The pulse of inflammation: heart rate variability, the cholinergic anti-inflammatory pathway and implications for therapy

Abstract

Biological therapeutics targeting TNF, IL-1 and IL-6 are widely used for treatment of rheumatoid arthritis, inflammatory bowel disease and a growing list of other syndromes, often with remarkable success. Now advances in neuroscience have collided with this therapeutic approach, perhaps rendering possible the development of nerve stimulators to inhibit cytokines. Action potentials transmitted in the vagus nerve culminate in the release of acetylcholine that blocks cytokine production by cells expressing acetylcholine receptors. The molecular mechanism of this cholinergic anti-inflammatory pathway is attributable to signal transduction by the nicotinic alpha 7 acetylcholine receptor subunit, a regulator of the intracellular signals that control cytokine transcription and translation. Favourable preclinical data support the possibility that nerve stimulators may be added to the future therapeutic armamentarium, possibly replacing some drugs to inhibit cytokines.

Conflict of interest statement

Conflict of interest statement

No conflict of interest was declared

© 2010 The Association for the Publication of the Journal of Internal Medicine.

Figures

Figure 1

Action potentials transiting the vagus nerve synapse in the celiac ganglion, the origin of the splenic nerve. The splenic nerve controls lymphocytes in the spleen, which can produce acetylcholine that interacts with α7 nicotinic acetylcholine receptors expressed on cytokine producing macrophages. Intracellular signal transduction through this receptor inhibits the activity of NFκB to suppress cytokine production. Nerve stimulators can provide an identical signal to initiate the antiinflammatory pathway, an approach that reverse signs and symptoms in preclinical disease models of arthritis, inflammatory bowel disease, ischemia-reperfusion injury, heart failure, pancreatitis, sepsis, and other syndromes.