Iliev Asparouh I, Stringaris Argyrios K, Nau Roland, Neumann Harald
Neuroimmunology Unit, European Neuroscience Institute Göttingen, Göttingen, Germany.
FASEB J. 2004 Feb;18(2):412-4. doi: 10.1096/fj.03-0670fje. Epub 2003 Dec 19.
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.
固有免疫细胞表达Toll样受体9（TLR9），并对感染期间从细菌释放的未甲基化、富含CG二核苷酸基序的DNA或自身免疫性组织损伤期间的内源性细胞作出反应。含有CG二核苷酸的寡核苷酸（CpG-DNA）模拟未甲基化DNA的作用并刺激TLR9。CpG-DNA对器官型脑培养物中的神经元具有细胞毒性。CpG-DNA的神经毒性是通过小胶质细胞介导的，并且如通过增强型绿色荧光蛋白（EGFP）转染神经元的延时成像所确定的，主要从神经突开始。培养的脑小胶质细胞表达TLR9，并通过产生炎症介质一氧化氮（NO）和肿瘤坏死因子-α（TNF-α）对CpG-DNA作出反应。一氧化氮合酶和TNF-α的阻断可防止神经突损伤和CpG-DNA的神经毒性。数据表明，通过TLR9刺激小胶质细胞以及随后释放NO和TNF-α是细菌和自身免疫性脑组织损伤中神经毒性的主要来源。
