Abstract
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.
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