Selective electrical stimulation of vagus nerve induces specific cytokine response.

Abstract

Neuro-immune communication and neural circuits regulating immunity have been therapeutically explored in preclinical models and successfully in recent human clinical trials. Implantable bioelectronic devices that stimulate the inflammatory reflex are effective in suppressing cytokine production during endoxtoxemia and other models of infection and injury. Whether vagus nerve stimulation can enhance cytokines was previously unknown. Here we analyzed serum cytokine levels in response to electrical stimulation of the vagus nerve using different pulse parameters. The cervical vagus nerve was isolated in adult male Balb/C mice and subjected to asymmetric charge-balanced stimulation using bipolar cuff electrodes. Animals were stimulated for 4 min using the following parameters: frequency 30–200 Hz, amplitude 50–750 μA, pulse width 50–250 μs. After 2 hrs, blood was collected and serum levels of TNFα, IL-6, IL-10, IL-12, and KC/GRO determined. Serum cytokine levels changed significantly (p<0.0001–0.05) and exhibited tuning curve properties when subjected to varying electrical pulse parameters, suggesting selective recruitment of efferent or afferent fibers that regulate specific cytokine production. Further insight into the nature of the neural circuits was ascertained through unilateral and bilateral vagotomies, distal and proximal to the stimulation location. Together, these studies demonstrate that systemic cytokine levels can be modulated by selectively stimulating the vagus nerve using specific combinations of frequency, amplitude, and pulse width. This study was funded in part by DARPA (HR0011-15-2-0016) and NIH (1R35GM118182-01).