Macrophages sense pathogens via DNA motifs: induction of tumor necrosis factor‐α‐mediated shock

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-xB, accumulate tumor necrosis factor (TNF)-α mRNA and release large amounts of TNF-α. In vivo these events culminate in acute cytokine-release syndrome which includes systemic but transient accumulation of TNF-α. D-Galactosamine (D-GalN)-sensitized mice succumb to lethal toxic shock due to macrophage-derived TNF-α resulting in fulminant apoptosis of liver cells. LPS and a specific oligonucleotide synergized in vivo as measured by TNF-α-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.