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      The Link Between Autonomic Nervous System and Rheumatoid Arthritis: From Bench to Bedside

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          Abstract

          Neuronal stimulation is an emerging field of research focused on the management and treatment of various diseases through the reestablishment of physiological homeostasis. Electrical vagus nerve stimulation has recently been proposed as a revolutionary therapeutic option for rheumatoid arthritis (RA) in combination with or even as a replacement for conventional and biological drugs. In the past few years, disruption of the autonomic system has been linked to RA onset and activity. Novel research on the link between the autonomic nervous system and the immune system (immune-autonomics) has paved the way for the development of innovative RA management strategies. Clinical evidence supports this approach. Cardiovascular involvement, in terms of reduced baroreflex sensitivity and heart rate variability-derived indices, and mood disorders, common comorbidities in patients with RA, have been linked to autonomic nervous system dysfunction, which in turn is influenced by increased levels of circulating pro-inflammatory cytokines. This narrative review provides an overview of the autonomic nervous system and RA connection, discussing most of the common cardiac and mental health-related RA comorbidities and their potential relationships to systemic and joint inflammation.

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          Most cited references154

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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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            A neurotrophic model for stress-related mood disorders.

            There is a growing body of evidence demonstrating that stress decreases the expression of brain-derived neurotrophic factor (BDNF) in limbic structures that control mood and that antidepressant treatment reverses or blocks the effects of stress. Decreased levels of BDNF, as well as other neurotrophic factors, could contribute to the atrophy of certain limbic structures, including the hippocampus and prefrontal cortex that has been observed in depressed subjects. Conversely, the neurotrophic actions of antidepressants could reverse neuronal atrophy and cell loss and thereby contribute to the therapeutic actions of these treatments. This review provides a critical examination of the neurotrophic hypothesis of depression that has evolved from this work, including analysis of preclinical cellular (adult neurogenesis) and behavioral models of depression and antidepressant actions, as well as clinical neuroimaging and postmortem studies. Although there are some limitations, the results of these studies are consistent with the hypothesis that decreased expression of BDNF and possibly other growth factors contributes to depression and that upregulation of BDNF plays a role in the actions of antidepressant treatment.
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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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                Author and article information

                Contributors
                Journal
                Front Med (Lausanne)
                Front Med (Lausanne)
                Front. Med.
                Frontiers in Medicine
                Frontiers Media S.A.
                2296-858X
                07 December 2020
                2020
                : 7
                : 589079
                Affiliations
                [1] 1Division of Clinical Rheumatology, Gaetano Pini Hospital , Milan, Italy
                [2] 2Department of Clinical Sciences and Community Health, Research Center for Adult and Pediatric Rheumatic Diseases, Università degli Studi di Milano , Milan, Italy
                [3] 3Department of Neurosciences and Mental Health, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca'Granda Ospedale Maggiore Policlinico , Milan, Italy
                [4] 4Department of Pathophysiology and Transplantation, Università degli Studi di Milano , Milan, Italy
                [5] 5Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano , Milan, Italy
                Author notes

                Edited by: Helena Canhao, New University of Lisbon, Portugal

                Reviewed by: Theodoros Dimitroulas, Aristotle University of Thessaloniki, Greece; Jose Inciarte-Mundo, Hospital Clínic de Barcelona, Spain

                This article was submitted to Rheumatology, a section of the journal Frontiers in Medicine

                †These authors have contributed equally to this work

                Article
                10.3389/fmed.2020.589079
                7750536
                33365319
                1eb88aa7-7377-4642-a934-e2f667fd96b9
                Copyright © 2020 Ingegnoli, Buoli, Antonucci, Coletto, Esposito and Caporali.

                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
                : 30 July 2020
                : 30 October 2020
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 154, Pages: 11, Words: 9517
                Funding
                Funded by: Università degli Studi di Milano 10.13039/100012352
                Categories
                Medicine
                Review

                vagus nerve,central nervous system,autonomic nervous system,mood disorder,rheumatoid arthritis,depression,therapy

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