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Posts Tagged ‘sepsis’

19 July 2011 Role of the Vagus Nerve at the Neural-Immune Interface

Friday, 20 August 2010
K Ondicova & B Mravec
Ja Teline

timthumbEvidence 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 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.’, ‘


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 of immune 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 term cholinergic 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.

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 in inflammation-affected tissues. The motor arm of this reflex consists of the efferent vagal pathways that constitute the cholinergic anti-inflammatory pathway (Fig. 1).


Fig. 1 | Inflammatory reflex of the vagus nerve
Infection or injury induces production of cytokines by immune cells. Stimulation of paraganglia cells by tissue or circulating cytokines leads to activation of afferent vagal pathways. Immune-related signals are transmitted to the nucleus of the solitary tract (NTS). Consequently, the activated dorsal motor nucleus of the vagus may inhibit immune cell activity either directly or indirectly by activation of sympathetic postganglionic neurons innervating the spleen.

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 tissues from 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 of ischemia-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 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 have wide 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 spleen indirectly 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 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 immune functions; 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.


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.

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.


K Ondicova // Institute of Pathophysiology, Faculty of Medicine, Comenius University, 811 08 Bratislava
B Mravec // Institute of Experimental Endocrinology, Slovak Academy of Sciences, 833 06 Bratislava, Slovak Republic

Nonstandard Abbreviations: alpha7nAChR, alpha7 subtype acetylcholine receptors; HMGB1, high-mobility group box 1; IL, interleukin; LPS, lipopolysaccharide; TNF-alpha, tumor necrosis factor alpha


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1 June 2011 Vagus Nerve Connects Your Brain and Immune System

By Jody Smith
June 1, 2011

The brain is directly tied in with the immune system, transmitting messages that controls the inflammatory response in regards to infection, to sepsis and to autoimmune diseases. In 2007, this revelation turned the scientific understanding of the time on its head.

Dr. Kevin Tracey is director and chief executive of The Feinstein Institute for Medical Research. His laboratory was the site of research concerning the vagus nerve and its role in the body’s inflammatory response and disease.

He spoke on their findings at the 2007 Stetten Lecture at the National Institutes of Health in Bethesda, MD.

The hope that sprang from this research was that it would be possible to corral natural healing defenses and reduce sepsis before it does too much damage. Sepsis is the end result when the body unleashes its immune response upon systemic infection. This sepsis can be too efficient for the individual’s good, all too often leading to death.

Tracey has learned that the vagus nerve uses a neurochemical called acetylcholine, to be in direct communication with the immune system. Stimulation of the vagus nerve tells the immune system not to issue forth toxic inflammatory markers.

In 2009, Tracey again presented new findings at the American College of Rheumatology/ Association of Rheumatology Health Professionals (ACR/ARHP) Annual Scientific Meeting in Philadelphia, PA.

It had been previously known that the nervous system is activated by inflammatory mediators via the bloodstream, and through the blood-brain barrier, or by the production of cytokines in the brain. According to an article published in the May 2010 issue of The Rheumatologist, it has now been learned that inflammatory mediators can use the vagus nerve to activate the nervous system.

Dr. Gary Firestein is a professor of medicine, and chief of rheumatology, allergy and immunology, as well as dean of translational medicine at the University of California, San Diego. Research performed by Firestein and his team had shown that the central nervous system senses peripheral inflammation, triggering a series of events that ultimately affects the body’s inflammatory responses.

Tracey and Firestein have been working together to puzzle out more about the connection between the central nervous system and the immune system.

Paul-Peter Tak, MD, PhD, of the Academic Medical Center at the University of Amsterdam, The Netherlands, added his voice and experience as he spoke at the ACR/ARHP meeting. The consensus is that the autonomic nervous system is involved in the regulation of immune responses to inflammatory stimuli.

According to the three researchers, the immune system should no longer be viewed as an island, but rather as an actively involved partner with the central nervous system, in dealing with inflammatory stimuli.

It is possible that therapies for rheumatoid arthritis and other autoimmune diseases may evolve from this new light on the vagus nerve and its greater circle of communication and influence within the body.

19 November 2010 New understanding of vagus nerve’s role in regulating inflammation




It used to be dogma that the brain was shut away from the actions of the immune system, shielded from the outside forces of nature.

But that’s not how it is at all. In fact, thanks to the scientific detective work of Kevin Tracey, MD, it turns out that the brain talks directly to the immune system, sending commands that control the body’s inflammatory response to infection and autoimmune diseases.

Understanding the intimate relationship is leading to a novel way to treat diseases triggered by a dangerous inflammatory response.

