Figure 4. Effects of pathways of the ANS on inflammation during sepsis.

The balance between the two branches of the autonomic nervous system (ANS) can direct the inflammatory response towards pro- or anti-inflammatory outcomes. Whereas activation of the cholinergic anti-inflammatory pathway (part of parasympathetic branch of the ANS) dampens inflammation, stimulation of the adrenergic pathways leads to amplification of the inflammatory response. a. In the adrenergic pro-inflammatory pathway, high concentrations of circulating catecholamines amplify the initial inflammatory response, particularly in the early phase of sepsis. Sources for catecholamine production and release are the adrenal medulla, sympathetic neurons and leukocytes (phagocytic cells and lymphocytes). Catecholamines exert their immunomodulatory effects through α- and β-adrenergic receptors that are expressed by various cell types, resulting in the increased release of pro-inflammatory mediators. b. By contrast, the activation of the cholinergic anti-inflammatory pathway in sepsis attenuates the inflammatory response. These effects are mediated through engagement of α7-nicotinic acetylcholine receptors (α7nAChRs). Acetylcholine is released following vagus-nerve stimulation, resulting in inhibition of the synthesis and release of pro-inflammatory mediators such as high-mobility group box 1 protein and tumour-necrosis factor.