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      Chloroquine modulates inflammatory autoimmune responses through Nurr1 in autoimmune diseases

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          Abstract

          For over a half-century the anti-malarial drug chloroquine (CQ) has been used as a therapeutic agent, alone or in combination, to treat autoimmune diseases. However, neither the underlying mechanism(s) of action nor their molecular target(s) are well defined. The orphan nuclear receptor Nurr1 (also known as NR4A2) is an essential transcription factor affecting the development and maintenance of midbrain dopaminergic neurons. In this study, using in vitro T cell differentiation models, we demonstrate that CQ activates T REG cell differentiation and induces Foxp3 gene expression in a Nurr1-dependent manner. Remarkably, CQ appears to induce Nurr1 function by two distinct mechanisms: firstly, by direct binding to Nurr1’s ligand-binding domain and promoting its transcriptional activity and secondly by upregulation of Nurr1 expression through the CREB signaling pathway. In contrast, CQ suppressed gene expression and differentiation of pathogenic T H17 cells. Importantly, using a valid animal model of inflammatory bowel disease (IBD), we demonstrated that CQ promotes Foxp3 expression and differentiation of T REG cells in a Nurr1-dependent manner, leading to significant improvement of IBD-related symptoms. Taken together, these data suggest that CQ ameliorates autoimmune diseases via regulating Nurr1 function/expression and that Nurr1 is a promising target for developing effective therapeutics of human inflammatory autoimmune diseases.

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          Most cited references32

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          Inflammatory bowel disease.

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            Generation of Pathogenic Th17 Cells in the Absence of TGF-β Signaling

            CD4+ T cells that selectively produce interleukin (IL)-17, are critical for host defense and autoimmunity 1–4 . Crucial for T helper17 (Th17) cells in vivo 5,6 , IL-23 has been thought to be incapable of driving initial differentiation. Rather, IL-6 and transforming growth factor (TGF)-β1 have been argued to be the factors responsible for initiating specification 7–10 . Herein, we show that Th17 differentiation can occur in the absence of TGF-β signaling. Neither IL-6 nor IL-23 alone efficiently generated Th17 cells; however, these cytokines in combination with IL-1β effectively induced IL-17 production in naïve precursors, independently of TGF-β. Epigenetic modification of the Il17a/Il17f and Rorc promoters proceeded without TGF-β1, allowing the generation of cells that co-expressed Rorγt and T-bet. T-bet+ Rorγt+ Th17 cells are generated in vivo during experimental allergic encephalomyelitis (EAE), and adoptively transferred Th17 cells generated with IL-23 without TGF-β1 were pathogenic in this disease model. These data suggest an alternative mode for Th17 differentiation. Consistent with genetic data linking IL23R with autoimmunity, our findings re-emphasize the importance of IL-23 and therefore have may have therapeutic implications.
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              A function for interleukin 2 in Foxp3-expressing regulatory T cells.

              Regulatory T cells (T(reg) cells) expressing the forkhead family transcription factor Foxp3 are critical mediators of dominant immune tolerance to self. Most T(reg) cells constitutively express the high-affinity interleukin 2 (IL-2) receptor alpha-chain (CD25); however, the precise function of IL-2 in T(reg) cell biology has remained controversial. To directly assess the effect of IL-2 signaling on T(reg) cell development and function, we analyzed mice containing the Foxp3(gfp) knock-in allele that were genetically deficient in either IL-2 (Il2(-/-)) or CD25 (Il2ra(-/-)). We found that IL-2 signaling was dispensable for the induction of Foxp3 expression in thymocytes from these mice, which indicated that IL-2 signaling does not have a nonredundant function in the development of T(reg) cells. Unexpectedly, Il2(-/-) and Il2ra(-/-) T(reg) cells were fully able to suppress T cell proliferation in vitro. In contrast, Foxp3 was not expressed in thymocytes or peripheral T cells from Il2rg(-/-) mice. Gene expression analysis showed that IL-2 signaling was required for maintenance of the expression of genes involved in the regulation of cell growth and metabolism. Thus, IL-2 signaling seems to be critically required for maintaining the homeostasis and competitive fitness of T(reg) cells in vivo.
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                Author and article information

                Contributors
                pleblanc@mclean.harvard.edu
                kskim@mclean.harvard.edu
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                29 October 2019
                29 October 2019
                2019
                : 9
                : 15559
                Affiliations
                [1 ]ISNI 000000041936754X, GRID grid.38142.3c, Molecular Neurobiology Laboratory, Department of Psychiatry and McLean Hospital, Harvard Medical School, ; 115 Mill Street, Belmont, Massachusetts 02478 USA
                [2 ]ISNI 0000 0001 2224 0361, GRID grid.59025.3b, School of Biological Sciences, Nanyang Technological University, 50 Nanyang Avenue, ; Singapore, 639798 Singapore
                [3 ]ISNI 0000 0000 8795 072X, GRID grid.240206.2, Program in Neuroscience and Harvard Stem Cell Institute, McLean Hospital, Harvard Medical School, ; Belmont, MA 02478 USA
                Author information
                http://orcid.org/0000-0001-6358-9375
                http://orcid.org/0000-0002-8243-3904
                Article
                52085
                10.1038/s41598-019-52085-w
                6820774
                31664129
                52cbe15d-7f4c-42be-a14d-d2af42844fdd
                © The Author(s) 2019

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 4 July 2019
                : 12 October 2019
                Funding
                Funded by: FundRef https://doi.org/10.13039/100000009, Foundation for the National Institutes of Health (Foundation for the National Institutes of Health, Inc.);
                Award ID: NS070577
                Award ID: NS084869
                Award ID: OD024622
                Award ID: NS070577
                Award ID: NS084869
                Award ID: OD024622
                Award ID: NS070577
                Award ID: NS084869
                Award ID: OD024622
                Award ID: NS084869
                Award ID: OD024622
                Award ID: NS070577
                Award ID: NS070577
                Award ID: NS084869
                Award ID: OD024622
                Award Recipient :
                Categories
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                © The Author(s) 2019

                Uncategorized
                autoimmunity,nmr spectroscopy
                Uncategorized
                autoimmunity, nmr spectroscopy

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