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
Abstract:
Toll-like receptor (TLR)-9 plays a critical role in the recognition of the CpG motifs,
which are frequently observed in bacterial DNA. To date, there have been few reports examining expression of TLR-9 in organs,
or regarding the role of bacterial DNA in the systemic circulation in the development of sepsis.
In this study, we examined TLR-9 expression in the liver and spleen in a murine peritonitis model
(cecum ligation and puncture; CLP) using flow cytometry.
We also measured the cytokine response of mononuclear cells (MNCs) from normal and CLP mice to CpG
oligodeoxynucleotides (ODN) in vitro and in vivo.
TLR-9 expression on F4/80+ and NK1.1+ cells in the liver of CLP mice was elevated compared to
sham-operated mice. Furthermore, among the population of NK1.1+ cells,
TLR-9 expression was elevated on NK1.1+CD3ε+ cells, but not on NK1.1+CD3ε- cells in these
animals. With regard to cytokine production, we found that CpG ODN markedly stimulated the production of inflammatory cytokines
by murine macrophages and liver MNCs. In addition, the intravenous injection of CpG ODN in mice
that underwent CLP 12 hrs earlier led to their increased production of MIP-2, IL-12, IFNγ,
and IL-10. Such treatment also resulted in an elevation in serum alanine aminotransferase (ALT)
levels and histopathologically discernable liver injury that resulted in an increased mortality.
In conclusion, our results suggest that in generalized peritonitis, bacterial DNA may induce hepatic
injury that is mediated by liver NKT cells and macrophages that express high levels of TLR-9.
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