The neuronal strategy for inflammation

Abstract

Severe sepsis, a leading cause of death in hospitalized patients, is one of the most dramatic examples of the pathological potential of inflammation. Since inflammation contributes to multiple clinical scenarios, it may not be surprising that diverse infectious and inflammatory disorders converge in the pathogenesis of severe sepsis. The physiological regulation of the immune responses by the nervous system represents effective anti-inflammatory mechanisms that can be exploited against inflammatory disorders. Recent studies indicate that acetylcholine, the principal cholinergic neurotransmitter, also functions as an immune cytokine that prevents macrophage activation through a 'nicotinic anti-inflammatory pathway'. Nicotine is more efficient than acetylcholine at inhibiting the NF-kappaB pathway and attenuating the production of pro-inflammatory cytokines from macrophages through a mechanism dependent on the alpha7-nicotinic acetylcholine receptor (alpha7n AChR). Treatment with nicotinic agonists attenuated systemic inflammation and improved survival in experimental sepsis in a clinically relevant time frame. Nicotine has already been used in clinical trials, but its clinical potential is limited by its collateral toxicity. Similar to the development of selective agonists for adrenergic receptors, selective nicotinic agonists for the alpha7nAChR may represent a promising pharmacological strategy against infectious and inflammatory diseases.