Boris Mravec Role of the Vagus Nerve at the Neural Immune Interface

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Role of the Vagus Nerve at the Neural-Immune Interface

Written by K Ondicova & B Mravec

Friday, 20 August 2010 00:00

Evidence shows that the central nervous system monitors and modulates the activity of both

circulating and tissue immune cells via the neuroendocrine system and autonomic nerves.

Furthermore, findings over the last decade have demonstrated that the vagus nerve represents

an important bi-directional link between the brain and immune system.

Afferent vagal pathways transmit information to the brain related to peripheral inflammation so

as to participate in the activation of adaptive reactions, including fever and sickness behavior.

On the other side, efferent vagal pathways inhibit the synthesis and release of pro-inflammatory

cytokines by peripheral immune cells. Because activation of afferent vagal pathways by immune

stimuli leads to suppression of immune reactions, the term inflammatory reflex was introduced.

The inflammatory reflex adjusts the intensity and duration of inflammatory reactions according

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to actual needs, thus protecting an organism from tissue damage induced by excessive

inflammation. Both experimental and clinical studies suggest that inappropriate activation of the

inflammatory reflex participates in the development of diseases characterized by excessive

production of cytokines.', '

Introduction

Regulation of immune system activity by the central nervous system plays an important role in

both physiological and pathological conditions. This is shown by several studies demonstrating

that the vagus nerve represents one of the key brain structures participating in monitoring

immune system activity. The vagus nerve is involved in the transmission of information from

inflamed peripheral tissues to the brain, and participates in both homeostatic and behavioral

adaptation reactions, including the induction of fever and sickness behavior. Vagal afferent

pathways are activated by immune stimuli either directly or indirectly via vagal paraganglia cells.These paraganglia cells possess receptors for immune signaling molecules (e.g. IL-1) and

transmit signals from immune cells to the afferent vagal pathways. The importance of afferent

vagal pathways in the transmission of immune-related signals is demonstrated by the inhibitory

effect of subdiaphragmatic vagotomy on the development of fever responses induced by

intraperitoneal injection of low doses of IL-1beta [1,2].

Although the role of afferent vagal pathways in the transmission of immune signals to the brain

has been demonstrated over time, the role of efferent vagal pathways in the modulation ofimmune cells activity has only recently been shown. This occurred during the search for a new

compound for the treatment of excessive inflammatory reactions (e.g. sepsis) with the synthesis

of CNI-1493 (tetravalent guanyl-hydrazone). This compound was shown to inhibit the release of

pro-inflammatory cytokines from macrophages, significantly prolonging the survival of animals in

experimental models of sepsis induced by endotoxin [3]. Moreover, it was found that application

of CNI-1493 increased the activity of efferent vagal pathways and that its anti-inflammatory

effects were blocked by vagotomy [4]. Later studies demonstrated that CNI-1493 inhibits both

the synthesis and release of pro-inflammatory cytokines from immune cells through activation of

efferent vagal pathways at the level of central nervous system. Later, this inhibitory effect of the

vagus nerve on immune cells activity was found to be mediated by acetylcholine, and the termcholinergic anti-inflammatory pathway was introduced [5,6].

Inflammatory reflex and cholinergic anti-inflammatory pathway

The synthesis and release of cytokines represents one of the most basic activities during

immune reactions. However, inappropriate cytokine synthesis may stimulate excessive

inflammatory reactions causing damage to peripheral tissues and organs. It is therefore not

surprising that organisms have several mechanisms regulating the intensity of inflammation,

including the inflammatory reflex of the vagus nerve.

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The pathways of the vagus nerve that participate in the monitoring and modulation of immune

reactions in the periphery of an organism make up the sensory arm of the inflammatory reflex.

This “arm” consists of afferent vagal pathways transmitting signals to the brain generated ininflammation-affected tissues. The motor arm of this reflex consists of the efferent vagal

pathways that constitute the cholinergic anti-inflammatory pathway (Fig. 1).

As a result of activating the motor arm, acetylcholine released from vagal nerve endings

potently inhibits the production of cytokines by macrophages, thus protecting peripheral tissuesfrom inflammatory injury [7]. As a result of these observations, it was concluded that the

inflammatory reflex represents a crucial neural mechanism controlling the synthesis and release

of cytokines [5,6].

Either pharmacological or electrical stimulation of efferent vagal pathways significantly inhibits

the release of TNF-alpha in animals given a lethal dose of endotoxin. Furthermore, studies have

shown that stimulation of the efferent pathways of the vagus nerve has beneficial effects such

as inhibiting the development of pathological consequences in animal models ofischemia-reperfusion injury, myocardial ischemia, hemorrhagic shock, shock induced by

occlusion of splanchnic artery, ileus, experimental arthritis, pancreatitis, and burn-induced organ

dysfunction [8-12].

The inhibition of cytokine biosynthesis by the cholinergic anti-inflammatory pathway is caused

by cholinergic neurotransmission acting on alpha7 subtype acetylcholine receptors

(alpha7nAChR) located on macrophages and other cytokine synthesizing cells [13,14]. As

evidence of this, both direct electrical stimulation of the vagus nerve and the application of

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alpha7nAChR agonists inhibit synthesis of TNF-alpha, IL-1beta, IL-6, IL-8, and HMGB1. This

binding of acetylcholine and acetylcholine analogues to the alpha7nAChR of immune cells also

induces a reduction in the nuclear translocation of NF-kappaB, a pro-inflammatory gene

regulatory protein. Furthermore, as other immune cells, including lymphocytes and microglia

express alpha7nAChR, this suggests that the cholinergic anti-inflammatory pathway may havewide effects across various immune cells [14]. This assumption is supported by the finding of

increased proliferation and cytokine secretion by CD4+ T cells in mice that have undergone

subdiaphragmatic vagotomy. Furthermore, administration of nicotine restored the reactivity of

immune cells in these animals, while administration of nicotine receptor antagonists induced an

effect similar to subdiaphragmatic vagotomy. These findings suggest that efferent vagal

pathways modulate a tonic inhibition of macrophage and T cell activity. Regardless of the

whatever else is learned about this system, it can be agreed that the involvement of the vagus

nerve in regulation of immune function is highly complex [15].

