The vagus nerve and the nicotinic anti-inflammatory pathway

Key Points Inflammation is a fundamental physiological process that is crucial for survival, but at the same time it is one of the major causes of human morbidity and mortality. The production of pro-inflammatory cytokines is beneficial and protects the organism against infections and injury. However, excessive production of these cytokines can be more dangerous than the original infection, resulting in lethal systemic inflammation. These cytokines are successful pharmacological targets for the treatment of a variety of clinical disorders. Severe sepsis, the leading cause of death in intensive care units, is one of the most dramatic examples of the pathological potential of inflammation is sepsis. Severe sepsis is the third leading cause of death in developed societies, equals the number of fatalities from acute myocardial infarction, and accounts for 9.3% of overall deaths in the United States annually. Vagus-nerve stimulation, acetylcholine and nicotine inhibit the production of pro-inflammatory cytokines from macrophages through a 'nicotinic anti-inflammatory pathway' that is dependent on the α7 nicotinic acetylcholine receptor (α7nAChR). Similar to the development of α- and β-agonists for adrenergic receptors, the design of selective nicotinic agonists for the α(α7nAChR could represent a promising pharmacological strategy against infectious and inflammatory diseases. The therapeutic potential of nicotinic agonists has been limited by the characterization of the specific receptors for drug development. The recent characterization of the α7nAChR in macrophages supports the design of selective nicotine agonists that can overcome the toxic effect of nicotine mediated by other receptors. Physiological anti-inflammatory mechanisms are selected by evolution to effectively control the immune system and can be exploited for the treatment of inflammatory disorders. Recent studies indicate that the vagus nerve (which is the longest of the cranial nerves and innervates most of the peripheral organs) can modulate the immune response and control inflammation through a 'nicotinic anti-inflammatory pathway' dependent on the α7-nicotinic acetylcholine receptor (α7nAChR). Nicotine has been used in clinical trials for the treatment of ulcerative colitis, but its clinical applications are limited by its unspecific effects and subsequent toxicity. This article reviews recent advances supporting the therapeutic potential of selective nicotinic agonists in several diseases.