Title

 

Authors

F. Squadrito¹, A. Bitto¹, S. Guarini², D. Giuliani², L. Minutoli¹, D. Altavilla¹.

¹Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Italy.
²Department of Biomedical Sciences, Section of Pharmacology, University of Modena and Reggio Emilia, Modena, Italy.

 

Abstract

The cholinergic anti-inflammatory pathway is a neurophysiological mechanism that regulates the immune system. The inflammatory reflex, mediated by vagus nerve, comprises an afferent arm that senses inflammation and an efferent arm that influence inflammatory cells. This pathway inhibits inflammation by suppressing cytokine synthesis via release of acetylcholine in organs of the reticuloendothelial system, including the lungs, spleen, liver, kidneys and gastrointestinal tract. Acetylcholine can interact with alpha7 nicotinic acetylcholine receptors (alpha7 nAchR) expressed by macrophages and other cytokine producing cells, which inhibits NF-kappaB nuclear translocation and down-regulate pro-inflammatory cytokine synthesis and prevent tissue damage. The cholinergic anti-inflammatory pathway has been studied in splanchnic artery occlusion (SAO), hemorrhagic and endotoxic shock by our and other groups. In these experimental conditions, the magnitude of the cytokine response is critical, because a deficient response may result in secondary infections, while an excessive response may be more injurious than the original insult. We demonstrated that vagus nerve stimulation inhibits the release of TNF and other cytokines, and protects against endotoxemia, hemorrhagia and ischemia-reperfusion injury. Recent observations from our and other laboratories have shown that activation of central (brain) cholinergic transmission by selective muscarinic receptor ligands results in lower systemic TNF levels in rodents and indicate that the efferent vagus nerve may provide a functional brain-to-immune connection. Thus, central cholinergic signalling is implicated in the activation of the cholinergic anti-inflammatory pathway. Electrical vagus nerve stimulation could be utilized to control inflammation. Advances in understanding the receptor and molecular mechanisms of cholinergic anti-inflammatory signalling indicate that selective alpha7 nicotinic receptor agonists and centrally acting cholinergic enhancers can be used in the treatment of pathological conditions characterized by cytokine overproduction.