The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20080162
The Journal of Experimental Medicine, Vol. 205, No. 6, 1277-1283
The Rockefeller University Press, 0022-1007 $30.00
© Plitas et al.
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BRIEF DEFINITIVE REPORT

 Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis

George Plitas, Bryan M. Burt, Hoang M. Nguyen, Zubin M. Bamboat, and Ronald P. DeMatteo

Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065

CORRESPONDENCE Ronald P. DeMatteo: dematter{at}mskcc.org

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.

© 2008 Plitas et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jgp.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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