The role of the spleen

The spleen plays a key role in the regulation of immune function by the vagus nerve. During

their passage through the spleen, circulating immune cells are exposed to vagus nerve endings

[16]. Moreover, as the spleen is a prominent source of circulating TNF-alpha during

endotoxemia and stimulation of the vagus nerve inhibits endotoxin-induced increases in plasma

TNF-alpha, it is possible that lymphoid compartments of the spleen represent a target for vagal

anti-inflammatory action [17]. However, the role of direct vagal fibers innervating the spleen in

the regulation of inflammation remains questionable. In fact, anatomical and physiological

studies indicate that the vagus nerve modulates the activity of immune cells within the spleenindirectly via activation of sympathetic postganglionic neurons localized in the coeliac ganglia. It

is therefore possible that the vagus nerve modulates immune system activity in the spleen

indirectly through regulation of norepinephrine release from sympathetic nerve endings [18].

The importance of cholinergic anti-inflammatory pathway in human

medicine

The majority of data related to anti-inflammatory effects of the vagus nerve have been obtained

in animal studies. However, several clinical studies on the role of cholinergic anti-inflammatory

pathway in humans were published recently. In one study administration of nicotine before

activation of the immune system by lipopolysaccharide attenuated increases in body

temperature and increased plasma IL-10 and corticosterone levels [19].

Anti-inflammatory effect of the vagus nerve may explain several clinical findings. For example,

increased plasma levels of C reactive protein, IL-6, and TNF-alpha were found in patients with

insulin resistance, diabetes mellitus type 2, hypertension, hyperlipidemia, metabolic syndrome,

and Alzheimer’s disease; all conditions characterized by low-grade inflammation. Interestingly,

increased plasma and tissue activity of butyrylcholinesterase and acetylcholinesterase were

found in these patients. Since increased activation of these enzymes leads to decreased

transmission of cholinergic signals and acetylcholine represents a key molecule in the

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cholinergic anti-inflammatory pathway, increased degradation of acetylcholine may participate in

exaggerated inflammatory reactions [20]. Moreover, the beneficial effects of nicotine treatment

in patients with ulcerative colitis suggests that inappropriate activity of cholinergic

anti-inflammatory pathway may participate in its development as well [18].

Several methods can be used to stimulate the cholinergic anti-inflammatory pathway. For

example, it is possible to activate the afferent and/or efferent arm of inflammatory reflex by

stimulating the cholinergic anti-inflammatory pathway at the central level by administration of

muscarine receptor agonists, ACTH, ghrelin, or centrally acting acetylcholinesterase inhibitors

[5,21,22]. Ingestion of polyunsaturated fatty acids also increases vagal anti-inflammatory activity

[23] and therefore may represent a potent and simple therapeutic method for the treatment of

inflammatory diseases. Moreover, decreased pro-inflammatory immune cell responses were

found in patients with epilepsy treated by electrical stimulation of the vagus nerve [24].

Based on published data it is suggested that activation of cholinergic anti-inflammatory pathway

may represent a useful therapeutic approach. However, exaggerated activation of the

cholinergic anti-inflammatory pathway may excessively suppress immune function, thereby

inducing unfavorable consequences [25]. Therefore, it is necessary to consider two

consequences of activating the cholinergic-anti-inflammatory pathway: 1) inhibition of

inflammation that has beneficial effects during septic or hemorrhagic shock,

ischemia-reperfusion injury, and other situations related to excessive stimulation of immunefunctions; 2) inhibition of immune functions may negatively influence defense mechanisms

against invading pathogens, such as during the early stages of bacterial pancreatitis.

Furthermore, the consequences of activating the cholinergic anti-inflammatory pathway may

depend on not only the pathological situation, but the stage of disease as well. This is seen

during the early stages of inflammatory reaction where induced activation of the cholinergic

anti-inflammatory pathway will produce negative effects; while in later stages it may be

beneficial, protecting organisms from injury induced by excessive inflammatory reaction.

Conclusions

Animal studies have unambiguously shown that the vagus nerve plays an important role in the

regulation of immune reactions in various animal models of inflammatory diseases. While

several studies in humans also indicate the importance of the vagus nerve in the regulation of

immune function, it is necessary to take into consideration the fact that these studies used

mainly ex vivo approaches, using heart rate variability as a marker of cholinergic

anti-inflammatory pathway activity. Therefore, further experimental and clinical studies will be

necessary to elucidate the role of the vagus nerve in the modulation of inflammatory reactions in

humans.

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Acknowledgments

This work was supported by the Slovak Research and Development Agency under the contract

No. APVV-0045-06, VEGA grants (1/0258/10, 1/0260/10, 2/0010/09) and European Regional

Development Fund Research and Development Grant No. NFP26240120024.

Nonstandard Abbreviations: alpha7nAChR, alpha7 subtype acetylcholine receptors;

HMGB1, high-mobility group box 1; IL, interleukin; LPS, lipopolysaccharide; TNF-alpha, tumor

necrosis factor alpha

Author(s) Affiliation

K Ondicova - Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08Bratislava

B Mravec - Institute of Experimental Endocrinology, Slovak Academy of Sciences, 833 06

Bratislava, Slovak Republic

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Boris Mravec Role of the Vagus Nerve at the Neural Immune Interface