Tanner D C, Campbell A, O'Banion K M, Noble M, Mayer-Pröschel M
Department of Biomedical Genetics, School of Medicine and Dentistry, University of Rochester, Rochester, NY 14642, USA.
Department of Neurobiology and Anatomy, School of Medicine and Dentistry, University of Rochester, 601 Elmwood Avenue, Box 633, Rochester, NY 14642, USA.
Cell Death Differ. 2015 Sep;22(9):1489-501. doi: 10.1038/cdd.2014.237. Epub 2015 Jan 30.
Neuroinflammation associated with degenerative central nervous system disease and injury frequently results in oligodendrocyte death. While promoting oligodendrocyte viability is a major therapeutic goal, little is known about protective signaling strategies. We report that in highly purified rat oligodendrocytes, interferon gamma (IFNγ) activates a signaling pathway that protects these cells from tumor necrosis factor alpha (TNFα)-induced cytotoxicity. IFNγ protection requires Jak (Janus kinase) activation, components of the integrated stress response and NF-κB activation. Although NF-κB activation also occurred transiently in the absence of IFNγ and presence of TNFα, this activation was not sufficient to prevent induction of the TNFα-responsive cell death pathway. Genetic inhibition of NF-κB translocation to the nucleus abrogated IFNγ-mediated protection and did not change the cell death induced by TNFα, suggesting that NF-κB activation via IFNγ induces a different set of responses than activation of NF-κB via TNFα. A promising candidate is the NF-κB target cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein), which is protease-deficient caspase homolog that inhibits caspase-3 activation. We show that IFNγ-mediated protection led to upregulation of cFLIP. Overexpression of cFLIP was sufficient for oligodendrocyte protection from TNFα and short hairpin RNA knockdown of cFLIP-abrogated IFNγ -mediated protection. To determine the relevance of our in vitro finding to the more complex in vivo situation, we determined the impact on oligodendrocyte death of regional cFLIP loss of function in a murine model of neuroinflammation. Our data show that downregulation of cFLIP during inflammation leads to death of oligodendrocytes and decrease of myelin in vivo. Taken together, we show that IFNγ-mediated induction of cFLIP expression provides a new mechanism by which this cytokine can protect oligodendrocytes from TNFα-induced cell death.
与中枢神经系统退行性疾病和损伤相关的神经炎症常导致少突胶质细胞死亡。虽然促进少突胶质细胞的存活是主要治疗目标，但对于保护性信号传导策略却知之甚少。我们报告，在高度纯化的大鼠少突胶质细胞中，干扰素γ（IFNγ）激活一条信号通路，保护这些细胞免受肿瘤坏死因子α（TNFα）诱导的细胞毒性。IFNγ的保护作用需要Jak（Janus激酶）激活、综合应激反应的成分以及NF-κB激活。虽然在没有IFNγ且存在TNFα的情况下NF-κB也会短暂激活，但这种激活不足以防止TNFα反应性细胞死亡途径的诱导。对NF-κB向细胞核易位的基因抑制消除了IFNγ介导的保护作用，且未改变TNFα诱导的细胞死亡，这表明通过IFNγ激活NF-κB诱导的反应与通过TNFα激活NF-κB诱导的反应不同。一个有前景的候选分子是NF-κB靶标cFLIP（细胞FLICE（FADD样白细胞介素-1β转换酶）抑制蛋白），它是一种缺乏蛋白酶活性的半胱天冬酶同源物，可抑制半胱天冬酶-3的激活。我们表明，IFNγ介导的保护作用导致cFLIP上调。cFLIP的过表达足以保护少突胶质细胞免受TNFα的损伤，而cFLIP的短发夹RNA敲低则消除了IFNγ介导的保护作用。为了确定我们体外研究结果与更复杂的体内情况的相关性，我们在神经炎症小鼠模型中确定了区域cFLIP功能丧失对少突胶质细胞死亡的影响。我们的数据表明，炎症期间cFLIP的下调会导致体内少突胶质细胞死亡和髓鞘减少。综上所述，我们表明IFNγ介导的cFLIP表达诱导提供了一种新机制，通过该机制这种细胞因子可以保护少突胶质细胞免受TNFα诱导的细胞死亡。
