The Cholinergic Anti-Inflammatory Pathway

Figure 1. Stimulation of the vagus nerve elicits release of acetylcholine (ACh) that binds to alpha 7 nicotinic ACh receptors on macrophages and leads to decreases in local and systemic levels of tumor necrosis factor (TNF).

The innate immune system provides the first line of defense in response to invading pathogens. Cells, including macrophages and neutrophils, release a barrage of inflammatory cytokines that increase blood flow and swelling, elevate temperature, and recruit several immune cell subtypes to the affected area. When tightly regulated, this inflammatory response is beneficial but when chronic or excessive, can lead to tissue destruction, autoimmune disorders, or sepsis.

Studies have uncovered a mechanism by which the inflammatory process can be regulated by activity of the parasympathetic nervous system. ^1,2 More specifically, efferent (motor) signals carried by the vagus nerve via the neurotransmitter acetylcholine (ACh), can modulate the activity of resident macrophages and attenuate local and systemic inflammation.^1,2 This regulatory activity has been termed "the cholinergic anti-inflammatory pathway".^1,2 The vagus nerve is finely branched, innervating several major organ systems including the liver, heart, spleen, and gastrointestinal tract. Its motor functions include regulating heart rate, gastric motility, and pupil constriction. In mice, electrical stimulation of the nerve suppresses endotoxin-induced increases in serum levels of tumor necrosis factor (TNF), a cytokine known to mediate both local and systemic inflammatory responses.^1,3 In addition, vagotomy without electrical stimulation of the nerve leads to significant increases in serum TNF levels.¹

Macrophages express ACh receptors, ligand-gated ion channels most often associated with the neuromuscular junction and peripheral and central nervous systems.^2,4 ACh receptors are homo- and/or heteromeric pentamers that in humans are composed of combinations of 16 identified subunits (alpha 1-7, alpha 9-10, beta 1-4, gamma, delta, and epsilon) characterized by subunit stoichiometry, structure, expression patterns, ion permeability, and pharmacology.⁵ In vitro, exposure of macrophages to ACh inhibits the production of TNF, an effect blocked by the selective ACh receptor antagonist alpha bungarotoxin.¹ Several ACh receptor subtypes, including homomeric receptors composed of alpha 7 subunits, exhibit binding to alpha bungarotoxin.⁶ Tracey and colleagues show that knockout mice deficient in the alpha 7 subunit produce significantly higher levels of inflammatory cytokines, including TNF, in response to endotoxin treatment.² In addition, protection from endotoxemia via vagal nerve stimulation is blocked in alpha 7 knockout mice.² Intracellular signaling associated with alpha 7-mediated activation of the cholinergic anti-inflammatory pathway is unknown, although in vitro studies suggest that it occurs at a post-transcriptional level involving suppression of TNF translation (Figure 1).¹

References

1. Borovikova, L.V. et al. (2000) Nature 405:458.
2. Wang, H. et al. (2003) Nature 421:384.
3. Tracey, K.J. et al. (1987) Nature 330:662.
4. Matsunaga, K. et al. (2001) J. Immunol. 167:6518.
5. Le Novère, N. et al. (2002) J. Neurobiol. 53:447.
6. Couturier, S. et al. (1990) Neuron 5:847.