Dr. Tracey, director and chief executive of The Feinstein Institute for Medical Research, will be giving the 2007 Stetten Lecture on Wednesday, Oct. 24, at the National Institutes of Health in Bethesda, MD. His talk – Physiology and Immunology of the Cholinergic Anti-inflammatory Pathway – will highlight the discoveries made in his laboratory and the clinical trials underway to test the theory that stimulation of the vagus nerve could block a rogue inflammatory response and treat a number of diseases, including life-threatening sepsis.

With this new understanding of the vagus nerve’s role in regulating inflammation, scientists believe that they can tap into the body’s natural healing defenses and calm the sepsis storm before it wipes out its victims. Each year, 750,000 people in the United States develop severe sepsis, and 215,000 will die no matter how hard doctors fight to save them. Sepsis is triggered by the body’s own overpowering immune response to a systemic infection, and hospitals are the battlegrounds for these potentially lethal conditions.

The vagus nerve is located in the brainstem and snakes down from the brain to the heart and on through to the abdomen. Dr. Tracey and others are now studying ways of altering the brain’s response or targeting the immune system itself as a way to control diseases.

Dr. Tracey is a neurosurgeon who came into research through the back door of the operating room. More than two decades ago, he was treating a young girl whose body had been accidentally scorched by boiling water and she was fighting for her life to overcome sepsis. She didn’t make it. Dr. Tracey headed into the laboratory to figure out why the body makes its own cells that can do fatal damage. Dr. Tracey discovered that the vagus nerve speaks directly to the immune system through a neurochemical called acetylcholine. And stimulating the vagus nerve sent commands to the immune system to stop pumping out toxic inflammatory markers. “This was so surprising to us,” said Dr. Tracey, who immediately saw the potential to use vagus stimulation as a way to shut off abnormal immune system responses. He calls this network “the inflammatory reflex.”

Research is now underway to see whether tweaking the brain’s acetylcholine system could be a natural way to control the inflammatory response. Inflammation is key to many diseases – from autoimmune conditions like Crohn’s disease and rheumatoid arthritis to Alzheimer’s, where scientists have identified a strong inflammatory component.

Dr. Tracey has presented his work to the Dalai Lama, who has shown a great interest in the neurosciences and the mind-body connection. He has also written a book called Fatal Sequence, about the double-edge sword of the immune system.

19 November 2010 Inflammation: A nervous connection

Claude Libert

Clockwise from lower right: many bacteria contain lipopolysaccharide in their cell walls, which stimulates macrophages. These immune cells then make and release various cytokine ('alarm') molecules, including tumour-necrosis factor (TNF) and interleukin-1. But too much TNF in the blood can be harmful, leading to excessive inflammation and septic shock. Several drugs (orange boxes) inhibit steps in TNF synthesis. In addition, Tracey and colleagues have found that when the vagus nerve detects interleukin-1 (left), it releases acetylcholine (right), which binds to the alpha7 receptor2 on macrophages and inhibits cytokine production. This suggests possible new ways of controlling inflammation: through electrically stimulating the vagus nerve, by acupuncture, or with the use of nicotine (which mimics acetylcholine).

The molecular details of a connection between the nervous system and the inflammatory response to disease have been uncovered. This suggests new avenues of research into controlling excessive inflammation.

Sepsis is a complex, exaggerated and chaotic version of the usually well-organized inflammatory arm of our immune defences, and kills over 175,000 people each year in the United States alone1. Although a great deal of time and effort has been spent researching septic shock, it remains difficult to understand and treat. One promising lead was provided two years ago, when it was discovered that there is a connection between inflammation and the involuntary nervous system. The details of this link have, however, been unclear — until now. Writing on page 384 of this issue, Kevin Tracey and colleagues2 describe how they identified a receptor protein that is stimulated by the nervous system and which in turn inhibits a key molecular mediator of inflammation and septic shock. This receptor might make a good target for future drugs to treat sepsis.

Inflammation has several roles in the body, one of which is to contribute to the immune system’s ability to fight off intruding microorganisms. For instance, molecules that are produced during the inflammatory response increase blood flow to infected areas, or help to recruit immune cells. One way in which inflammation is triggered is in response to lipopolysaccharides — components of the cell walls of many bacteria — which activate the immune system’s macrophages. These cells in turn release ‘alarm’ molecules, namely cytokines, some of which have powerful pro-inflammatory properties. Tumour-necrosis factor (TNF) is one such molecule. This protein can affect nearly all cell types, and has a range of biological activities. For instance, it induces the expression of a large number of genes that encode essential inflammatory molecules (such as other cytokines; enzymes that help to break down the barriers between cells, allowing the migration of immune cells; and adhesion molecules that again enhance immune-cell migration)3, 4.

