Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis Journal Article
| Authors: | Plitas, G.; Burt, B. M.; Nguyen, H. M.; Bamboat, Z. M.; DeMatteo, R. P. |
| Article Title: | Toll-like receptor 9 inhibition reduces mortality in polymicrobial sepsis |
| 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. © 2008 Plitas et al. The Rockefeller University Press. |
| Keywords: | survival; controlled study; mortality; nonhuman; mouse; animals; mice; mice, knockout; dendritic cell; animal experiment; animal model; inflammation; wild type; mice, inbred c57bl; survivors; cytokines; dendritic cells; cpg oligodeoxynucleotide; sepsis; adoptive transfer; cytokine production; inhibition kinetics; innate immunity; leukocyte count; bacterial infections; lymphocytes; granulocyte; toll-like receptor 9; toll like receptor 9; peritonitis; granulocytes; cecum disease |
| Journal Title: | Journal of Experimental Medicine |
| Volume: | 205 |
| Issue: | 6 |
| ISSN: | 0022-1007 |
| Publisher: | Rockefeller University Press |
| Date Published: | 2008-06-09 |
| Start Page: | 1277 |
| End Page: | 1283 |
| Language: | English |
| DOI: | 10.1084/jem.20080162 |
| PUBMED: | 18474631 |
| PROVIDER: | scopus |
| PMCID: | PMC2413026 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 34" - "Export Date: 17 November 2011" - "CODEN: JEMEA" - "Source: Scopus" |
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