Sirtuin2 通过抑制信号转导子和转录激活子 3 的表达抑制调节性 T 细胞向 Th17 细胞的极化，在小鼠结肠炎模型中。
Sirtuin2 suppresses the polarization of regulatory T cells toward T helper 17 cells through repressing the expression of signal transducer and activator of transcription 3 in a mouse colitis model.
机构信息
Department of Gastroenterology, Hubei Clinical Center and Key Laboratory for Intestinal and Colorectal Diseases, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Hematology and Oncology, Wuhan Children's Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
出版信息
Immun Inflamm Dis. 2024 Feb;12(2):e1160. doi: 10.1002/iid3.1160.
INTRODUCTION
Regulatory T cells (Tregs) play an important role in inflammatory bowel diseases (IBDs) through modulating intestinal inflammation. However, the factors affecting Treg function and plasticity during IBD progression are not thoroughly disclosed. The current study aims to reveal new molecular mechanisms affecting Treg plasticity.
METHODS
A mouse strain, in which tdTomato and enhanced green fluorescent protein were under the control of the Foxp3 promoter and Il17a promoter, was established and subjected to colitis induction with dextran sulfate sodium. The existence of Tregs and IL-17-expressing Tregs (i.e., Treg/T helper 17 [Th17] cells) were observed and sorted from the spleen, mesenteric lymph nodes, and lamina propria by flow cytometry, followed by measuring Sirtuin2 (Sirt2) expression using quantitative reverse transcription polymerase chain reaction and Immunoblotting. Lentivirus-induced Sirt2 silencing was applied to determine the impact of Sirt2 on Treg polarization to Treg/Th17 cells and even Th17 cells. The effect of Sirt2 on Stat3 was analyzed by flow cytometry and immunoblotting.
RESULTS
Sirt2 was highly expressed in lamina propria Tregs and it moderately suppressed Foxp3 expression as well as the immunosuppressive function of Tregs. Surprisingly, lentivirus-mediated Sirt2 silencing promoted the generation of Treg/Th17 cells out of Tregs. Sirt2 silencing also enhanced the generation of Th17 cells out of Tregs under the Th17 induction condition. Furthermore, Sirt2 inhibited Th17 induction by suppressing the protein level of the signal transducer and activator of transcription 3.
CONCLUSION
Sirt2 suppresses Treg function but also inhibits Treg polarization toward Treg/Th17 cells and Th17 cells. The ultimate effect of Sirt2 on colitis might depend on the balance among Tregs, Treg/Th17 cells, and Th17 cells.
简介
调节性 T 细胞（Tregs）通过调节肠道炎症在炎症性肠病（IBD）中发挥重要作用。然而，在 IBD 进展过程中影响 Treg 功能和可塑性的因素尚未完全揭示。本研究旨在揭示影响 Treg 可塑性的新分子机制。
方法
建立了一种在 Foxp3 启动子和 Il17a 启动子控制下表达 tdTomato 和增强型绿色荧光蛋白的小鼠品系，并通过葡聚糖硫酸钠诱导结肠炎。通过流式细胞术观察并从脾、肠系膜淋巴结和固有层中分离出 Tregs 和表达 IL-17 的 Tregs（即 Treg/T 辅助 17 [Th17] 细胞），并用定量逆转录聚合酶链反应和免疫印迹法测量 Sirtuin2（Sirt2）表达。应用慢病毒诱导的 Sirt2 沉默来确定 Sirt2 对 Treg 向 Treg/Th17 细胞甚至 Th17 细胞极化的影响。通过流式细胞术和免疫印迹法分析 Sirt2 对 Stat3 的影响。
结果
Sirt2 在固有层 Tregs 中高表达，适度抑制 Foxp3 表达和 Tregs 的免疫抑制功能。令人惊讶的是，慢病毒介导的 Sirt2 沉默促进了 Tregs 向 Treg/Th17 细胞的转化。Sirt2 沉默在 Th17 诱导条件下也增强了 Tregs 向 Th17 细胞的转化。此外，Sirt2 通过抑制信号转导和转录激活因子 3 的蛋白水平抑制 Th17 诱导。
结论
Sirt2 抑制 Treg 功能，但也抑制 Treg 向 Treg/Th17 细胞和 Th17 细胞的极化。Sirt2 对结肠炎的最终影响可能取决于 Tregs、Treg/Th17 细胞和 Th17 细胞之间的平衡。
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