The principal autonomic neurotransmitters, acetylcholine and noradrenaline, are involved in immune regulation in the context of inflammation through various molecular pathways. Circadian oscillations in the activity of the autonomic nervous system allow concerted actions of immune cells.
Recent studies have not only confirmed the connection between the nervous and immune systems. They elucidated that one well-characterized cytokine-inhibiting mechanism, termed the “inflammatory reflex,” is dependent upon vagus nerve signals. This inflammatory reflex is enabled by a neural circuit that regulates the immune response to injury and invasion. The afferent arc of the reflex is activated by cytokines and is projecting to sympathoexcitatory neurons of the medullary nucleus ambiguous. The efferent vagal arc directly suppresses the cytokine production and thereby inhibiting inflammation and preventing organ damage. Experimental data obtained in rats suggested that via vagal stimulation the cytokine production can be inhibited and arthritis is attenuated (Levine YA et al. Neurostimulation of the cholinergic anti-inflammatory pathway ameliorates disease in rat collagen-induced arthritis. PLoS One 2014, 9: e104530).
Kilohertz frequency nerve block enhances anti-inflammatory effects of vagus nerve stimulation. Scientific Reports, 7:38810: Combining a 60s cervical vagus nerve stimulation (cVNS) of 10-30 Hz, once daily with kilohertz nerve block of the afferent vagal nerve fibres, Yogi Patel et al. from Department of Biomedical Engineering, Georgia Institute of Technology were able to selectively enhance the vagus nerve efference and to inhibit the peripheral production of TNF, IL-1β, and IL-6. Selective efferent cVNS stimulation had anti-inflammatory effects. Their results also demonstrated that the complete afferent nerve block enhances this anti-inflammatory effect.
Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. PNAS, 29(113): 8284–8289. In their carefully reported observation in patients receiving vagus nerve stimulation in order to reduce the frequency of epileptic seizures, Koopman et al have shown that the vagus nerve stimulation (up to four times daily) had an effect also on the activity of rheumatoid arthritis. The vagus nerve stimulation significantly inhibited the TNF production for up to 84 d. Moreover, the disease severity, as measured by standardized clinical composite scores, improved significantly. Together, these results establish that vagus nerve stimulation modulates TNF production and reduces inflammation in humans.
A growing number of neuromodulation studies focussing on the vagus nerve points at a new, non-pharmacological approach to support the therapy of rheumatoid arthritis and possibly also other autoimmune and autoinflammatory diseases.