UC Davis

The vagus nerve is critical in mediating inflammatory diseases characterized by increases in immune cell activity and elevations of cytokines and chemokines. Vagus nerve stimulation (VNS) is a therapy proposed to mitigate immune cell exacerbation of a pathology. Promising results in research settings and small-scale clinical trials have demonstrated the utility of these therapies in the regulation of immunopathologies, such as sepsis, rheumatoid arthritis, and inflammatory bowel disease. While exciting, there remains much unknown regarding the foundational mechanism that VNS exerts to mitigate disease-induced upregulation of immune cell activity. This dissertation sheds light on novel aspects regarding the mechanism of VNS, including the identification of key synapses and organs that facilitate the anti-inflammatory effects. We demonstrate that the cholinergic anti-inflammatory pathway (CAIP) relies on signaling through the superior mesenteric ganglion and subsequently propagates these anti-inflammatory signals to the mesenteric lymph nodes (MLN) of the intestinal tract, which contain the cellular machinery required for the CAIP. Vagal afferent neurons were found to be immunomodulatory as well, significantly reducing LPS-induced inflammatory cytokine release in the spleen and MLNs, in a mechanism distinct from that of the CAIP. Finally, we identify a novel anti-inflammatory circuit facilitated by vagal afferent neurons within the lung, capable of reducing TLR7-induced inflammation. Overall, we demonstrate several novel components contributing to the immunomodulatory effects of VNS, which ultimately informs the optimization and advancement of electrical therapies.