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Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor-alpha-mediated shock
T Sparwasser1, T Miethke, G Lipford
1Institute of Medical Microbiology, Immunology and Hygiene, Technical University of Munich, Germany.
Abstract:
Cell surface components of pathogens, such as lipopolysaccharide (LPS), are an important signal for receptor-mediated activation of immune cells. Here we demonstrate that DNA of gram-positive and gram-negative bacteria or certain synthetic oligonucleotides displaying unmethylated CpG-motifs can trigger macrophages in vitro to induce nuclear translocation of nuclear factor-kappa B, accumulate tumor necrosis factor (TNF)-alpha mRNA and release large amounts of TNF-alpha. In vivo these events culminate in acute cytokine-release syndrome which includes systemic but transient accumulation of TNF-alpha. D-Galactosamine (DGalN)-sensitized mice succumb to lethal toxic shock due to macrophage-derived TNF-alpha resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF-alpha-release, suggesting that macrophages integrate the respective signals. The ability of macrophages to discriminate and to respond to bacterial DNA with acute release of pro-inflammatory cytokines may point out an important and as yet unappreciated sensing mechanism for foreign DNA.
Insights
Bacterial DNA, particularly CpG-motifs, activates macrophages to release tumor necrosis factor-alpha (TNF-alpha), a key cytokine in immune responses. This discovery highlights a novel sensing mechanism for foreign DNA in macrophages.
Area of Science:
- Immunology
- Microbiology
- Molecular Biology
Background:
- Pathogen cell surface components like lipopolysaccharide (LPS) activate immune cells.
- Macrophages play a crucial role in innate immunity and pathogen recognition.
Purpose of the Study:
- To investigate the immune-activating properties of bacterial DNA.
- To elucidate the signaling pathways triggered by bacterial DNA in macrophages.
Main Methods:
- In vitro stimulation of macrophages with bacterial DNA and synthetic CpG oligonucleotides.
- Analysis of nuclear factor-kappa B (NF-kappa B) translocation.
- Quantification of tumor necrosis factor-alpha (TNF-alpha) mRNA and protein levels.
- In vivo studies using D-Galactosamine (DGalN)-sensitized mice to assess toxic shock.
Main Results:
- Bacterial DNA and CpG-motifs induced NF-kappa B translocation, TNF-alpha mRNA accumulation, and TNF-alpha release in macrophages.
- In vivo administration led to acute cytokine-release syndrome with systemic TNF-alpha accumulation.
- LPS and CpG oligonucleotides showed synergistic effects on TNF-alpha release in vivo.
- Macrophage-derived TNF-alpha caused lethal toxic shock and liver cell apoptosis in DGalN-sensitized mice.
Conclusions:
- Macrophages possess a sensing mechanism for bacterial DNA, triggering pro-inflammatory cytokine release.
- This response is critical in host defense but can lead to detrimental effects like toxic shock.
- The findings reveal an unappreciated pathway for detecting foreign DNA and initiating immune responses.