Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation

作者：Ma, Bo; Yu, Jia; Xie, Chengsong; Sun, Lixin; Lin, Shannon; Ding, Jinhui; Luo, Jing; Cai, Huaibin^*

来源：Journal of Neuroscience, 2015, 35(30): 10799-10814.

DOI：10.1523/JNEUROSCI.2455-14.2015

• microglia
• mitochondria
• neuroinflammation
• NFAT
• Toll-like receptor

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-beta (TRIF) pathway blocks the mitochondrial translocation of NFAT1. Functionally, inhibition of NFAT1 reduces the TRIF-mediated expression of interferon-beta 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.

• 出版日期2015-7-29
• 单位NIH; 北京师范大学