Abstract
The recent insight that the immune system is innervated has initiated a search for neural reflex circuits suitable for therapeutic targeting in human inflammatory diseases. The inflammatory reflex, signaling along the vagus system to maintain immune system homeostasis, is the best characterized such circuit. Proinflammatory molecules, extracellularly released during infectious or sterile injury, are sensed by afferent vagal nerves that transmit this information to the nucleus of tractus solitarius in the brainstem. The afferent signals generate efferent action potentials that travel from the brainstem via efferent vagal nerves to the spleen and other organs. This culminates in T cell release of acetylcholine, which interacts with α7 nicotinic acetylcholine receptors on immunocompetent cells to inhibit proinflammatory cytokine release. These mobile anti-inflammatory T lymphocytes thus operate both inside and outside compartments innervated by the vagus system. Therapeutic proof-of-concept anti-inflammatory studies following surgical implantation of electrical vagus nerve stimulators were first conducted in rheumatoid arthritis and Crohn´s disease. Long term use of these devices was uneventful, while the initial surgical procedure caused adverse effects in some patients. The auricular branch of the vagus nerve reaches superficial parts in the concha and tragus in both ears, enabling transcutaneous electrical auricular vagus nerve stimulation (taVNS) as a safer therapeutic alternative. Invasive VNS and taVNS activate similar parts of the central nervous system indicated by functional imaging methods. Pilot taVNS studies in patients with inflammatory diseases have so far been conducted to treat rheumatoid arthritis, osteoarthritis, lupus, pediatric inflammatory bowel diseases, and pediatric nephrotic syndromes.