Divergence of neuroimmune circuits activated by afferent and efferent vagal nerve stimulation in the regulation of inflammation

It has previously been shown that afferent and efferent vagal nerve stimulation potently inhibits LPS-induced inflammation Our data show inhibition of inflammation by efferent but not afferent vagal nerve stimulation requires T-cell derived acetylcholine We show that afferent and efferent neuroimmune circuits require β2 -adrenergic receptor signaling ABSTRACT: Chronic inflammation due to inappropriate immune cell activation can have significant effects on a variety of organ systems, reducing lifespan and quality of life. As such, highly targeted control of immune cell activation is a major therapeutic goal. Vagus nerve stimulation (VNS) has emerged as a therapeutic modality that exploits neuro-immune communication to reduce immune cell activation and consequently inflammation. Although vagal efferent fibers were originally identified as the primary driver of anti-inflammatory actions, the vagus nerve in most species of animals is predominantly comprised of afferent fibers. Stimulation of vagal afferent fibers can also reduce inflammation; it is however uncertain how these two neuro-immune circuits diverge. Here we show that afferent VNS induces a distinct mechanism from efferent VNS, ameliorating LPS-induced inflammation independent from T-cell derived acetylcholine (ACh) that is required by efferent VNS. Using a β2 -adrenergic receptor antagonist (β2 -AR), we find that immune regulation induced by intact, afferent, or efferent VNS occur in a β2- AR-dependent manner. Together, our findings indicate that intact VNS activates at least two distinct neuroimmune circuits each with unique mechanisms of action. Selective targeting of either the vagal efferent or afferent fibers may provide more personalized, robust, and effective control over inappropriate immune responses. This article is protected by copyright. All rights reserved.

Keywords: inflammation; neuroimmunology; peripheral nervous system; vagal afferent; vagal nerve stimulation; vagus nerve.

PMID: 33491187 DOI: 10.1113/JP281189