The cholinergic anti-inflammatory pathway and neuro-immune regulation

The immune system serves to protect the body from infection, to elicit a protective response to insult or injury, and to maintain homeostasis. A rapidly growing body of work suggests that the nervous and immune systems work synergistically and communicate reciprocally towards these ends. Similarly to the presence of both innate and adaptive immune cells that reside throughout the body, the sensory branch of the nervous system also innervates tissues and organs throughout the body, including the skin, gastrointestinal tract, heart, lungs, and the brain. Like the innate immune system, the sensory arm of the nervous system perceives and responds to environmental cues, as a constant surveillance for changes in the environment, monitoring damage, inflammation, and stressors. A hallmark of the sensory response to environmental alterations is pain, which can serve as the first indicator of infection or damage. While the sensory nervous system monitors the external environment, the autonomic nervous system monitors the internal systems, such as blood pressure and heart rate. The autonomic nervous system is comprised of two branches that include the sympathetic arm, often referred to as the “fight or flight” arm, and the parasympathetic nervous system, often described as the “rest and repair” response, with the two arms working in tandem. The sympathetic branch produces and responds to catecholamines, such as norepinephrine (NE) and adrenaline, while the parasympathetic branch utilizes the neurotransmitter acetylcholine (ACh) and is referred to as cholinergic. Both arms innervate most tissues and organs of the body. However, a notable exception are the secondary lymphoid organs of the immune system. These tissues are innervated by sensory and adrenergic nerves, but not by cholinergic nerves. Instead, adaptive immune cells, including both T and B cells, can produce ACh, similarly to cholinergic nerves. As has been elegantly demonstrated by multiple studies, this distinction provides a powerful regulatory tool at the intersection between the nervous system and the immune system.Immune cells express many neurotransmitter receptors, including receptors for ACh, NE, and neuropeptides, thus the nervous system can readily modulate the function of immune cells. Reciprocally, immune cells produce neurotransmitters, notably as described above, ACh. Dr. Kevin Tracy and his team pioneered the discovery of what is now known as the “cholinergic anti-inflammatory pathway,” a reflex arc that induces efferent vagus nerve stimulation that reduces immune cell activation (and mortality in animal models of sepsis). The activation of the vagus nerve results in sympathetic innervation and release of NE in secondary lymphoid organs, including the spleen. NE binds to and activates b2 adrenergic receptors on a subset of T cells, known as Tchats, that express choline acetyltransferase (chat), synthesize ACh, and become the alternate source of ACh in the spleen and lymphoid organs. ACh, produced by Tchats, binds to alpha 7 nicotinic acetylcholine receptors (a7 nAChR) that are expressed on antigen presenting cells (including macrophages and B cells) and ACh engagement of a7 nAChR results in suppression of pro-inflammatory cytokine release.While in neurons, ACh-mediated activation a7 nAChR results in rapid Ca++ influx and leads to excitatory neurotransmission, synaptic plasticity, and learning, its function and signaling on immune cells is distinct. ACh binding to a7 nAChR on peripheral macrophages and microglia in the brain is metabotropic, involves the Jak/stat signaling pathway, and results in the suppression of NFkB signaling, thereby reducing the production and release of pro-inflammatory cytokines and increasing phagocytosis. Thus, there are key differences between neuronal and non-neuronal/peripheral a7 nAChR functions. The impact of each on the other, but also their implications for immunity and health, remain largely unknown. In addition, approximately 1 to 5% of splenic CD4+ T cells express chat, and approximately 30% of these chat-expressing T cells are FoxP3-expressing Tregs in mice. Interestingly, the majority of the Tchats are “antigen experienced.” It is tempting to speculate that these cells are important for maintaining self-tolerance by virtue of a previous encounter with self-antigens, perhaps during thymic maturation. However, genetic ablation of chat in T cells also results in poor bacterial control, suggesting an important role for Tchats in immunity to pathogens that warrants further investigation.Despite the rapid and significant advances in the field, there remain significant gaps in our knowledge. The overarching goal of this Research Topic is to broaden our understanding of the way bidirectional and multifunctional neuro-immune pathways contribute to, and regulate, the immune response and reciprocally how the immune response contributes to, and regulates, neurological functions. By inviting both pioneers in the field, as well as newcomers to the area, this effort has the potential to transform our understanding of neuroimmune responses to infection, cancer, neurodegenerative diseases, and autoimmunity. Topic editors: M. Karen Newell-Rogers, Richard P Tobin Source: https://www.frontiersin.org/research-topics/78256/the-cholinergic-anti-inflammatory-pathway-and-neuro-immune-regulation