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Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells
CD19(+)CD24(hi)CD27(+) memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746849/ https://www.ncbi.nlm.nih.gov/pubmed/33343576 http://dx.doi.org/10.3389/fimmu.2020.603288 |
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author | Li, Jinyang Gao, Ji Zhou, Haoming Zhou, Jinren Deng, Zhenghua Lu, Yunjie Rao, Jianhua Ji, Guwei Gu, Jian Yang, Xinxiang Xia, Yongxiang Wang, Xuehao |
author_facet | Li, Jinyang Gao, Ji Zhou, Haoming Zhou, Jinren Deng, Zhenghua Lu, Yunjie Rao, Jianhua Ji, Guwei Gu, Jian Yang, Xinxiang Xia, Yongxiang Wang, Xuehao |
author_sort | Li, Jinyang |
collection | PubMed |
description | CD19(+)CD24(hi)CD27(+) memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases. |
format | Online Article Text |
id | pubmed-7746849 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-77468492020-12-19 Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells Li, Jinyang Gao, Ji Zhou, Haoming Zhou, Jinren Deng, Zhenghua Lu, Yunjie Rao, Jianhua Ji, Guwei Gu, Jian Yang, Xinxiang Xia, Yongxiang Wang, Xuehao Front Immunol Immunology CD19(+)CD24(hi)CD27(+) memory Breg cells exhibit decreased abundance in patients with chronic graft-versus-host disease (cGVHD) after liver transplantation and produce less IL-10 than those from patients without cGVHD and healthy donors. Due to the lack of Breg cells and the difficulty in expanding them in vitro, in mouse models and early human clinical trials, the adoptive transfer of Breg cells to autoimmune diseases is greatly restricted. Glycogen synthase kinase 3β (GSK-3β) is a multifunctional serine/threonine (ser/thr) protein kinase that can participate in B cell growth, metabolic activity, and proliferation. Phosphoprotein array analysis showed that p-GSK-3β-s9 was highly expressed in mBreg cells. Furthermore, here, we demonstrated that GSK-3β expression in mBreg cells is lower than that observed in B cells by flow cytometry. We found that the treatment of B cells with the specific GSK-3β inhibitor SB216763 can significantly increase the proportion and immunosuppressive function of mBreg cells in vitro. Nuclear factor of activated T cells (NFAT) is one of a pivotal regulator of gene expression in adaptive immune system. Here, we observed that inhibition of GSK-3β by SB216763 results in enhanced expression of NFATc1 in B cells, which is essential in regulating the ability of B cells to secrete IL-10. By constructing a xGVHD mouse model, we observed that SB216763-treated mBreg cells effectively prevent xenogeneic GVHD. Here we propose a novel strategy using SB216763 to inhibit GSK-3β and then enhance the proportion and immunosuppressive function of mBreg cells by increasing the expression of NFATc1. This approach may be used as a therapy to ameliorate GVHD and inflammatory diseases. Frontiers Media S.A. 2020-12-04 /pmc/articles/PMC7746849/ /pubmed/33343576 http://dx.doi.org/10.3389/fimmu.2020.603288 Text en Copyright © 2020 Li, Gao, Zhou, Zhou, Deng, Lu, Rao, Ji, Gu, Yang, Xia and Wang http://creativecommons.org/licenses/by/4.0/ 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. |
spellingShingle | Immunology Li, Jinyang Gao, Ji Zhou, Haoming Zhou, Jinren Deng, Zhenghua Lu, Yunjie Rao, Jianhua Ji, Guwei Gu, Jian Yang, Xinxiang Xia, Yongxiang Wang, Xuehao Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title | Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title_full | Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title_fullStr | Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title_full_unstemmed | Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title_short | Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells |
title_sort | inhibition of glycogen synthase kinase 3β increases the proportion and suppressive function of cd19(+)cd24(hi)cd27(+) breg cells |
topic | Immunology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746849/ https://www.ncbi.nlm.nih.gov/pubmed/33343576 http://dx.doi.org/10.3389/fimmu.2020.603288 |
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