Electrical activation of vagal efferent or afferent neurons elicits two distinct mechanisms of anti-inflammatory actions.

Abstract Inhibition of inflammation by reducing macrophage activation and pro-inflammatory cytokine production by electrical vagal nerve stimulation is well documented. Despite this ability to regulate inflammation, the mechanisms and intermediaries in this process are not completely understood. Vagal efferent neurons are thought to be the primary source of anti-inflammatory activity, despite the composition of the vagus nerve, which is predominantly vagal afferent neurons. Activation of vagal efferent neurons ameliorates lipopolysaccharide (LPS)-induced sepsis and is dependent on acetylcholine (ACh) derived from choline acetyltransferase (ChAT+) T-cells. Recent studies have identified vagal afferent fibers as anti-inflammatory as well, however the circuitry, including whether these vagal-mediated anti-inflammatory mechanisms converge, is unknown. Here, we show that VNS is capable of eliciting two distinct, anti-inflammatory mechanisms orchestrated by vagal efferent or afferent neurons. Using ChAT+ T-cell conditional KO mice, we show that afferent VNS reduced LPS-induced inflammation independently of T-cell derived ACh by measuring serum and lymphatic organ TNF-α and IL-6 levels. Using a highly selective β2-adrenergic receptor (β2-AR) antagonist, we show that intact, efferent, and notably afferent VNS regulates immunity in a β2-AR-dependent fashion. Together, these findings demonstrate that VNS is capable of eliciting two unique neuro-immune circuits with distinct mechanistic elements. Continued development of these circuits will inform the design of future vagal nerve stimulators, that may improve the efficacy of these devices in the regulation of immunity.