title: Toll-Like Receptors Promote Mitochondrial Translocation of Nuclear Transcription Factor Nuclear Factor of Activated T-Cells in Prolonged Microglial Activation.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Transgenics Section and.
authors.forename: Bo
authors.initials: B
authors.lastname: Ma
authors.affiliation: Transgenics Section and.
authors.forename: Jia
authors.initials: J
authors.lastname: Yu
authors.affiliation: Transgenics Section and.
authors.forename: Chengsong
authors.initials: C
authors.lastname: Xie
authors.affiliation: Transgenics Section and.
authors.forename: Lixin
authors.initials: L
authors.lastname: Sun
authors.affiliation: Transgenics Section and.
authors.forename: Shannon
authors.initials: S
authors.lastname: Lin
authors.affiliation: Bioinformatics Core, Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland 20892, and.
authors.forename: Jinhui
authors.initials: J
authors.lastname: Ding
authors.affiliation: Transgenics Section and Department of Biochemistry and Molecular Biology, Beijing Normal University, Beijing Key Laboratory, Beijing 100875, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Luo
authors.affiliation: Transgenics Section and caih@mail.nih.gov.
authors.forename: Huaibin
authors.initials: H
authors.lastname: Cai
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000378:metabolism*; D021381:Protein Transport / Q000502:physiology; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D014162:Transfection
chemical_list: D008070:Lipopolysaccharides; D050778:NFATC Transcription Factors; C494007:Nfatc2 protein, mouse; D034741:RNA, Small Interfering; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4
keywords: NFAT; Toll-like receptor; microglia; mitochondria; neuroinflammation