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      Cholinergic System and Its Therapeutic Importance in Inflammation and Autoimmunity

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          Abstract

          Neurological and immunological signals constitute an extensive regulatory network in our body that maintains physiology and homeostasis. The cholinergic system plays a significant role in neuroimmune communication, transmitting information regarding the peripheral immune status to the central nervous system (CNS) and vice versa. The cholinergic system includes the neurotransmitter\ molecule, acetylcholine (ACh), cholinergic receptors (AChRs), choline acetyltransferase (ChAT) enzyme, and acetylcholinesterase (AChE) enzyme. These molecules are involved in regulating immune response and playing a crucial role in maintaining homeostasis. Most innate and adaptive immune cells respond to neuronal inputs by releasing or expressing these molecules on their surfaces. Dysregulation of this neuroimmune communication may lead to several inflammatory and autoimmune diseases. Several agonists, antagonists, and inhibitors have been developed to target the cholinergic system to control inflammation in different tissues. This review discusses how various molecules of the neuronal and non-neuronal cholinergic system (NNCS) interact with the immune cells. What are the agonists and antagonists that alter the cholinergic system, and how are these molecules modulate inflammation and immunity. Understanding the various functions of pharmacological molecules could help in designing better strategies to control inflammation and autoimmunity.

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          Most cited references406

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          Nicotinic acetylcholine receptor alpha7 subunit is an essential regulator of inflammation.

          Excessive inflammation and tumour-necrosis factor (TNF) synthesis cause morbidity and mortality in diverse human diseases including endotoxaemia, sepsis, rheumatoid arthritis and inflammatory bowel disease. Highly conserved, endogenous mechanisms normally regulate the magnitude of innate immune responses and prevent excessive inflammation. The nervous system, through the vagus nerve, can inhibit significantly and rapidly the release of macrophage TNF, and attenuate systemic inflammatory responses. This physiological mechanism, termed the 'cholinergic anti-inflammatory pathway' has major implications in immunology and in therapeutics; however, the identity of the essential macrophage acetylcholine-mediated (cholinergic) receptor that responds to vagus nerve signals was previously unknown. Here we report that the nicotinic acetylcholine receptor alpha7 subunit is required for acetylcholine inhibition of macrophage TNF release. Electrical stimulation of the vagus nerve inhibits TNF synthesis in wild-type mice, but fails to inhibit TNF synthesis in alpha7-deficient mice. Thus, the nicotinic acetylcholine receptor alpha7 subunit is essential for inhibiting cytokine synthesis by the cholinergic anti-inflammatory pathway.
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            Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin.

            Vertebrates achieve internal homeostasis during infection or injury by balancing the activities of proinflammatory and anti-inflammatory pathways. Endotoxin (lipopolysaccharide), produced by all gram-negative bacteria, activates macrophages to release cytokines that are potentially lethal. The central nervous system regulates systemic inflammatory responses to endotoxin through humoral mechanisms. Activation of afferent vagus nerve fibres by endotoxin or cytokines stimulates hypothalamic-pituitary-adrenal anti-inflammatory responses. However, comparatively little is known about the role of efferent vagus nerve signalling in modulating inflammation. Here, we describe a previously unrecognized, parasympathetic anti-inflammatory pathway by which the brain modulates systemic inflammatory responses to endotoxin. Acetylcholine, the principle vagal neurotransmitter, significantly attenuated the release of cytokines (tumour necrosis factor (TNF), interleukin (IL)-1beta, IL-6 and IL-18), but not the anti-inflammatory cytokine IL-10, in lipopolysaccharide-stimulated human macrophage cultures. Direct electrical stimulation of the peripheral vagus nerve in vivo during lethal endotoxaemia in rats inhibited TNF synthesis in liver, attenuated peak serum TNF amounts, and prevented the development of shock.
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              The cholinergic system in the pathophysiology and treatment of Alzheimer’s disease

              Hampel et al. review the role of the cholinergic system in cognition and how cholinergic deficits in Alzheimer’s disease interact with other aspects of disease pathophysiology. They document the benefits of cholinergic therapies at various stages of disease, and argue that the weight of the evidence confirms their continued value. Cholinergic synapses are ubiquitous in the human central nervous system. Their high density in the thalamus, striatum, limbic system, and neocortex suggest that cholinergic transmission is likely to be critically important for memory, learning, attention and other higher brain functions. Several lines of research suggest additional roles for cholinergic systems in overall brain homeostasis and plasticity. As such, the brain’s cholinergic system occupies a central role in ongoing research related to normal cognition and age-related cognitive decline, including dementias such as Alzheimer’s disease. The cholinergic hypothesis of Alzheimer’s disease centres on the progressive loss of limbic and neocortical cholinergic innervation. Neurofibrillary degeneration in the basal forebrain is believed to be the primary cause for the dysfunction and death of forebrain cholinergic neurons, giving rise to a widespread presynaptic cholinergic denervation. Cholinesterase inhibitors increase the availability of acetylcholine at synapses in the brain and are one of the few drug therapies that have been proven clinically useful in the treatment of Alzheimer’s disease dementia, thus validating the cholinergic system as an important therapeutic target in the disease. This review includes an overview of the role of the cholinergic system in cognition and an updated understanding of how cholinergic deficits in Alzheimer’s disease interact with other aspects of disease pathophysiology, including plaques composed of amyloid-β proteins. This review also documents the benefits of cholinergic therapies at various stages of Alzheimer’s disease and during long-term follow-up as visualized in novel imaging studies. The weight of the evidence supports the continued value of cholinergic drugs as a standard, cornerstone pharmacological approach in Alzheimer’s disease, particularly as we look ahead to future combination therapies that address symptoms as well as disease progression.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                15 April 2021
                2021
                15 April 2021
                : 12
                : 660342
                Affiliations
                [1] Laboratory of Autoimmunity and Tolerance, National Centre for Cell Science , Ganeshkhind, Pune, India
                Author notes

                Edited by: Agnieszka Paradowska-Gorycka, Rheumatology and Rehabilitation, Poland

                Reviewed by: Chiara D’Angelo, University of Studies G. d’Annunzio Chieti and Pescara, Italy; Takeshi Fujii, Doshisha Women’s College of Liberal Arts, Japan

                *Correspondence: Girdhari Lal, glal@ 123456nccs.res.in

                This article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2021.660342
                8082108
                33936095
                8abd7d73-9017-4f24-881a-5a0e220826c3
                Copyright © 2021 Halder and Lal

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 29 January 2021
                : 26 March 2021
                Page count
                Figures: 3, Tables: 4, Equations: 0, References: 408, Pages: 29, Words: 12162
                Funding
                Funded by: Department of Science and Technology, Ministry of Science and Technology, India 10.13039/501100001409
                Award ID: DST/SJF/LSA-01/2017-18
                Funded by: Department of Biotechnology, Ministry of Science and Technology, India 10.13039/501100001407
                Award ID: BT/PR15533/MED/30/1616/2015, BT/PR14156/BRB/10/1515/2016
                Categories
                Immunology
                Review

                Immunology
                choline acetyltransferase (chat),cholinergic system (cs),muscarinic acetylcholine receptors (machr),neuroimmunology,neurotransmitters,nicotinic acetylcholine receptors (nachr)

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