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Department of Rheumatology, Göteborg University, Göteborg, Sweden
Unmethylated CpG motifs are frequently found in bacterial DNA, and
have recently been shown to exert immunostimulatory effects on
leukocytes. Since bacterial 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 were
characterized by an influx of monocytic, Mac-3+ cells and
by a lack of 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-
B using antisense technology
led to down-regulation of proinflammatory cytokine production and
frequency of meningitis. Furthermore, specific interactions with
vascular selectin expression and inhibition of NO synthase led to a
significant amelioration of meningitis, altogether indicating that this
condition is 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 meningitis, and indicates that this
condition is mediated in vivo by activated
macrophages.
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