Figure 4. Afferent VNS vs efferent VNS schematic.

Proposed mechanisms of action elicited by afferent (A) and efferent (B) VNS based on our reported findings and current literature. Afferent VNS induces activation of sympathetic neurons, in the celiac/superior mesenteric plexus. These sympathetic nerves innervate the spleen and MLN, and their activation causes NE released that can act on β₂AR on immune cells, such as macrophages, reducing activation and inhibition of TNFα release (A). In contrast, activation of vagal efferent neurons induces sympathetic innervation originating in the celiac/superior mesenteric ganglia, to release NE release in the spleen and MLN. NE in these secondary lymphoid organs elicits Ach release from ChAT+ T-cells in a β₂AR dependent manner, to inhibit TNFα production (Created with BioRender.com).