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This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: 294/5/F1050    most recent 00461.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Yasuda, H. Articles by Star, R. A. PubMed PubMed Citation Articles by Yasuda, H. Articles by Star, R. A.

EDITORIAL FOCUS

Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury

¹Renal Diagnostics and Therapeutics Unit, National Institute of Diabetes and Digestive and Kidney Diseases, ²Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda; and ³Cancer and Inflammation Program, National Cancer Institute, Frederick, Maryland

Submitted 5 October 2007 ; accepted in final form 25 February 2008

Mortality from sepsis has remained high despite recent advances in supportive and targeted therapies. Toll-like receptors (TLRs) sense bacterial products and stimulate pathogenic innate immune responses. Mice deficient in the common adapter protein MyD88, downstream from most TLRs, have reduced mortality and acute kidney injury (AKI) from polymicrobial sepsis. However, the identity of the TLR(s) responsible for the host response to polymicrobial sepsis is unknown. Here, we show that chloroquine, an inhibitor of endocytic TLRs (TLR3, 7, 8, 9), improves sepsis-induced mortality and AKI in a clinically relevant polymicrobial sepsis mouse model, even when administered 6 h after the septic insult. Chloroquine administration attenuated the decline in renal function, splenic apoptosis, serum markers of damage to other organs, and prototypical serum pro- and anti-inflammatory cytokines TNF- and IL-10. An oligodeoxynucleotide inhibitor (H154) of TLR9 and TLR9-deficient mice mirror the actions of chloroquine in all functional parameters that we tested. In addition, chloroquine decreased TLR9 protein abundance in spleen, further suggesting that TLR9 signaling may be a major target for the protective actions of chloroquine. Our findings indicate that chloroquine improves survival by inhibiting multiple pathways leading to polymicrobial sepsis and that chloroquine and TLR9 inhibitors represent viable broad-spectrum and targeted therapeutic strategies, respectively, that are promising candidates for further clinical development.

multiple organ failure; innate immune system; bacterial products; cytokines