The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation

Abstract

This review outlines the mechanisms underlying the interaction between the nervous and immune systems of the host in response to an immune challenge. The main focus is the cholinergic anti-inflammatory pathway, which we recently described as a novel function of the efferent vagus nerve. This pathway plays a critical role in controlling the inflammatory response through interaction with peripheral a7 subunit-containing nicotinic acetylcholine receptors expressed on macrophages. We describe the modulation of systemic and local inflammation by the cholinergic anti-inflammatory pathway and its function as an interface between the brain and the immune system. The clinical implications of this novel mechanism also are discussed.

Figure 1

Neural and humoral pathways in immunomodulation. During immune challenge activated macrophages and other immune and nonimmune cells release cytokines that signal the brain for activation of immunomodulatory mechanisms. Central immunomodulation is achieved by the cholinergic anti-inflammatory pathway, HPA axis, and SNS (see text for details). AP, area postrema; NTS, nucleus tractus solitarius; DMN, dorsal motor nucleus of the vagus; PVN, paraventricular nucleus; RVM, rostral ventrolateral medulla; LC, locus coeruleus; SNS, sympathetic nervous system; ACTH, adrenocorticotropin hormone; GC, glucocorticoids; EN, epinephrine; NE, norepinephrine; ACh, acetylcholine; LPS, lipopolysaccharide (endotoxin).

Figure 2

Vagus nerve stimulation attenuates the endotoxin-induced serum TNF response, hepatic TNF response, and development of endotoxemic shock. Rats were subjected to sham surgery (A and B: Sham, □; C:•; n = 7), bilateral cervical vagotomy (A and B: VGX, ▧, C:▴; n = 7), or vagotomy and electrical stimulation (A and B: VGX + STIM, ▩ C: ▪; n = 7). A: Serum TNF response. B: Hepatic TNF response. C: Development of endotoxemic shock. Mean arterial blood pressure data are normalized to MABP at time = 0. Sham-surgery, vagotomy, and electrical stimulation with vagotomy did not significantly affect MABP in vehicle-treated controls (not shown). Data are means +/− SEM. *P < 0.05; **P < 0.005 compared with SHAM + endotoxin; #P < 0.05 compared with VGX + endotoxin. Taken from Borovikova and others (16) with Nature’s copyright permission <http://www.nature.com>.

Figure 3

Vagus nerve stimulation does not inhibit TNF in nicotinic acetylcholine receptor α7 subunit–deficient mice. α7 Subunit–deficient mice (−/−) or age- and sex-matched wild-type littermates (+/+) were subjected to either sham operation (Sham) or vagus nerve stimulation (VNS, left vagus, 1 volt, 2 ms, 1 Hz); blood was collected 2 h after endotoxin administration. Serum TNF levels were determined by ELISA. Sham α7^+/+, n = 10; VNS α7^+/+, Sham α7^−/−, VNS α7^−/−, n = 11. *P < 0.05 compared with Sham α^7+/+. Taken from Wang and others (105) with Nature’s copyright permission: <http://www.nature.com>.