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

More documents

Recommendations

Info

The vagus nerve a modulator of intestinal inflammation permeability, resulting in the passage of serum proteins into the lumen, possibly by opening tight junctions and paracellular pathways 37 . On the other hand, other animal studies show that vagus nerve activity can be protective in maintaining gut barrier function under pathological conditions. Hemorrhagic shock results in gut barrier failure leading to translocation of endotoxin and bacteria. Luyer et al demonstrate that administration of high-fat nutrition, leading to the release of CCK inhibits bacterial translocation, reduces disruption of the tight junctions and attenuates TNFα and IL-6 production in hemorrhagic shock rat model 38 . High fat nutrition failed to reduce the inflammatory response in VGX mice 23 , indicating that this effect required CCK-induced activation of the vagus nerve. The observed maintenance of epithelial barrier integrity after vagus nerve stimulation may be a direct effect of cholinergic signaling, or indirect, via the reduced pro-inflammatory cytokine release 39 . Altogether, the epithelial barrier function is affected by cholinergic signaling, presumably via activation of muscarinic receptors expressed on epithelial cells. Differential effects of cholinergic signaling on tight junction integrity are reported. It is important to consider that altered barrier function may not necessarily be indicative of pathophysiology, but could also be a physiologically adaptive response to increase luminal antigen sampling. THE VAGUS NERVE MODULATING THE RESPONSE TO PERITONEAL BACTERIAL INFECTION AND CLEARANCE The function of vagus nerve firing has been well established in models of sterile inflammation, in which vagus nerve stimulation attenuates inflammation by dampening immune cell activation. However, in infectious diseases, such as bacterial peritonitis, or bacterial sepsis, the host defense is a delicate balance between pro-inflammatory pathways aimed at the rapid elimination of bacteria and antiinflammatory responses to prevent systemic inflammation. Therefore, the role of cholinergic modulation of the immune response in microbial infection and bacterial clearance is an important topic of interest. In mice that underwent cecal ligation and puncture (CLP), causing lethal peritonitis induced by a polymicrobial infection, nicotine administration attenuates clinical symptoms of sepsis and improves survival 40 . These effects can be contributed to acute reduction of HMGB-1 and pro-inflammatory cytokines, rather than effects on bacterial outgrowth as mice received nicotine 24hrs after CLP. Moreover, to mimic the clinical scenario, these mice received antibiotics shortly after CLP, obscuring the potential effect of cholinergic signaling on bacterial outgrowth. In a septic peritonitis model induced by ip injection of E.Coli, vagotomy exaggerates, whereas nicotine reduces pro-inflammatory cytokine release, neutrophil influx and liver damage 9 . Interestingly, 23
Chapter 2 nicotine treatment impairs bacterial clearance and significantly enhances mortality during this E.Coli induced peritonitis 9 . In line with this, in vitro studies indicate that nicotine can significantly impair antimicrobial activity of macrophages 41 . In contrast to nicotine, unilateral vagotomy does not affect bacterial outgrowth and survival in E.Coli induced peritonitis 9 . Bilateral vagotomy however, tested in a polymicrobial colon ascendens stent peritonitis model, has no effect on bacterial outgrowth, but does result in significantly increased mortality 42 . Mice that are deficient for the nAChR α7 subunit had enhanced neutrophil recruitment in early infection with E.Coli in comparison to WT mice 43 . These results are in accordance with the anti-inflammatory properties of cholinergic nAChR α7 signaling 12 . However, 20 hrs after infection, nAChR α7 KO mice displayed an accelerated bacterial clearance compared to WT mice 43 . As a result of reduced bacterial loads, α7 nAChR KO mice had reduced numbers of infiltrating neutrophils and lower circulating cytokine levels at that time point 43 . These data suggest that stimulation of cholinergic α7 nAChRs reduces early neutrophil migration to the site of infection, finally resulting in a reduction of bacterial clearance and decreased survival. Although vagus nerve stimulation can reduce excessive inflammation and acute reaction to sepsis, vagus nerve firing and nAChR α7 receptor activation can have a detrimental effect on host defense against bacteria. HOW DOES VAGUS NERVE STIMULATION MODULATE THE IMMUNE RESPONSE IN VIVO? Several lines of evidence indicate that vagus nerve stimulation can inhibit immune cell activation and modulate inflammation via its peripheral release of ACh. Many reports point towards the macrophage nAChR α7 as an essential player in mediating the anti-inflammatory effect of ACh 4,8,12,17,44-47 . Specifically, nicotine exerts antiinflammatory effects on human macrophages that can be counteracted by specific nAChR α7 antagonists or anti-sense oligonucleotides 12 . In addition, nAChR α7 KO mice display enhanced TNF production compared to WT mice in an endotoxemia model, which cannot be counteracted by vagus nerve stimulation 12 . In various animal models of inflammation, nAChR α7 agonists ARR17779 and GTS-21 ameliorate disease 8,17,48 . These data point towards the nAChR α7 as a crucial player in cholinergic modulation of inflammation. However, it remains to be elucidated if ACh released from vagus nerve termini actually reaches the immune cells, and if so, in what quantities. Given the short halflife of ACh, cholinergic modulation of immune cell activation most likely requires close contact. Although macrophages are found in close anatomical apposition to cholinergic fibers in rat small intestine 4 , there is currently no evidence that parasympathetic neurons indeed innervate macrophages. As the vagus nerve 24
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: Chapter 2 THE VAGUS NERVE AND CHOLI
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 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

Create successful ePaper yourself

Delete template?

Save as template?