition of proinflammatory cytokine release by macrophages, because STAT3 is a negative regulator of the inflammatory response 6,27 . In our studies, the anti-inflammatory effect of nicotine on macrophages required DNA binding and transactivation of STAT3, as nicotine failed to inhibit TNF production in macrophages overexpressing STAT3 altered in its in DNA-binding capacity 17 . Likewise, activation of STAT3 is required for the anti-inflammatory properties of IL-10 (refs. 8, 28) and the IL-10-induced attenuation of cytokine production and proliferation 28 . In addition, STAT3 phosphorylation is required for IL-6-induced growth arrest and differentiation 29 . SOCS3 specifically disables STAT3 phosphorylation via IL-6R but does not interfere with IL-10R signaling 9, 10, 30 . Conditional knockout mice specifically lacking SOCS3 in their macrophages (LysM-Socs3 fl/- ) show resistance to endotoxemia, explained by the anti-inflammatory effect of sustained STAT3 activation through IL-6R ligands 10 . Regardless of that finding, our results have indicated that the enhanced expression of SOCS3 did not contribute to the anti-inflammatory effect of nAChR activation, as blockade of SOCS3 expression did not prevent the anti-inflammatory action of nicotine. Hence, the anti-inflammatory effect of cholinergic activation in macrophages rests mainly on enhanced STAT3 rather than SOCS3 activation. We have shown that STAT3 was activated by nicotine directly and that involvement of enhanced signaling via IL-10R here was unlikely, as we found the macrophage deactivation induced by stimulation of the vagus nerve to be similarly effective in IL-10-deficient mice. Moreover, nicotine-induced STAT3 activation could be prevented by nAChR blockers. Our observations suggest that the molecular route exerting the anti-inflammatory effect of nAChR activation mimics the signaling pathway of IL-10R without the requirement of IL-10 itself. That hypothesis is supported by our finding and those of another study 2 that, consistent with the action of IL-10 (ref. 31), nicotine does not alter TNF mRNA expression but decreases the release of TNF protein. Furthermore, LysM-Stat3 fl/- mice have a phenotype resembling that of IL-10-deficient mice 6 . Nicotine-induced inhibition of the release of high-mobility group box 1 in mouse RAW264.7 macrophages is associated with inhibition of NF-ĸB p65 transcriptional activity 3 . Our finding that nicotine repressed macrophage activity via STAT3 may very well explain that observation, as IL-10−STAT3 (ref. 28) signaling blocks NF-ĸB DNA-binding 32, 33 , possibly through direct interaction of dimerized STAT3 with the p65 subunit 34 . We have shown here that recruitment of inflammatory infiltrates induced by bowel manipulation and the resulting symptoms of postoperative ileus were reduced substantially by stimulation of the vagus nerve. Our results have shown strict cholinergic control of macrophage activation in vivo, which may be substantiated by the observation that cholinergic (vesicular acetylcholine transporter−positive) nerve fibers are situated in close proximity to resident macrophages in intestinal myenteric 58
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 and 50: Chapter 3 reports 2 . We next incub
Page 51 and 52: Chapter 3 Figure 5. Perioperative e
Page 53: Chapter 3 Figure 7. Stimulation of
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
Page 103 and 104: Nederlandse samenvatting
Page 105 and 106:
Chapter 7 van STAT3 in de ‘cholin
Page 107 and 108:
Chapter 7 De bevinding dat nicotine
Page 109 and 110:
Chapter 7 macrofagen aan te tonen (
Page 111 and 112:
Chapter 7 18. Yu Z, Zhang W, Kone B
Page 113 and 114:
Shizuo Akira Department of Host Def
Page 115 and 116:
List of publications
Page 117 and 118:
Dankwoord
Page 119 and 120:
om de ene keer olijfolie te drinken
Page 121:
Curriculum Vitae Curriculum Vitae E
show all

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

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?