MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium.
MicroRNA-23a Curbs Necrosis during Early T Cell Activation by Enforcing Intracellular Reactive Oxygen Species Equilibrium.
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DOI：
10.1016/j.immuni.2016.01.007
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发表时间：
2016-03-15
期刊：
影响因子：
32.4
通讯作者：
Li QJ
中科院分区：
文献类型：
--
作者：
Zhang B;Liu SQ;Li C;Lykken E;Jiang S;Wong E;Gong Z;Tao Z;Zhu B;Wan Y;Li QJ
在抗原结合时，需要增加胞浆内的活性氧(ROS)来实现最佳的T细胞受体(TCR)信号。然而，不受控制的ROS产生是导致坏死的一个重要原因，这会引起过度炎症和组织损伤。因此，编程激活的T细胞以达到ROS平衡是至关重要的。在这里，我们确定miR-23a对于效应器CD4+T细胞的扩增是不可或缺的，特别是通过提供对过度坏死的早期保护。从机制上讲，miR-23a以PPIF为靶点，PPIF是线粒体通透性转换孔的守门人，从而限制ROS通量并维持线粒体的完整性。在急性单核细胞增多性李斯特菌感染时，缺失T细胞miR-23a会导致过度炎症、大量肝损伤和死亡率显著增加，这突显了miR-23a在维持免疫平衡中的重要作用。
Upon antigen engagement, augmented cytosolic reactive oxygen species (ROS) are needed to achieve optimal T cell receptor (TCR) signaling. However, uncontrolled ROS production is a prominent cause of necrosis, which elicits hyper-inflammation and tissue damage. Hence, it is critical to program activated T cells to achieve ROS equilibrium. Here, we determined that miR-23a is indispensable for effector CD4+ T cell expansion, particularly by providing early protection from excessive necrosis. Mechanistically, miR-23a targeted PPIF, gatekeeper of the mitochondria permeability transition pore, thereby restricting ROS flux and maintaining mitochondrial integrity. Upon acute Listeria monocytogenes infection, deleting miR-23a in T cells resulted in excessive inflammation, massive liver damage and a marked mortality increase, which highlights the essential role of miR-23a in maintaining immune homeostasis.