A critical role of CpG motifs in a murine peritonitis model by their binding to highly expressed toll-like receptor-9 on liver NKT cells

Backgrounds: Toll-like receptor (TLR)-9 plays a critical role in the recognition of the CpG motifs, which is frequently observed in bacterial DNA. To date, there have not been any reports regarding the role of bacterial DNA in the systemic circulation on the development of sepsis. Methods: We examined the expression of TLR-9 in the liver and spleen in a murine peritonitis model (CLP mice). We also measured the cytokine response of mononuclear cells (MNCs) from normal and CLP mice to CpG oligodeoxynucleotides (ODN) in vitro and in vivo. Results: TLR-9 expression on F4/80(+) and NK1.1(+)CD3 epsilon(+) cells in the liver of CLP mice was elevated compared to sham-operated mice. With regard to cytokine production, we found that CpG ODN markedly stimulated the production of inflammatory cytokines by murine macrophages and liver MNCs. The intravenous injection of CpG ODN in mice that underwent CLP 12 h earlier led to their increased cytokine production and their increased mortality. In addition, the depletion of NK/NKT cells contributed to improve their survival rate. Conclusions: Our results suggest that, in patients with overwhelming bacterial infection, bacterial DNA may induce liver toxicity that is mediated by liver NKT cells and macrophages that express high levels of TLR-9. (c) 2006 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.