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Intracisternally localized bacterial DNA containing CpG motifs induces meningitis
G M Deng1, Z Q Liu, A Tarkowski
1Department of Rheumatology, Göteborg University, Göteborg, Sweden. guo-min@rheuma.gu.se
Abstract:
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-kappaB 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.
Insights
Bacterial DNA containing unmethylated CpG motifs can trigger meningitis by activating macrophages in the central nervous system. This study reveals a novel mechanism of meningitis induction, highlighting the role of prokaryotic DNA in brain inflammation.
Area of Science:
- Neuroimmunology
- Infectious Diseases
- Molecular Biology
Background:
- Unmethylated CpG motifs in bacterial DNA possess immunostimulatory properties.
- Bacterial infections in the central nervous system (CNS) release prokaryotic DNA, potentially triggering inflammatory responses.
Purpose of the Study:
- To investigate if bacterial DNA with CpG motifs can induce meningitis.
- To elucidate the mechanisms underlying CpG-induced meningitis.
Main Methods:
- Intracisternal injection of bacterial DNA and CpG oligonucleotides into rodents.
- Histopathological analysis to assess meningitis.
- Depletion of monocyte/macrophage populations.
- Antisense technology targeting NF-kappaB.
- Assessment of vascular selectin expression and nitric oxide synthase (NOS) inhibition.
Main Results:
- Bacterial DNA induced meningitis characterized by monocytic influx and absence of T lymphocytes.
- Monocyte/macrophage depletion abrogated brain inflammation.
- NF-kappaB inhibition reduced pro-inflammatory cytokine production and meningitis frequency.
- Inhibition of vascular selectin and NOS ameliorated meningitis.
- Neutrophils, NK cells, T/B lymphocytes, IL-12, and complement were not critical.
Conclusions:
- Bacterial DNA containing unmethylated CpG motifs is a potent inducer of meningitis.
- CpG-induced meningitis is primarily mediated by activated macrophages and their products.
- This pathway is independent of adaptive immunity and complement system.