Neural control of inflammation

Abstract: Pioneering research on neural control of inflammation has paved the way for new and exciting developments in the growing field of bioelectronic medicine. In the past couple of decades, pre-clinical research on the role of the vagus nerve in inflammation and immunity has brought electrical stimulation of select nerves into clinical trials for the treatment of chronic inflammatory diseases. Bioelectronic medicine continues to evolve and address challenges in optimizing interfaces and stimulation configurations for activation of specific neural circuits, and deciphering nerve signals that regulate inflammation and immunity with the goal of targeting specific nerve fibers for treatment of excessive inflammation. Ongoing basic, preclinical research strives to provide the insight necessary to develop therapeutic vagus nerve stimulation to mitigate inflammation in disease. Inflammation is normally a protective process that defends from microbial invasion and promotes healing, provided that it is adequately resolved in a timely manner. Dysregulation of resolving mechanisms can result in chronic inflammation and thus, a better understanding of the mechanisms that regulate inflammation is important for improving diagnosis, prevention, and treatment of chronic diseases. Discoveries over three decades show that the central and peripheral nervous systems along with the immune system work together to regulate inflammation. The vagus nerve bridges communication between the central and peripheral nervous systems and other tissues, regulates homeostasis, and serves an immunoregulatory function. Work delineating vagus nerve-mediated regulation of inflammation in experimental models of disease has led to important breakthroughs toward enabling treatment methods using electronic interfaces and devices that activate homeostatic reflexes that regulate the immune system. Considering the speed of action potentials and the anatomical specificity of neurons, activation of nerves that regulate immune cell function and activity, potentially provides an anatomically and temporally precise method to deliver therapeutic interventions in excessive inflammation. Clinical trials aimed at investigating neural control of chronic inflammatory responses in conditions such as inflammatory bowel disease and rheumatoid arthritis have been launched and data is encouraging, however, not yet fully conclusive. Together, these studies show the potential that neural control of inflammation works as a strategy to control excessive inflammation. Accordingly, additional studies with improved design in terms of randomization and controls are needed to evaluate targeted neural stimulation for regulation of the molecular and cellular mechanisms that underlie regulation of inflammation and its resolution. The work in this thesis sets forth to understand neural control mechanisms of inflammation by establishing methods and technology to study mechanisms of neural regulation of excessive inflammation in experimental models. In Study I, we found that a minute-long electrical vagus nerve stimulation impacts the cytokine response to inflammatory stimuli for two days. Study II establishes an effective method for vagus nerve stimulation for studies of experimental inflammation. Study III provides evidence that the vagus nerve accelerates the active resolution phase of inflammation through a cholinergic mechanism that requires release of pro-resolving mediators. Because available methods for vagus nerve stimulation are not suitable for longterm experiments in mice, the understanding of mechanisms of vagus nerve regulation of inflammation in chronic diseases is yet incomplete. In Study IV, we developed technology that attempts to address this methodological shortcoming and enable studies of vagus nerve stimulation in genetic mouse models of chronic inflammatory diseases.

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