The cholinergic anti‐inflammatory pathway revisited

Abstract

Inflammatory bowel disease negatively affects the quality of life of millions of patients around the world. Although the precise etiology of the disease remains elusive, aberrant immune system activation is an underlying cause. As such, therapies that selectively inhibit immune cell activation without broad immunosuppression are desired. Inhibition of immune cell activation preventing pro-inflammatory cytokine production through neural stimulation has emerged as one such treatment. These therapeutics are based on the discovery of the cholinergic anti-inflammatory pathway, a reflex arc that induces efferent vagal nerve signaling to reduce immune cell activation and consequently mortality during septic shock. Despite the success of preclinical and clinical trials, the neural circuitry and mechanisms of action of these immune-regulatory circuits are controversial. At the heart of this controversy is the protective effect of vagal nerve stimulation despite an apparent lack of neuroanatomical connections between the vagus and target organs. Additional studies have further emphasized the importance of sympathetic innervation of these organs, and that alternative neural circuits could be involved in neural regulation of the immune system. Such controversies also extend to the regulation of intestinal inflammation, with the importance of efferent vagus nerve signals in question. Experiments that better characterize these pathways have now been performed by Willemze et al. in this issue of Neurogastroenterology & Motility. These continued efforts will be critical to the development of better neurostimulator based therapeutics for inflammatory bowel disease.

Anti-inflammatory reflex action of splanchnic sympathetic nerves is distributed across abdominal organs

“…Concomitantly, we found that levels of the anti-inflammatory cytokine IL-10 were diminished by splanchnic nerve section (25). Those findings indicate that the splanchnic nerves normally mediate a coordinated physiological antiinflammatory action (24,25,30). The suppressive action against proinflammatory cytokines persists for at least 6 h (25).…”

Dysfunction of the Autonomic Nervous System and Its Role in the Pathogenesis of Septic Critical Illness (Review)

“…With the development of inflammation, an afferent impulse is transmitted along the vagal nerve from the periphery to the brain stem. In the opposite direction, the vagal efferent pathway transmits signals to the spleen, liver, intestines, and other organs [8][9][10][11][12][13][14][15][16]. Stimulation of the efferent vagal nerve, as well as the use of cholinesterase blockers, results in accumulation of acetylcholine in these organs.…”

Effects of effortful swallowing on cardiac autonomic control in individuals with neurogenic dysphagia: a prospective observational analytical study

“…Therefore, the interaction between cardiac autonomic regulation and swallowing is founded on the parasympathetic nervous system activity 22 . The parasympathetic fibers that exit the vagus nerve are accountable for cardiovascular autonomic regulation 23,24 . The myelinated portion of the vagus nerve provides efferent control of the heart through regulation of the sinus node 25 and this has an impact on HRV during respiratory sinus arrhythmia; when HR increases during inspiration owing to vagal withdrawal and decreases during expiration because of vagal recovery 26 .…”