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      CCL20 secreted from IgA1-stimulated human mesangial cells recruits inflammatory Th17 cells in IgA nephropathy

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          Abstract

          IgA nephropathy (IgAN) is the most common primary glomerulonephritis characterized by human mesangial cells (HMC) proliferation and extracellular matrix expansion associated with immune deposits consisting of galactose-deficient IgA1. However, how IgA1 contributes to IgAN has yet to be completely elucidated. In this study, the expression profile of chemokines was more altered in IgA1-treated HMC than in the control group. CCL20 was significantly higher either in the serum of IgAN patients or in IgA1-treated HMC. Further experiments demonstrated that CCR6, the only receptor of CCL20, was highly expressed in activated T cells. Intracellular staining assay and cytokine expression profile implied that CCR6 + T cells produced high IL-17 levels. Transwell experiment immunohistochemistry and immunofluorescence experiments extensively demonstrated that CCL20 could recruit inflammatory Th17 cells to the kidneys. These phenomena caused a series of immune inflammatory responses and further damaged the kidneys. Therefore, HMC stimulated by IgA1 could produce CCL20 and consequently recruit inflammatory Th17 cells to the kidneys to induce further lesion in IgA nephropathy.

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          Preferential recruitment of CCR6-expressing Th17 cells to inflamed joints via CCL20 in rheumatoid arthritis and its animal model

          This report shows that interleukin (IL) 17–producing T helper type 17 (Th17) cells predominantly express CC chemokine receptor (CCR) 6 in an animal model of rheumatoid arthritis (RA). Th17 cells induced in vivo in normal mice via homeostatic proliferation similarly express CCR6, whereas those inducible in vitro by transforming growth factor β and IL-6 additionally need IL-1 and neutralization of interferon (IFN) γ and IL-4 for CCR6 expression. Forced expression of RORγt, a key transcription factor for Th17 cell differentiation, induces not only IL-17 but also CCR6 in naive T cells. Furthermore, Th17 cells produce CCL20, the known ligand for CCR6. Synoviocytes from arthritic joints of mice and humans also produce a large amount of CCL20, with a significant correlation (P = 0.014) between the amounts of IL-17 and CCL20 in RA joints. The CCL20 production by synoviocytes is augmented in vitro by IL-1β, IL-17, or tumor necrosis factor α, and is suppressed by IFN-γ or IL-4. Administration of blocking anti-CCR6 monoclonal antibody substantially inhibits mouse arthritis. Thus, the joint cytokine milieu formed by T cells and synovial cells controls the production of CCL20 and, consequently, the recruitment of CCR6+ arthritogenic Th17 cells to the inflamed joints. These results indicate that CCR6 expression contributes to Th17 cell function in autoimmune disease, especially in autoimmune arthritis such as RA.
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            IgA nephropathy.

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              Chemokines and leukocyte traffic.

              Twenty years after the discovery of chemokines is an appropriate time to review leukocyte traffic and to assess the knowledge and opportunities that have arisen from countless studies of the large and tight-knit family of chemotactic proteins.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                26 May 2017
                2017
                : 12
                : 5
                : e0178352
                Affiliations
                [1 ]Department of Internal Medicine, Division of Nephrology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu Province, People’s Republic of China
                [2 ]Institutes of Biology and Medical Sciences, Soochow University, Suzhou, Jiangsu Province, People’s Republic of China
                INSERM1163, FRANCE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: JPZ GYL.

                • Data curation: JPZ XPZ.

                • Formal analysis: XPZ GYL JPZ.

                • Funding acquisition: JPZ.

                • Investigation: XPZ YL JQS.

                • Methodology: JPZ GYL.

                • Project administration: JPZ.

                • Resources: GYL LS QQ.

                • Supervision: JPZ GYL.

                • Validation: GYL LS QQ JPZ XPZ.

                • Visualization: XPZ YL JQS.

                • Writing – original draft: JPZ XPZ.

                • Writing – review & editing: JPZ XPZ.

                Author information
                http://orcid.org/0000-0001-5537-5131
                Article
                PONE-D-17-01866
                10.1371/journal.pone.0178352
                5446182
                28552941
                4887ef4e-c3bc-4d87-b53e-6525f00ac7ae
                © 2017 Lu et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 15 January 2017
                : 11 May 2017
                Page count
                Figures: 7, Tables: 2, Pages: 15
                Funding
                This work was supported by grants from the Priority Academic Development Program of Jiangsu Higher Education Institutions (PAPD); Program for Changjiang Scholars and Innovative Research Team in University (PCSIRT, IRT1075); Jiangsu Key Laboratory of Infection and Immunity, Institutes of Biology and Medical Sciences of Soochow University; Soochow University (Q413401810); National Natural Science Foundation of China (31270939, 81471526); Training Program of the Major Research Plan in regional immunology of the National Natural Science Foundation of China (91442110); Key University Science Research Project of Jiangsu Province (13KJA310004).
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
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                Biology and Life Sciences
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                Biology and Life Sciences
                Anatomy
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                Medicine and Health Sciences
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                Medicine and Health Sciences
                Inflammatory Diseases
                Biology and Life Sciences
                Cell Biology
                Cell Motility
                Chemotaxis
                Chemokines
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