Anti-inflammatory properties of the vagus nerve: potential therapeutic implications of vagus nerve stimulation

Brain and viscera interplay within the autonomic nervous system where the vagus nerve (VN), containing approximately 80% afferent and 20% efferent fibres, plays multiple key roles in the homeostatic regulations of visceral functions. Recent data have suggested the anti-inflammatory role of theVN. This vagal function is mediated through several pathways, some of them still debated. The first one is the anti-inflammatory hypothalamic-pituitary-adrenal axis which is stimulated by vagal afferent fibres and leads to the release of cortisol by the adrenal glands. The second one, called the cholinergic anti-inflammatory pathway, is mediated through vagal efferent fibres that synapse onto enteric neurons which release acetylcholine (ACh) at the synaptic junction with macrophages. ACh binds to alpha-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)alpha, a pro-inflammatory cytokine. The last pathway is the splenic sympathetic anti-inflammatory pathway, where the VN stimulates the splenic sympathetic nerve. Norepinephrine (noradrenaline) released at the distal end of the splenic nerve links to the beta 2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNF alpha by spleen macrophages through alpha-7-nicotinic ACh receptors. Understanding of these pathways is interesting from a therapeutic point of view, since they could be targeted in various ways to stimulate anti-inflammatory regulation in TNF alpha-related diseases such as inflammatory bowel disease and rheumatoid arthritis. Among others, VN stimulation, either as an invasive or non-invasive procedure, is becoming increasingly frequent and several clinical trials are ongoing to evaluate the potential effectiveness of this therapy to alleviate chronic inflammation.