Editors' ChoiceAutoimmunity

A shocking way to suppress inflammation

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Science Translational Medicine  03 Aug 2016:
Vol. 8, Issue 350, pp. 350ec122
DOI: 10.1126/scitranslmed.aah4509

Therapeutic electricity has had a narrow scope of disease applications, but mechanistic studies have shown that stimulation of the vagus nerve releases norepinephrine into synapse-like structures in the spleen containing a subset of T cells that respond by producing acetylcholine. Acetylcholine released by these T cells binds to the α7 nicotinic acetylcholine receptor on splenic macrophages to down-regulate cytokine production by inhibiting nuclear translocation of NF-κB. Koopman et al. have now applied the knowledge of this neural-immune circuit to a human trial.

The translation of this pathway was accelerated by the established use of vagus nerve stimulators to treat epilepsy. The investigators implanted stimulators in 17 patients with rheumatoid arthritis refractory to one or more drugs. Based on clinical response and prior animal data, they titrated a small current given in 60-second bursts and repeated up to 4 times daily; the total current dose was substantially lower than that used in epilepsy. Based on two standard disease activity scores, there was clinical improvement over 84 days that was responsive to planned interruptions in device output. Consistent with the proposed mechanism of action, the degree of improvement was correlated with the suppression of endotoxin-induced tumor necrosis factor–α (TNF-α) release from patients’ blood cells and with serum interleukin-6 (IL-6) levels. While the trial lacked a control group, a placebo effect seems unlikely given that cytokine production was also suppressed by transient stimulation delivered to patients that were unconscious during general anesthesia. Data from larger trials of longer duration are necessary to firmly establish benefit and assess how the balance of suppressing harmful inflammation while retaining control of infection compares with that of current therapies.

TNF-α and IL-6 are also implicated in other inflammatory disorders, such as inflammatory bowel disease and psoriasis. For the many patients that either fail to respond to medications, suffer from side effects, or prefer an implantable device, vagus nerve stimulation offers hope. This approach should stimulate further study of other methods to augment vagus nerve output such as exercise, breathing, meditation, and diet, and this might just be the first in a line of devices with the promise of spatiotemporal control of immunity.

F. A. Koopman et al., Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc. Natl. Acad. Sci. U.S.A. 113, 8284–8289 (2016). [Full Text]

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