Modulatory effects of vagal stimulation on neurophysiological parameters and the cellular immune response in the rat brain during systemic inflammation

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Abstract

Background

Stimulation of the vagus nerve has modulating, anti-inflammatory effects on the cellular immune response in the blood and the spleen, stabilizing brain function. Here, we aimed to investigate its potential effects on immune-to-brain communication focusing on neurophysiological readouts and leukocyte migration to the brain during severe sepsis-like endotoxemia.

Methods

Systemic inflammation was induced by intravenous administration of lipopolysaccharide (LPS; 5 mg/kg). Animals received either no manipulation of the vagus nerve, vagotomy, or vagotomy plus vagus nerve stimulation of the distal trunk. Somatosensory evoked potentials and evoked flow velocity response were measured for 4.5 h as indicators of brain function and neurovascular coupling, respectively. In addition, brain areas with (cortex) and without (hypothalamus) tight blood-brain barrier were studied separately using immunohistochemistry and RT-PCR. Moreover, plasma cytokine and leptin levels were analyzed by ELISA.

Results

LPS induced a decline of both neurophysiological parameters, which was prevented by vagus nerve stimulation. As for peripheral organs, LPS-stimulated neutrophil counts increased in the brain and colocalized in the brain with endothelial intercellular adhesion molecule (ICAM)-1. Interestingly, vagal stimulation reduced this colocalization and decreased nuclear translocation of the brain cell activation marker nuclear factor interleukin 6 (NF-IL6). Furthermore, it reduced the gene expression of inflammatory markers and extravasation signals (IL-6, CXCL-1, ICAM-1) in the hypothalamus but not the cortex linked to a moderate decrease in circulating cytokine levels (interleukin 6, tumor necrosis factor alpha) as well as lower plasma leptin concentration.

Conclusions

Our data suggest beneficial effects of anti-inflammatory vagus nerve stimulation on brain function by reducing the interaction of neurotrophil granulocytes with the brain endothelium as well as attenuating inflammatory responses in brain areas lacking a blood-brain barrier.

Electronic supplementary material

The online version of this article (doi:10.1186/s40635-016-0091-4) contains supplementary material, which is available to authorized users.

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Most cited references 37

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The cholinergic anti-inflammatory pathway: a critical review.

D Martelli, N M McKinley, D Martelli … (2014)

From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-α production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia. Copyright © 2014 Elsevier B.V. All rights reserved.

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MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines

Yang Sun, Qi-Wei Li, Huan Gui … (2013)

The vagus nerve can control inflammatory response through a 'cholinergic anti-inflammatory pathway', which is mediated by the α7-nicotinic acetylcholine receptor (α7nAChR) on macrophages. However, the intracellular mechanisms that link α7nAChR activation and pro-inflammatory cytokine production remain not well understood. In this study, we found that miR-124 is upregulated by cholinergic agonists in LPS-exposed cells and mice. Utilizing miR-124 mimic and siRNA knockdown, we demonstrated that miR-124 is a critical mediator for the cholinergic anti-inflammatory action. Furthermore, our data indicated that miR-124 modulates LPS-induced cytokine production by targeting signal transducer and activator of transcription 3 (STAT3) to decrease IL-6 production and TNF-α converting enzyme (TACE) to reduce TNF-α release. These results also indicate that miR-124 is a potential therapeutic target for the treatment of inflammatory diseases.

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Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7.

E Takada, K Nara, M Kurokawa … (2006)

Macrophages/monocytes and the proinflammatory mediators, such as tumour necrosis factor (TNF)-alpha, prostaglandin E(2) (PGE(2)), macrophage inflammatory protein (MIP)-1alpha and MIP-1alpha, play a critical role in the progression of immunological disorders including rheumatoid arthritis, Behçet's disease and Crohn's disease. In addition, the nicotinic acetylcholine receptor-alpha7 (alpha7nAChR) subunit is an essential regulator of inflammation. In this study, we evaluated the expression of the alpha7nAChR subunit on human peripheral monocytes and the effect of nicotine on the production of these proinflammatory mediators by activated monocytes. Fluorescein isothiocyanate (FITC)-labelled alpha-bungarotoxin demonstrated the cell surface expression of the alpha7nAchR subunit. Pretreatment with low-dose nicotine caused inhibition of TNF-alpha, PGE(2), MIP-1alpha and MIP-1alpha production, and mRNA expression of TNF-alpha, MIP-1alpha and MIP-1alpha and COX-2 in lipopolysaccharide (LPS)-activated monocytes. These suppressive effects of nicotine were caused at the transcriptional level and were mediated through alpha7nAChR. Nicotine suppressed the phosphorylation of I-kappaB, and then inhibited the transcriptional activity of nuclear factor-kappaB. These immunosuppressive effects of nicotine may contribute to the regulation of some immune diseases.

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Author and article information

Contributors

Hanna Schweighöfer: Hanna.Schweighoefer@vetmed.uni-giessen.de

Christoph Rummel: Christoph.D.Rummel@vetmed.uni-giessen.de

Joachim Roth: Joachim.Roth@vetmed.uni-giessen.de

Bernhard Rosengarten: 0049 (641) 985 45445 , Bernhard.Rosengarten@neuro.med.uni-giessen.de

Journal

Journal ID (nlm-ta): Intensive Care Med Exp

Journal ID (iso-abbrev): Intensive Care Med Exp

Title: Intensive Care Medicine Experimental

Publisher: Springer International Publishing (Cham )

ISSN (Electronic): 2197-425X

Publication date (Electronic): 29 June 2016

Publication date PMC-release: 29 June 2016

Publication date Collection: December 2016

Volume: 4

Electronic Location Identifier: 19

Affiliations

[ ]Department of Neurology, Justus-Liebig-University Giessen, Klinikstr. 33, 35392 Giessen, Germany

[ ]Institute of Veterinary Physiology and Biochemistry, Justus-Liebig-University Giessen, 35392 Giessen, Germany

Article

Publisher ID: 91

DOI: 10.1186/s40635-016-0091-4

PMC ID: 4927529

PubMed ID: 27357828

SO-VID: 1d6ad942-2619-4d1c-bfc5-25e7806ba9e0

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

History

Date received : 26 February 2016

Date accepted : 19 June 2016

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;

Award ID: RU 1397/2-1

Award Recipient : Christoph Rummel

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Keywords: sepsis,neurovascular coupling,immune-to-brain signaling,vagus nerve stimulation,nuclear factor kappa b,nuclear factor interleukin 6,cytokines,leptin,prostaglandins

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Keywords: sepsis, neurovascular coupling, immune-to-brain signaling, vagus nerve stimulation, nuclear factor kappa b, nuclear factor interleukin 6, cytokines, leptin, prostaglandins

Modulatory effects of vagal stimulation on neurophysiological parameters and the cellular immune response in the rat brain during systemic inflammation

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HLA-G and immune tolerance in pregnancy

Most cited references 37

The cholinergic anti-inflammatory pathway: a critical review.

MicroRNA-124 mediates the cholinergic anti-inflammatory action through inhibiting the production of pro-inflammatory cytokines

Nicotine inhibits the production of proinflammatory mediators in human monocytes by suppression of I-kappaB phosphorylation and nuclear factor-kappaB transcriptional activity through nicotinic acetylcholine receptor alpha7.

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