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The cholinergic anti-inflammatory pathway

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Abstract

The regulation of the innate immune response is critical for controlling inflammation and for the prevention and treatment of diseases. We recently demonstrated that the efferent vagus nerve inhibits pro-inflammatory cytokine release and protects against systemic inflammation, and termed this vagal function “the cholinergic anti-inflammatory pathway.” The discovery that the innate immune response is regulated partially through this neural pathway provides a new understanding of the mechanisms that control inflammation. In this review, we outline the cholinergic anti-inflammatory pathway and summarize the current insights into the mechanisms of cholinergic modulation of inflammation. We also discuss possible clinical implications of vagus nerve stimulation and cholinergic modalities in the treatment of inflammatory diseases.

Introduction

Inflammatory responses to infection and tissue damage are characterized by the complex interaction between pro- and anti-inflammatory cytokines, and other inflammatory mediators directed toward eradicating invaders and promoting healing. The release of tumor necrosis factor (TNF), interleukin-1β (IL-1β), high mobility group box 1 (HMGB1), and other pro- and anti-inflammatory cytokines from immune cells is regulated partially through autonomic nervous system pathways (Elenkov et al., 2000, Pavlov et al., 2003, Pavlov and Tracey, 2004, Tracey, 2002). The sympathetic division of the autonomic nervous system is associated with a dual mode of regulation of inflammatory responses, as summarized by Hasko and Szabo (1998) and Elenkov et al. (2000). Epinephrine (adrenaline) secreted from the adrenal medulla and norepinephrine (noradrenaline), both secreted from the adrenal medulla and released from sympathetic nerve axons, modulate the release of cytokines and inflammation through α- and β-adrenoceptors on immune cells (Hasko and Szabo, 1998). Afferent vagus nerve fibers convey peripheral inflammatory signals to the brain, which in turn triggers sickness responses (Goehler et al., 2000, Watkins et al., 1995). Recently, we discovered that efferent vagus nerve signals suppress pro-inflammatory cytokine release and inhibit inflammation, and termed this novel vagal function “the cholinergic anti-inflammatory pathway” (Borovikova et al., 2000a). Here, we summarize our recent studies on the cholinergic anti-inflammatory pathway, and its peripheral and central regulation. We also discuss the potential therapeutic implications of the cholinergic anti-inflammatory pathway and cholinergic-based modalities for the treatment of inflammatory diseases.

Section snippets

Parasympathetic regulation of inflammation: the cholinergic anti-inflammatory pathway

TNF is an early cytokine mediator of the local inflammatory response, functioning to control microbial invasion and promote healing processes (Tracey, 2002). An excessive release of TNF causes inflammation, secondary tissue damage, and ultimately the development of lethal shock (Tracey, 2002). TNF synthesis and release are regulated within a critical range to prevent the development of inflammation. Anti-TNF-based therapeutic approaches have been applied successfully to the treatment of

Peripheral and central mechanisms of regulation of systemic inflammation through the cholinergic anti-inflammatory pathway

A critical step towards better characterization and understanding of the cholinergic anti-inflammatory pathway mechanisms was the discovery of the receptor responsible for transmitting the vagus nerve cholinergic signal to TNF producing cells. Two types of receptors mediate the effect of acetylcholine in CNS and periphery: muscarinic (metabotropic) and nicotinic (ionotropic). These two receptor types are subclassified further; the muscarinic, G-protein coupled receptors are five subtypes

The concept of the inflammatory reflex

The bi-directional brain–periphery communication, which occurs through reciprocal autonomic nervous system mechanisms, hormones and humoral factors, is vital for regulating visceral functions and maintaining homeostasis. Neural autonomic reflex mechanisms respond rapidly to fluctuations in cardiovascular, respiratory, and gastrointestinal functions to restore homeostasis. The bi-directional communication between the brain and the immune system plays a critical role in the control of

Therapeutic implications of vagus nerve stimulation and cholinergic modalities

Many experimental and clinical strategies for the treatment of inflammatory diseases are based on targeting pro-inflammatory cytokines. Harnessing the cholinergic anti-inflammatory pathway for the treatment of inflammatory diseases represents an important potential for development of therapies. A better understanding of the role of this unique mechanism in the regulation of inflammation, including its receptor and molecular mechanisms, may contribute to the development of successful therapeutic

Summary and future studies

Our recent studies revealed that the efferent vagus nerve is critically involved in regulating innate immunity and inflammation, in addition to its well-known role as a parasympathetic regulator of vital functions, including heart rate, respiration, and gastrointestinal motility. Electrical vagus nerve stimulation results in lower organ and serum TNF and other pro-inflammatory cytokine levels, and ultimately, attenuation of systemic inflammation. The peripheral component of this novel, efferent

Acknowledgments

The authors thank Jared M. Huston and Margot Gallowitsch Puerta for critically reading the manuscript. This work was supported in part by The North Shore-LIJ GCRC, M01 RR018535, NIGMS, and The Department of Defense (DARPA).

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