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

Abstract

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 the VN. 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 α-7-nicotinic ACh receptors of those macrophages to inhibit the release of tumour necrosis (TNF)α, 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 β2 adrenergic receptor of splenic lymphocytes that release ACh. Finally, ACh inhibits the release of TNFα by spleen macrophages through α-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 TNFα-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.

Figure 1. Schematic diagram showing the central autonomic network modulation of visceral activity

An autonomic vagovagal loop includes visceral inputs to the nucleus of the solitary tract (NTS) that sends outputs to the dorsal motor nucleus (DMN), to the rostral ventrolateral medullary (RVLM) and to the intermediate lateral medulla (ILM) to adapt the balance between the sympathetic and parasympathetic activities to body constraints. This autonomic forebrain loop is modulated by a forebrain autonomic loop, through cross‐talk between the NTS and brain areas (hypothalamus, amygdala, cingulate cortex, insula, prefrontal cortex) that are also involved in neuroendocrine, emotional and cognitive controls of behaviour. Figure adapted from Thayer & Lane (2009).

Figure 2. The functional anatomy of the inflammatory reflex (according to Pavlov & Tracey, 2015 )

AChE, acetylcholinesterase; AP, area postrema; DMN, dorsal motor nucleus of the vagus nerve; LPS, lipopolysaccharide (endotoxin); mAChR, muscarinic acetylcholine receptor; NA, nucleus ambiguus; NLRs, nucleotide‐binding oligomerization domain‐like receptors; NTS, nucleus tractus solitarii; TLR4, Toll‐like receptor 4.