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      Neuroimmunomodulation of vagus nerve stimulation and the therapeutic implications

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          Abstract

          Vagus nerve stimulation (VNS) is a technology that provides electrical stimulation to the cervical vagus nerve and can be applied in the treatment of a wide variety of neuropsychiatric and systemic diseases. VNS exerts its effect by stimulating vagal afferent and efferent fibers, which project upward to the brainstem nuclei and the relayed circuits and downward to the internal organs to influence the autonomic, neuroendocrine, and neuroimmunology systems. The neuroimmunomodulation effect of VNS is mediated through the cholinergic anti-inflammatory pathway that regulates immune cells and decreases pro-inflammatory cytokines. Traditional and non-invasive VNS have Food and Drug Administration (FDA)-approved indications for patients with drug-refractory epilepsy, treatment-refractory major depressive disorders, and headaches. The number of clinical trials and translational studies that explore the therapeutic potentials and mechanisms of VNS is increasing. In this review, we first introduced the anatomical and physiological bases of the vagus nerve and the immunomodulating functions of VNS. We covered studies that investigated the mechanisms of VNS and its therapeutic implications for a spectrum of brain disorders and systemic diseases in the context of neuroimmunomodulation.

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          Most cited references122

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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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            The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems

            The gut-brain axis (GBA) consists of bidirectional communication between the central and the enteric nervous system, linking emotional and cognitive centers of the brain with peripheral intestinal functions. Recent advances in research have described the importance of gut microbiota in influencing these interactions. This interaction between microbiota and GBA appears to be bidirectional, namely through signaling from gut-microbiota to brain and from brain to gut-microbiota by means of neural, endocrine, immune, and humoral links. In this review we summarize the available evidence supporting the existence of these interactions, as well as the possible pathophysiological mechanisms involved. Most of the data have been acquired using technical strategies consisting in germ-free animal models, probiotics, antibiotics, and infection studies. In clinical practice, evidence of microbiota-GBA interactions comes from the association of dysbiosis with central nervous disorders (i.e. autism, anxiety-depressive behaviors) and functional gastrointestinal disorders. In particular, irritable bowel syndrome can be considered an example of the disruption of these complex relationships, and a better understanding of these alterations might provide new targeted therapies.
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              Overview of General and Discriminating Markers of Differential Microglia Phenotypes

              Inflammatory processes and microglia activation accompany most of the pathophysiological diseases in the central nervous system. It is proven that glial pathology precedes and even drives the development of multiple neurodegenerative conditions. A growing number of studies point out the importance of microglia in brain development as well as in physiological functioning. These resident brain immune cells are divergent from the peripherally infiltrated macrophages, but their precise in situ discrimination is surprisingly difficult. Microglial heterogeneity in the brain is especially visible in their morphology and cell density in particular brain structures but also in the expression of cellular markers. This often determines their role in physiology or pathology of brain functioning. The species differences between rodent and human markers add complexity to the whole picture. Furthermore, due to activation, microglia show a broad spectrum of phenotypes ranging from the pro-inflammatory, potentially cytotoxic M1 to the anti-inflammatory, scavenging, and regenerative M2. A precise distinction of specific phenotypes is nowadays essential to study microglial functions and tissue state in such a quickly changing environment. Due to the overwhelming amount of data on multiple sets of markers that is available for such studies, the choice of appropriate markers is a scientific challenge. This review gathers, classifies, and describes known and recently discovered protein markers expressed by microglial cells in their different phenotypes. The presented microglia markers include qualitative and semi-quantitative, general and specific, surface and intracellular proteins, as well as secreted molecules. The information provided here creates a comprehensive and practical guide through the current knowledge and will facilitate the choosing of proper, more specific markers for detailed studies on microglia and neuroinflammatory mechanisms in various physiological as well as pathological conditions. Both basic research and clinical medicine need clearly described and validated molecular markers of microglia phenotype, which are essential in diagnostics, treatment, and prevention of diseases engaging glia activation.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                06 July 2023
                2023
                : 15
                : 1173987
                Affiliations
                [1] 1Department of Neurology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                [2] 2Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                [3] 3Institute of Clinical Medicine, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                [4] 4Cross College Elite Program, National Cheng Kung University , Tainan, Taiwan
                [5] 5Research Center for Mind, Brain and Learning, National Chengchi University , Taipei, Taiwan
                [6] 6School of Medicine, College of Medicine, National Cheng Kung University , Tainan, Taiwan
                Author notes

                Edited by: Vanessa Castelli, University of L'Aquila, Italy

                Reviewed by: Stephanie Chee Yee Tjen-A-Looi, University of California, Irvine, United States; Michele D'Angelo, University of L'Aquila, Italy

                *Correspondence: Yi-Jen Wu wuyj@ 123456mail.ncku.edu.tw

                †These authors have contributed equally to this work

                Article
                10.3389/fnagi.2023.1173987
                10358778
                4d20df19-548d-4e90-a5a1-864953484d6f
                Copyright © 2023 Fang, Lin, Tseng, Tseng, Hua, Chao and Wu.

                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
                : 25 February 2023
                : 12 June 2023
                Page count
                Figures: 2, Tables: 4, Equations: 0, References: 122, Pages: 17, Words: 14172
                Funding
                Funded by: National Science and Technology Council, doi 10.13039/501100020950;
                Award ID: NSTC 111-2314-B-006-100
                Funded by: National Cheng Kung University Hospital, doi 10.13039/501100004844;
                Award ID: NCKUH-11202033
                We appreciate the research grants to Y-JW from the National Cheng Kung University Hospital (NCKUH-11202033) and the National Science and Technology Council, Taiwan (NSTC 111-2314-B-006-100).
                Categories
                Aging Neuroscience
                Review
                Custom metadata
                Neuroinflammation and Neuropathy

                Neurosciences
                vagus nerve,vagus nerve stimulation,non-invasive vns,neuroimmunomodulation,cholinergic anti-inflammatory pathway,inflammatory disease

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