Cholinergic anti-inflammatory pathway
Since the early 2000s, the cholinergic nervous system has been identified as an important pathway that modifies and controls the inflammatory response. Surgical dissection of the vagus nerve in mice led to enhanced TNF production and excessive response to endotoxin administration, while vagus nerve electrical stimulation inhibits the synthesis of TNF and prevents the acute inflammatory response. Several animal experimental models inducing pro-inflammatory cytokines, such as sepsis, ischemia-reperfusion and pancreatitis have shown that vagus stimulation improves outcomes. This effect is mediated by the nicotinic acetylcholine receptor (nAChR) α7 subunit on macrophages . Mice deficient of the α7 subunit exhibited increased endotoxin-induced TNF production, and electrical vagus innervation failed to reduce serum TNF levels. B-lymphocytes also express α7 nAChRs. Macrophages appear to be very sensitive to acetylcholine, which suggests that any source of acetylcholine, even from non-neuronal sources such as epithelial and endothelial cells, could also modulate the activity of adjacent macrophages. Besides TNF, other pro-inflammatory cytokines are inhibited by acetylcholine, such as high mobility group B1 (HMGB1), IL-1, and IL-6.
Modulation of inflammatory and immune response by the central nervous system (CNS) through the vagus nerve is based on bi-directional communication between the immune and nervous systems. Afferent vagus nerve fibers, located in nucleus tractus solitarius, provide sensory input to the CNS about the inflammatory status that can result in the transmission of efferent signals, originating from the dorsal motor nucleus, to control the inflammatory response. Such a response is rapid and localized, unlike the diffusible anti-inflammatory network, which is slow, distributed, non-integrated and dependent on concentration gradients.
The vagus nerve and the nicotinic anti-inflammatory pathway
The Cholinergic Anti-inflammatory Pathway: A Missing Link in Neuroimmunomodulation