Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis.
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.
Plitas
George
G
Hepatobiliary Service, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Burt
Bryan M
BM
Nguyen
Hoang M
HM
Bamboat
Zubin M
ZM
DeMatteo
Ronald P
RP
D019264:Adoptive Transfer; D000818:Animals; D001424:Bacterial Infections / Q000276:immunology / Q000503:physiopathology*; D016207:Cytokines / Q000502:physiology; D003713:Dendritic Cells / Q000276:immunology; D006098:Granulocytes / Q000502:physiology; D007249:Inflammation / Q000517:prevention & control*; D007958:Leukocyte Count; D008214:Lymphocytes / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018805:Sepsis / Q000276:immunology / Q000503:physiopathology*; D017741:Survivors; D051217:Toll-Like Receptor 9 / Q000172:deficiency*
D016207:Cytokines; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9