Physiology and immunology of the cholinergic antiinflammatory pathway
Kevin J. Tracey
Kevin J. Tracey
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Physiology and immunology of the cholinergic antiinflammatory pathway

Abstract

Cytokine production by the immune system contributes importantly to both health and disease. The nervous system, via an inflammatory reflex of the vagus nerve, can inhibit cytokine release and thereby prevent tissue injury and death. The efferent neural signaling pathway is termed the cholinergic antiinflammatory pathway. Cholinergic agonists inhibit cytokine synthesis and protect against cytokine-mediated diseases. Stimulation of the vagus nerve prevents the damaging effects of cytokine release in experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, arthritis, and other inflammatory syndromes. Herein is a review of this physiological, functional anatomical mechanism for neurological regulation of cytokine-dependent disease that begins to define an immunological homunculus.

Authors

Kevin J. Tracey

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Figure 2

Wiring of the cholinergic antiinflammatory pathway, which balances cytokine production.

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Wiring of the cholinergic antiinflammatory pathway, which balances cytok...
Pathogens as well as ischemia and other forms of injury activate cytokine production, which normally restores health. If the cytokine response is unbalanced or excessive, however, then these same mediators can cause disease. Efferent signals from the vagus nerve, which can be controlled by brain networks, inhibit cytokine production via pathways dependent on the α7 subunit of the AChR on macrophages and other cells. Efferent vagus nerve activity also increases instantaneous heart rate variability. A cholinergic brain network that is responsive to M1 agonists can increase the activity of the cholinergic antiinflammatory pathway and also increase instantaneous heart rate variability. Afferent signals carried in the vagus nerve can activate an efferent response that inhibits cytokine release, termed the inflammatory reflex.