Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation
Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation
复制标题
Toll 样受体在小胶质细胞长期激活过程中促进核转录因子核因子的线粒体易位
DOI：
10.1523/jneurosci.2455-14.2015
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发表时间：
2015-07-29
影响因子：
5.3
通讯作者：
Cai, Huaibin
中科院分区：
文献类型：
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作者：
Ma, Bo;Yu, Jia;Cai, Huaibin
小胶质细胞是CNS中的常驻巨噬细胞，其使用模式识别Toll样受体（TLR）来识别病原体、垂死细胞和分子。活化T细胞核因子（NFAT）家族转录因子也调节小胶质细胞中的炎症反应。然而，TLR和NFAT信号之间是否存在串扰尚不清楚。在这里，我们表明，长期刺激Toll样受体4（TLR 4）配体脂多糖（LPS）的小鼠小胶质细胞的慢性激活导致意外易位NFAT 1进入线粒体。NFAT 1的这种线粒体输入不依赖于钙/钙调神经磷酸酶信号。相反，抑制含有Toll/白细胞介素1受体结构域的衔接子诱导的干扰素-β（TRIF）途径阻断了NFAT 1的线粒体易位。在功能上，NFAT 1的抑制降低了TRIF介导的干扰素-β的表达，并损害了LPS处理的小胶质细胞中ATP和活性氧的产生。因此，我们的研究结果揭示了一种新的炎症信号通路，它将TLR与NFAT联系起来，调节慢性小胶质细胞活化过程中细胞因子的产生和线粒体活性。已知活化T细胞核因子（NFAT）家族转录因子在炎症刺激反应中发生核转位。在这项研究中，我们发现了一个令人惊讶的运输NFAT进入线粒体的小胶质细胞后，长时间的治疗与细菌内毒素脂多糖（LPS）。LPS激活Toll样受体4及其下游Toll/白细胞介素1受体结构域的衔接子诱导干扰素-β（TRIF），以调节小胶质细胞中NFAT的线粒体转位，而NFAT 1的遗传抑制则会损害TRIF介导的细胞因子产生，并减少ATP和活性氧的产生。这些发现揭示了一个以前未描述的线粒体易位NFAT在小胶质细胞响应延长激活Toll样受体介导的信号转导通路。
Microglia are resident macrophages in the CNS that scavenge pathogens, dying cells, and molecules using pattern recognition Toll-like receptors (TLRs). Nuclear factor of activated T-cells (NFAT) family transcription factors also regulate inflammatory responses in microglia. However, whether there exists cross talk between TLR and NFAT signaling is unclear. Here we show that chronic activation of murine microglia by prolonged stimulation of Toll-like receptor 4 (TLR4) ligand lipopolysaccharides (LPSs) leads to unexpected translocation of NFAT1 into mitochondria. This mitochondrial import of NFAT1 is independent of calcium/calcineurin signaling. Instead, inhibition of Toll/interleukin 1 receptor domain-containing adapter-inducing interferon-β (TRIF) pathway blocks the mitochondrial translocation of NFAT1. Functionally, inhibition of NFAT1 reduces the TRIF-mediated expression of interferon-β and compromises the production of ATP and reactive oxygen species in LPS-treated microglia. Therefore, our findings reveal a new inflammatory signaling pathway that links TLR with NFAT in regulating cytokine production and mitochondrial activity during chronic microglial activation. SIGNIFICANCE STATEMENT Nuclear factor of activated T-cells (NFAT) family transcription factors are known to undergo nuclear translocation in response to inflammatory stimulation. In this study, we uncovered a surprise transportation of NFATs into mitochondria in microglia after a prolonged treatment with bacteria endotoxin lipopolysaccharides (LPSs). LPSs activated Toll-like receptor 4 and its downstream Toll/interleukin 1 receptor-domain-containing adapter-inducing interferon-β (TRIF) to regulate the mitochondrial translocation of NFAT in microglia, whereas genetic inhibition of NFAT1 compromised TRIF-mediated cytokine production and reduced ATP and reactive oxygen species generation. These findings reveal a previously undescribed mitochondrial translocation of NFAT in microglia responding to extended activation of Toll-like receptor-mediated signaling transduction pathways.