School of Life Sciences and Biotechnology, Korea University, Seoul, Korea.
EMBO J. 2011 May 13;30(12):2465-76. doi: 10.1038/emboj.2011.152.
Microglia, the resident macrophages of the mammalian central nervous system, migrate to sites of tissue damage or infection and become activated. Although the persistent secretion of inflammatory mediators by the activated cells contributes to the pathogenesis of various neurological disorders, most activated microglia eventually undergo apoptosis through the process of activation-induced cell death (AICD). The molecular mechanism of AICD, however, has remained unclear. Here, we show that Daxx and mammalian Ste20-like kinase-1 (MST1) mediate apoptosis elicited by interferon-γ (IFN-γ) in microglia. IFN-γ upregulated the expression of Daxx, which in turn mediated the homodimerization, activation, and nuclear translocation of MST1 and apoptosis in microglial cells. Depletion of Daxx or MST1 by RNA interference also attenuated IFN-γ-induced cell death in primary rat microglia. Furthermore, the extent of IFN-γ-induced death of microglia in the brain of MST1-null mice was significantly reduced compared with that apparent in wild-type mice. Our results thus highlight new functions of Daxx and MST1 that they are the key mediators of microglial cell death initiated by the proinflammatory cytokine IFN-γ.
小胶质细胞是哺乳动物中枢神经系统的固有巨噬细胞，它们迁移到组织损伤或感染部位并被激活。尽管激活细胞持续分泌炎症介质有助于各种神经紊乱的发病机制，但大多数激活的小胶质细胞最终通过激活诱导的细胞死亡（AICD）过程而凋亡。然而，AICD 的分子机制仍不清楚。在这里，我们表明 Daxx 和哺乳动物 Ste20 样激酶-1（MST1）介导干扰素-γ（IFN-γ）在小胶质细胞中引发的凋亡。IFN-γ 上调了 Daxx 的表达，进而介导 MST1 的同源二聚化、激活和核易位以及小胶质细胞的凋亡。通过 RNA 干扰耗竭 Daxx 或 MST1 也可减轻原代大鼠小胶质细胞中 IFN-γ 诱导的细胞死亡。此外，与野生型小鼠相比，MST1 缺失小鼠大脑中 IFN-γ 诱导的小胶质细胞死亡程度明显降低。因此，我们的研究结果突出了 Daxx 和 MST1 的新功能，它们是由促炎细胞因子 IFN-γ 引发的小胶质细胞死亡的关键介质。
