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Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin

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Abstract

Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal1,2,3,4. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms5,6,7,8. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic–pituitary–adrenal anti-inflammatory responses9,10,11. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1β, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.

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Acknowledgements

We thank D. Nardi for help in ELISA assays and D. Prieto for administrative assistance.

Author information

Correspondence to Kevin J. Tracey.

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Further reading

Figure 1: Cholinergic agonists inhibit LPS-induced TNF synthesis in human macrophage cultures through a post-transcriptional mechanism.
Figure 2: ACh specifically inhibits release of pro-inflammatory cytokines by human macrophages, but does not suppress release of the anti-inflammatory cytokine, IL-10.
Figure 3: Vagus nerve stimulation attenuates the LPS-induced serum TNF response, hepatic TNF response, and development of endotoxic shock.

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