As long as TNF production remains confined to the site of infection, the inflammatory response is clearly beneficial. But once bacteria, and consequently TNF, invade the systemic blood circulation, blood ‘poisoning’ and sepsis can develop quickly. Furthermore, TNF has been found to be a central mediator of chronic inflammatory disorders such as rheumatoid arthritis and Crohn’s disease. So there is much interest in learning how to control the production, release and activity of TNF. Several means of doing so have been developed (Fig. 1), and have seen some success in treating certain inflammatory disorders5. For instance, there are drugs that inhibit the transcription of the TNF-encoding gene into messenger RNA, the translation of the mRNA into protein, or the release of the TNF protein. There are also antibodies and soluble receptors that bind to and block TNF once it has been released. But, although the value of these approaches is beyond doubt, they all take time to work — and time is usually short when treating patients with sepsis.

Tracey’s research team has been studying TNF since this protein was discovered (see, for instance, ref. 6). Recently, Tracey’s group described another level of control of TNF synthesis — namely by means of the vagus nerve7 — thereby providing a new and exciting link between the involuntary nervous system and inflammation. This ‘parasympathetic’ nerve emanates from the cranium and innervates all major organs in a subconscious way. It is finely branched and is composed of both sensory (input) and motor (output) fibres. This is of relevance because it means that the vagus nerve can on the one hand sense continuing inflammation (presumably by detecting cytokines through receptors on the nerve surface), and on the other hand suppress it. This suppression is efficient and, above all, a good deal faster than the mechanisms mentioned above. Tracey’s group found7 that, after injecting lipopolysaccharides into rats, electrically stimulating the vagus nerve prevented both the release of TNF from macrophages, and death. Conversely, surgically severing the nerve not only removed this protection but also sensitized the animals to lipopolysaccharide.

But how does the vagus nerve have this effect on macrophages? It was already known that, after this nerve is stimulated, its endings release the neurotransmitter molecule acetylcholine with lightning speed. Macrophages express acetylcholine receptors known as nicotinic receptors, and respond to the released acetylcholine (or the acetylcholine-mimicking nicotine) by suppressing TNF release. But the precise identity of the nicotinic receptors on macrophages was not known. From a therapeutic point of view, this is clearly important to know. It’s also very difficult to find out, as the receptors are pentamers containing different combinations of a possible 16 monomers.

In their latest paper, Tracey and colleagues2 pin down the relevant nicotinic acetylcholine receptor: it is one comprising five copies of the monomer alpha7. They started by using alpha-bungarotoxin, a molecule that binds to just a subset of receptor monomers, to show that macrophages express the alpha7 subunit. When the authors blocked the expression of this protein, acetylcholine and nicotine were no longer able to prevent the release of TNF — data that the authors confirmed by studying alpha7-deficient mice. In fact, such mutant mice displayed an exaggerated response to lipopolysaccharide in terms of their production of the cytokines TNF, interleukin-1 and interleukin-6. Finally, in a technical tour de force, Tracey and colleagues showed that electrically stimulating the vagus nerve of alpha7-deficient mice no longer afforded protection against lipopolysaccharide (in contrast to the situation in wild-type mice).

These findings2 could have therapeutic implications. The discovery of the connection between the involuntary nervous system and inflammation had already yielded new ideas about treating inflammatory disorders such as sepsis: for instance, a small compound has been developed that can trigger the vagus nerve in rats, thereby reducing inflammation8. Looking to the future, it would be interesting to stimulate the vagus nerve electrically in people — as is currently done in thousands of epilepsy patients, showing that the procedure is safe and feasible — and to study the effect on inflammation. More specifically, the new findings suggest that molecules that stimulate the alpha7 subunit would also be worth developing.

On a different note, nicotine has been found to have powerful immunosuppressive and inflammation-suppressing effects. Of course, the health risks associated with smoking are immense. Yet epidemiological studies indicate that nicotine protects against several inflammatory diseases, such as ulcerative colitis, Parkinson’s disease and even Alzheimer’s disease. It can also reduce fever and protect against otherwise lethal infection with the influenza virus9. The demonstration2 that nicotine binds to the alpha7 subunit on macrophages fleshes out the details of how nicotine produces such effects.

The data also make me reconsider the possibilities and molecular biology of ‘alternative’ medicine. Pavlovian-type conditioning, hypnosis and meditation are well known (since the beginning of the twentieth century in some cases) to reduce inflammation10. It might be worth finding out whether these effects, as well as the reported beneficial effects of prayer and acupuncture on inflammation (the last of which is known to depend on acetylcholine)11, 12, are mediated by the vagus nerve and the alpha7 subunit.


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