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J Exp Med. 2008 Jun 9;205(6):1277-83. doi: 10.1084/jem.20080162. Epub 2008 May 12.

Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis.

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  • 1Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Abstract

The high rate of mortality in patients with sepsis results from an inappropriately amplified systemic inflammatory response to infection. Toll-like receptors (TLRs) are important for the activation of innate immunity against microbial pathogens. We demonstrate a critical role of TLR9 in the dysregulated immune response and death associated with sepsis. Compared with wild-type (WT) mice, TLR9(-/-) mice exhibited lower serum inflammatory cytokine levels, higher bacterial clearance, and greater survival after experimental peritonitis induced by cecal ligation and puncture (CLP). Protection of TLR9(-/-) mice after CLP was associated with a greater number of peritoneal dendritic cells (DCs) and granulocytes than in WT controls. Adoptive transfer of TLR9(-/-) DCs was sufficient to protect WT mice from CLP and increased the influx of peritoneal granulocytes. Subsequent experiments with a depleting antibody revealed that granulocytes were required for survival in TLR9(-/-) mice. Remarkably, a single injection of an inhibitory CpG sequence that blocks TLR9 protected WT mice, even when administered as late as 12 h after CLP. Our findings demonstrate that the detrimental immune response to bacterial sepsis occurs via TLR9 stimulation. TLR9 blockade is a potential strategy for the treatment of human sepsis.

PMID:
18474631
[PubMed - indexed for MEDLINE]
PMCID:
PMC2413026
Free PMC Article

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