Neural Control of Inflammation: Bioelectronic Medicine in Treatment of Chronic Inflammatory Disease

Abstract

Inflammation is important for antimicrobial defense and for tissue repair after trauma. The inflammatory response and its resolution are both active processes that must be tightly regulated to maintain homeostasis. Excessive inflammation and nonresolving inflammation cause tissue damage and chronic disease, including autoinflammatory and cardiovascular diseases. An improved understanding of the cellular and molecular mechanisms that regulate inflammation has supported development of novel therapies for several inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease. Many of the specific anticytokine therapies carry a risk for excessive immunosuppression and serious side effects. The discovery of the inflammatory reflex and the increasingly detailed understanding of the molecular interactions between homeostatic neural reflexes and the immune system have laid the foundation for bioelectronic medicine in the field of inflammatory diseases. Neural interfaces and nerve stimulators are now being tested in human clinical trials and may, as the technology develops further, have advantages over conventional drugs in terms of better compliance, continuously adaptable control of dosing, better monitoring, and reduced risks for unwanted side effects. Here, we review the current mechanistic understanding of common autoinflammatory conditions, consider available therapies, and discuss the potential use of increasingly capable devices in the treatment of inflammatory disease.

Figure 1.

Regulation of the inflammatory response. Cytokines are key mediators of inflammation and their production and release is tightly regulated by a number of mechanisms that can be utilized for therapeutic intervention in excessive and nonresolving inflammation.

Figure 2.

Neural circuits regulate key mechanisms in experimental inflammation. Examples include: (A–C) The efferent vagus nerve connects with the myenteric plexus in the gut, as well as with the celiac ganglion, through the splenic nerve and to the spleen, where the signals are relayed by acetylcholine (ACh)-releasing T cells. Subsequent activation of cholinergic receptors may, for example, attenuate macrophage cytokine release or promote other physiological events. (D) Electrical vagus nerve stimulation is implicated in the reduction of antibody secretion and B-cell migration in the spleen. (E) Challenge with an antigen triggers a response in TRPV1⁻ Na_V1.8⁺ sensory neurons, which leads to restriction of antigen transit from local lymph node A to B. TNF-α, Tumor necrosis factor α; L-Arg, L-arginine; eNOS, endothelial nitric oxide synthase; EC, endothelial cell; SMC, smooth muscle cell; α7nAChR, α7 nicotinic acetylcholine receptor.

Figure 3.

VNS suppresses endotoxin-induced serum tumor necrosis factor (TNF) levels for over 24 h. Rats were subjected to 60 sec of VNS or sham surgery, followed by intraperitoneal endotoxin injection at a specified time after VNS. Serum was collected and analyzed for TNF by ELISA. Open squares, mean TNF ± SEM in sham animals; filled diamonds, mean TNF ± SEM in vagus nerve–stimulated animals (reproduced from Tarnawski et al. 2018).