Intracisternally localized bacterial DNA containing CpG motifs induces meningitis

Unmethylated CpG motifs are frequently found in bacterial DNA, and have rec ently been shown to exert immunostimulatory effects on leukocytes. Since ba cterial infections in the CNS will lead to local release of prokaryotic DNA , we wanted to investigate whether such an event might trigger meningitis. To that end, we have intracisternally injected mice and rats with bacterial DNA and oligonucleotides containing CpG motifs. Histopathological signs of meningitis were evident within 12 h and lasted for at least 14 days, and w ere characterized by an influx of monocytic, Mac-3(+) cells and by a lack o f T lymphocytes. To study the mechanisms whereby unmethylated CpG DNA gives rise to meningitis, we deleted the monocyte/macrophage population leading to abrogation of brain inflammation. Also, interaction with NF-KB using ant isense technology led to down-regulation of proinflammatory cytokine produc tion and frequency of meningitis. Furthermore, specific interactions with v ascular selectin expression and inhibition of NO synthase led to a signific ant amelioration of meningitis, altogether indicating that this condition i s dependent on macrophages and their products. In contrast, neutrophils, NK cells, T/B lymphocytes, IL-12, and complement system were not instrumental in meningitis triggered by bacterial DNA containing CpG motifs. This study proves that bacterial DNA containing unmethylated CpG motifs induces menin gitis, and indicates that this condition is mediated in vivo by activated m acrophages.