Foxp3+调节T细胞通过miR-342依赖的机制调节糖皮质激素的抗炎作用
2021/01/29
摘要
糖皮质激素（glucocorticoids, GC）是炎症性疾病的主要治疗药物。尽管GC已被广泛运用，但GC发挥其作用的机制并不完全清楚。本研究中，利用小鼠自身免疫性及过敏性炎症模型，作者发现了Foxp3+调节T（regulatory T, Treg）细胞在体内是不可替代的GC靶细胞。在没有Treg细胞的情况下，地塞米松（dexamethasone, Dex）完全失去其控制炎症的效力，且在缺失糖皮质激素受体的Terg细胞中Dex的治疗效果也消失了。从机制方面来看，Dex在Treg细胞中特异性诱导miR-342-3p表达，然后miR-342-3p直接作用于mTORC2组件Rictor。改变miR-342-3p或Rictor在Treg细胞中的表达导致Treg细胞的代谢进程失调，影响其在体内的调节功能。研究结果揭示了之前未知的Treg细胞在糖皮质激素治疗炎症过程中的作用及其通过Dex-miR-342-Rictor轴实现功能的潜在机制。
Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3+ Regulatory T Cells via a miR-342-Dependent Mechanism
Kim D, Nguyen QT, Lee J, Lee SH, Janocha A, Kim S, Le HT, Dvorina N, Weiss K, Cameron MJ, Asosingh K, Erzurum SC, Baldwin WM 3rd, Lee JS, Min B
Immunity. 2020;53(3):581-596.
ABSTRACT
Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.
糖皮质激素（glucocorticoids, GC）是炎症性疾病的主要治疗药物。尽管GC已被广泛运用，但GC发挥其作用的机制并不完全清楚。本研究中，利用小鼠自身免疫性及过敏性炎症模型，作者发现了Foxp3+调节T（regulatory T, Treg）细胞在体内是不可替代的GC靶细胞。在没有Treg细胞的情况下，地塞米松（dexamethasone, Dex）完全失去其控制炎症的效力，且在缺失糖皮质激素受体的Terg细胞中Dex的治疗效果也消失了。从机制方面来看，Dex在Treg细胞中特异性诱导miR-342-3p表达，然后miR-342-3p直接作用于mTORC2组件Rictor。改变miR-342-3p或Rictor在Treg细胞中的表达导致Treg细胞的代谢进程失调，影响其在体内的调节功能。研究结果揭示了之前未知的Treg细胞在糖皮质激素治疗炎症过程中的作用及其通过Dex-miR-342-Rictor轴实现功能的潜在机制。
(张丽1 张红萍1 王刚2 四川大学华西医院中西医结合科呼吸病组 610041 摘译)
（Immunity. 2020;53(3):581-596.）
（Immunity. 2020;53(3):581-596.）
Anti-inflammatory Roles of Glucocorticoids Are Mediated by Foxp3+ Regulatory T Cells via a miR-342-Dependent Mechanism
Kim D, Nguyen QT, Lee J, Lee SH, Janocha A, Kim S, Le HT, Dvorina N, Weiss K, Cameron MJ, Asosingh K, Erzurum SC, Baldwin WM 3rd, Lee JS, Min B
Immunity. 2020;53(3):581-596.
ABSTRACT
Glucocorticoids (GC) are the mainstay treatment option for inflammatory conditions. Despite the broad usage of GC, the mechanisms by which GC exerts its effects remain elusive. Here, utilizing murine autoimmune and allergic inflammation models, we report that Foxp3+ regulatory T (Treg) cells are irreplaceable GC target cells in vivo. Dexamethasone (Dex) administered in the absence of Treg cells completely lost its ability to control inflammation, and the lack of glucocorticoid receptor in Treg cells alone resulted in the loss of therapeutic ability of Dex. Mechanistically, Dex induced miR-342-3p specifically in Treg cells and miR-342-3p directly targeted the mTORC2 component, Rictor. Altering miRNA-342-3p or Rictor expression in Treg cells dysregulated metabolic programming in Treg cells, controlling their regulatory functions in vivo. Our results uncover a previously unknown contribution of Treg cells during glucocorticoid-mediated treatment of inflammation and the underlying mechanisms operated via the Dex-miR-342-Rictor axis.
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