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      Activation of Cholinergic Anti-Inflammatory Pathway in Peripheral Immune Cells Involved in Therapeutic Actions of α-Mangostin on Collagen-Induced Arthritis in Rats

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          Abstract

          Background

          Studies have shown that α-mangostin (MG) could exert anti-rheumatic effects in vivo by restoring immunity homeostasis, and have indicated that activation of the choline anti-inflammatory pathway (CAP) may contribute to this immunomodulatory property. The current study was designed to further investigate the effects of MG on the CAP in peripheral immune cells and clarify its relevance to the potential anti-rheumatic actions.

          Methods

          The catalytic activity of acetylcholinesterase (AChE) and expression of α7-nicotinic cholinergic receptor (α7nAChR) in peripheral blood mononuclear cells (PBMCs) from rats with collagen-induced arthritis (CIA) or human volunteers were evaluated after MG treatment. Consequent influences on the immune environment were assessed by flow cytometry and ELISA analyses. Indirect effects on joints resulting from these immune changes were studied in a co-culture system comprised of fibroblast-like synoviocytes (FLSs) and PBMCs.

          Results

          MG promoted α7nAChR expression in PBMCs both in vivo and in vitro, and inhibited the enzymatic activity of AChE simultaneously. Activation of the CAP was accompanied by a significant decrease in Th17 cells (CD4 +IL-17A +), while no obvious changes concerning the distribution of other T-cell subsets were noticed upon MG treatment. Meanwhile, MG decreased the secretion of TNF-α and IL-1β under inflammatory conditions. PBMCs from MG-treated CIA rats lost the potential to stimulate NF-κB activation and pro-inflammatory cytokine production of FLSs in the co-culture system.

          Conclusion

          Overall, the evidence suggested that MG can improve the peripheral immune milieu in CIA rats by suppressing Th17-cell differentiation through CAP activation, and achieve remission of inflammation mediated by FLSs.

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          Most cited references 21

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          The alpha7 nicotinic acetylcholine receptor as a pharmacological target for inflammation.

          The physiological regulation of the immune system encompasses comprehensive anti-inflammatory mechanisms that can be harnessed for the treatment of infectious and inflammatory disorders. Recent studies indicate that the vagal nerve, involved in control of heart rate, hormone secretion and gastrointestinal motility, is also an immunomodulator. In experimental models of inflammatory diseases, vagal nerve stimulation attenuates the production of proinflammatory cytokines and inhibits the inflammatory process. Acetylcholine, the principal neurotransmitter of the vagal nerve, controls immune cell functions via the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). From a pharmacological perspective, nicotinic agonists are more efficient than acetylcholine at inhibiting the inflammatory signaling and the production of proinflammatory cytokines. This 'nicotinic anti-inflammatory pathway' may have clinical implications as treatment with nicotinic agonists can modulate the production of proinflammatory cytokines from immune cells. Nicotine has been tested in clinical trials as a treatment for inflammatory diseases such as ulcerative colitis, but the therapeutic potential of this mechanism is limited by the collateral toxicity of nicotine. Here, we review the recent advances that support the design of more specific receptor-selective nicotinic agonists that have anti-inflammatory effects while eluding its collateral toxicity.
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            Combined treatment of etanercept and MTX reverses Th1/Th2, Th17/Treg imbalance in patients with rheumatoid arthritis.

            To explore the mechanism of Etanercept in the treatment of rheumatoid arthritis (RA), we investigated whether the Th1/Th2 and Th17/regulatory T cells (Treg) imbalance could be reversed by Etanercept and whether the reversal was related to the improvement of clinical indications. We conducted a 12-week study in 40 active RA patients, of whom 20 were given a stable weekly dose of methotrexate (MTX) alone and the other ten received a combined therapy of Etanercept and MTX. Ten healthy donors were chosen as controls. Frequencies of Th1, Th2, Th17, and Treg were quantified using flow cytometry, and related serum cytokines were detected by enzyme-linked immunosorbent assay. The composite 28-joint count Disease Activity Score, erythrocyte sedimentation rate, and C-reactive protein were assessed at each visit. Percentages of IFN-γ(+)Th1 and IL-17(+)Th17 among CD4(+) T cells were significantly higher, while CD4(+)CD25(high)Foxp3(+) Treg were significantly lower in RA patients compared with those in healthy control. After 12 weeks of therapy of MTX single or combination of MTX and Etanercept, the circulating Th17/Treg ratio significantly decreased, while no significant difference was observed in Th1/Th2 ratio. In combined therapy group, the Th17/Treg ratio was positively correlated with the remittance of disease activity. IL-1β, TNF-α, IL-6, IL-17, and IL-23 were significantly decreased, while TGF-β was significantly elevated. The Th17/Treg ratio was positively related to TGF-β, but negatively correlated with IL-6. Etanercept in combination with MTX ameliorates RA activity by normalizing the distribution of Th17 and Treg, and their related cytokines, which may partly explain the mechanism of combined therapy of Etanercept plus MTX in RA treatment.
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              The cholinergic anti-inflammatory pathway: towards innovative treatment of rheumatoid arthritis.

              The efferent vagus nerve can regulate inflammation via its principal neurotransmitter acetylcholine (ACh), a concept referred to as the 'cholinergic anti-inflammatory pathway'. ACh interacts with members of the nicotinic acetylcholine receptor (nAChR) family, in particular with the alpha7 subunit (alpha7nAChR), which is expressed not only by neurons but also macrophages and other cells involved in the inflammatory response. In these inflammatory cells, the stimulation of alpha7nAChR by ACh and other alpha7nAChR-specific agonists suppresses the release of proinflammatory cytokines. Recent work has suggested that alpha7nAChR could represent a new target for the treatment of rheumatic diseases. In this Perspective, we describe the cholinergic anti-inflammatory pathway and the therapeutic potential of modulating this pathway in rheumatoid arthritis.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                22 May 2020
                2020
                : 14
                : 1983-1993
                Affiliations
                [1 ]Department of Pharmacy, The Second Affiliated Hospital of Wannan Medical College , Wuhu 241000, People’s Republic of China
                [2 ]Department of Traditional Chinese Medicine, Yijishan Hospital of Wannan Medical College , Wuhu 241000, People’s Republic of China
                [3 ]Research Center of Integration of Traditional Chinese and Western Medicine, Wannan Medical College , Wuhu 241000, People’s Republic of China
                [4 ]Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College , Wuhu 241000, People’s Republic of China
                Author notes
                Correspondence: Jian Zuo Tel +86 15056477665 Email zuojian8178@163.com
                [*]

                These authors contributed equally to this work

                Article
                249865
                10.2147/DDDT.S249865
                7250306
                32546965
                © 2020 Yin et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 6, References: 23, Pages: 11
                Categories
                Original Research

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