Published online May 12, 2008
doi:10.1084/jem.20080162
The Journal of Experimental Medicine
The Rockefeller University Press, 0022-1007 $30.00
© 2008 Plitas et al.
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.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
