Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells.
Inhibition of Glycogen Synthase Kinase 3β Increases the Proportion and Suppressive Function of CD19(+)CD24(hi)CD27(+) Breg Cells.
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糖原合成酶激酶 3β 的抑制增加 CD19 CD24hiCD27 Breg 细胞的比例和抑制功能
DOI：
10.3389/fimmu.2020.603288
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发表时间：
2020
影响因子：
7.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Li J;Gao J;Zhou H;Zhou J;Deng Z;Lu Y;Rao J;Ji G;Gu J;Yang X;Xia Y;Wang X
CD19+CD24hiCD27+记忆Breg细胞在肝移植后慢性移植物抗宿主病(cGVHD)患者中表现出丰度降低，并且产生的IL-10比无cGVHD患者和健康供者的细胞少。由于Breg细胞缺乏且体外扩增困难，在小鼠模型和早期人体临床试验中，Breg细胞过继转移到自身免疫性疾病方面受到很大限制。糖原合成酶激酶 3β (GSK-3β) 是一种多功能丝氨酸/苏氨酸 (ser/thr) 蛋白激酶，可参与 B 细胞生长、代谢活动和增殖。磷蛋白阵列分析显示p-GSK-3β-s9在mBreg细胞中高表达。此外，我们通过流式细胞术证明 mBreg 细胞中的 GSK-3β 表达低于 B 细胞中观察到的表达。我们发现用特异性GSK-3β抑制剂SB216763处理B细胞可以在体外显着增加mBreg细胞的比例和免疫抑制功能。活化T细胞核因子（NFAT）是适应性免疫系统中基因表达的关键调节因子之一。在这里，我们观察到SB216763抑制GSK-3β会导致B细胞中NFATc1的表达增强，这对于调节B细胞分泌IL-10的能力至关重要。通过构建xGVHD小鼠模型，我们观察到SB216763处理的mBreg细胞有效预防异种GVHD。在这里，我们提出了一种新策略，利用SB216763抑制GSK-3β，然后通过增加NFATc1的表达来增强mBreg细胞的比例和免疫抑制功能。这种方法可用作改善 GVHD 和炎症性疾病的疗法。
CD19+CD24hiCD27+ 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.
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影响因子：
34.7
作者：
Hur, Eun-Mi;Zhou, Feng-Quan
通讯作者：
Zhou, Feng-Quan
影响因子：
3.6
作者：
Li L;Song H;Zhong L;Yang R;Yang XQ;Jiang KL;Liu BZ
通讯作者：
Liu BZ
影响因子：
32.4
作者：
Mizoguchi, A;Mizoguchi, E;Bhan, AK
通讯作者：
Bhan, AK
影响因子：
32.4
作者：
Neves, Patricia;Lampropoulou, Vicky;Fillatreau, Simon
通讯作者：
Fillatreau, Simon
影响因子：
20.3
作者：
Mielke, Stephan;Rezvani, Katayoun;Barrett, A. John
通讯作者：
Barrett, A. John