Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion

Bernik, Thomas R.; Friedman, Steven G.; Ochani, Mahendar; DiRaimo, Robert; Susarla, Srinivas M.; Czura, Christopher J.; Tracey, Kevin J.

doi:10.1067/mva.2002.129643

Cited by 211 publications

(156 citation statements)

References 11 publications

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“…This peripheral vagus nerve stimulation (VNS) in the vagotomized animals was not followed by enhanced glucocorticoid production, indicating that the suppressed TNF-α production could not be attributed to activation of the HPA axis, but was achieved merely through the efferent vagus nerve (58). This has been confirmed in subsequent studies, where VNS significantly attenuated TNF-α synthesis and improved clinical outcome in experimental models of hemorrhagic shock (59,60) and ischemia-reperfusion injury (59,60), and blocked leukocyte migration by inhibiting endothelial cell activation, a key regulator of leukocyte trafficking during inflammation, in the carrageenan air pouch rat model (61). This antiinflammatory influence of the efferent vagus nerve is now well known as the cholinergic antiinflammatory pathway (62).…”

Section: Role Of Vagus Nerve: Cholinergic Antiinflammatory Pathwaysupporting

confidence: 64%

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

Koopman

Stoof

Straub

et al. 2011

Mol Med

128

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The immunomodulatory effect of the autonomic nervous system has raised considerable interest over the last decades. Studying the influence on the immune system and the role in inflammation of the sympathetic as well as the parasympathetic nervous system not only will increase our understanding of the mechanism of disease, but also could lead to the identification of potential new therapeutic targets for chronic immune-mediated inflammatory diseases, such as rheumatoid arthritis (RA). An imbalanced autonomic nervous system, with a reduced parasympathetic and increased sympathetic tone, has been a consistent finding in RA patients. Studies in animal models of arthritis have shown that influencing the sympathetic (via α-and β-adrenergic receptors) and the parasympathetic (via the nicotinic acetylcholine receptor α7nAChR or by electrically stimulating the vagus nerve) nervous system can have a beneficial effect on inflammation markers and arthritis. The immunosuppressive effect of the parasympathetic nervous system appears less ambiguous than the immunomodulatory effect of the sympathetic nervous system, where activation can lead to increased or decreased inflammation depending on timing, doses and kind of adrenergic agent used. In this review we will discuss the current knowledge of the role of both the sympathetic (SNS) and parasympathetic nervous system (PNS) in inflammation with a special focus on the role in RA. In addition, potential antirheumatic strategies that could be developed by targeting these autonomic pathways are discussed.

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Section: Role Of Vagus Nerve: Cholinergic Antiinflammatory Pathwaysupporting

confidence: 64%

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

Koopman

Stoof

Straub

et al. 2011

Mol Med

128

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“…In our study, contrary to expectations, the cardiac levels of TNF-␣ and IL-1␤ during MI were reduced after vagotomy. This observation suggests the hypothesis that myocardial cytokine synthesis induced by tissue injury or mechanical stress within the heart itself might be regulated differently than myocardial cytokine synthesis induced by external stressors, the setting in which vagal efferent modulation of cytokines has been demonstrated (6,7).…”

Section: Discussionmentioning

confidence: 90%

Neural regulation of the proinflammatory cytokine response to acute myocardial infarction

Francis

Zhang

Weiß

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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Neural regulation of the proinflammatory cytokine response to acute myocardial infarction. Am J Physiol Heart Circ Physiol 287: H791-H797, 2004; 10.1152/ajpheart.00099.2004.-Within minutes of acute myocardial infarction (MI), proinflammatory cytokines increase in the brain, heart, and plasma. We hypothesized that cardiac afferent nerves stimulated by myocardial injury signal the brain to increase central cytokines. Urethane-anesthetized male Sprague-Dawley rats underwent ligation of the left anterior descending coronary artery (LAD) or sham LAD ligation after bilateral cervical vagotomy, sham vagotomy, or application of a 10% phenol solution to the epicardial surface of the myocardium at risk. MI caused a significant increase in tumor necrosis factor (TNF)-␣ and interleukin (IL)-1␤ in the plasma and heart, which was blunted by vagotomy. MI also caused a significant increase in hypothalamic TNF-␣ and IL-1␤, which was not affected by vagotomy. In contrast, epicardial phenol blocked MI-induced increases in hypothalamic TNF-␣ and IL-1␤ without affecting increases in the plasma and heart. These findings demonstrate that the appearance of proinflammatory cytokines in the brain after MI is independent of blood-borne cytokines and suggest that cardiac sympathetic afferent nerves activated by myocardial ischemia signal the brain to increase cytokine production. In addition, an intact vagus nerve is required for the full expression of proinflammatory cytokines in the injured myocardium and in the circulation. We conclude that the sympathetic and parasympathetic innervation of the heart both contribute to the acute proinflammatory response to MI. cardiac sympathetic afferents; cardiac vagal afferents; tumor necrosis factor-␣; interleukin-1␤; hypothalamus

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“…This pathway is controlled by brain muscarinic networks that depend on an intact vagus nerve to attenuate systemic cytokine production (5). Activation of the cholinergic antiinflammatory pathway, either by electrical stimulation of the vagus nerve or through pharmacological approaches, has been shown to significantly ameliorate cytokine-mediated disease models, including endotoxemia (2,6), sepsis (6,7), colitis (8), pancreatitis (9), and ischemia reperfusion (10,11).…”

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confidence: 99%

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

Rosas-Ballina¹,

Ochani²,

Parrish³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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619

569

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The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit ␣7, a mechanism termed ''the cholinergic antiinflammatory pathway.'' Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of ␣7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiacsuperior mesenteric plexus, and projecting in the splenic nerve.brain ͉ cytokine ͉ innate ͉ spleen ͉ vagus T he autonomic nervous system is divided into two major branches based on anatomy and function. These divisions, sympathetic and parasympathetic, control organ function through a set of two serially connected neurons, the first of which is located in the CNS and the second in the peripheral ganglia. Typically, parasympathetic neurons originate in the brainstem medulla and sacral portion of the spinal cord, and the ganglia are located close to or within the innervated organ. Sympathetic neurons originate in the thoracic and lumbar portion of the spinal cord, and the ganglia are situated close to the spinal cord.

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Cholinergic antiinflammatory pathway inhibition of tumor necrosis factor during ischemia reperfusion

Abstract: VNS significantly attenuates TNF synthesis and shock during reperfusion injury in a standard model of aortic occlusion. Clinical evaluation of VNS for this condition may be warranted.

Cited by 211 publications

References 11 publications

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

Restoring the Balance of the Autonomic Nervous System as an Innovative Approach to the Treatment of Rheumatoid Arthritis

Neural regulation of the proinflammatory cytokine response to acute myocardial infarction

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia

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