Neuronal injury mediated via stimulation of microglial toll-like receptor-9 (TLR9).
Innate immune cells express toll-like receptor-9 (TLR9) and respond to unmethylated, CG dinucleotide motif-rich DNA released from bacteria during infection or endogenous cells during autoimmune tissue injury. Oligonucleotides containing CG dinucleotide (CpG-DNA) mimic the effect of unmethylated DNA and stimulate TLR9. CpG-DNA was cytotoxic to neurons in organotypic brain cultures. Neurotoxicity of CpG-DNA was mediated via microglial cells and started primarily from neurites as determined by time-lapse imaging of enhanced green fluorescent protein (EGFP)-transfected neurons. Cultured brain microglial cells expressed TLR9 and responded to CpG-DNA by production of the inflammatory mediators nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha). Blockade of NO synthase and TNF-alpha prevented damage of neurites and neurotoxicity of CpG-DNA. The data suggest that stimulation of microglia via TLR9 and subsequent release of NO and TNF-alpha is a major source of neurotoxicity in bacterial and autoimmune brain tissue injury.
Iliev
Asparouh I
AI
Neuroimmunology Unit, European Neuroscience Institute Göttingen, Göttingen, Germany.
Stringaris
Argyrios K
AK
Nau
Roland
R
Neumann
Harald
H
D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000473:pathology; D018899:CpG Islands / Q000235:genetics; D004247:DNA / Q000235:genetics / Q000633:toxicity; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology; D066298:In Vitro Techniques; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D008954:Models, Biological; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D009569:Nitric Oxide / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics / Q000633:toxicity; D011956:Receptors, Cell Surface / Q000378:metabolism*; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D004268:DNA-Binding Proteins; D009841:Oligonucleotides; D011956:Receptors, Cell Surface; D051217:Toll-Like Receptor 9; D014409:Tumor Necrosis Factor-alpha; D009569:Nitric Oxide; D004247:DNA