title: Chloroquine and inhibition of Toll-like receptor 9 protect from sepsis-induced acute kidney injury.
abstract: 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-alpha 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.
authors.forename: Hideo
authors.initials: H
authors.lastname: Yasuda
authors.forename: Asada
authors.initials: A
authors.lastname: Leelahavanichkul
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Tsunoda
authors.forename: James W
authors.initials: JW
authors.lastname: Dear
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Takahashi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ito
authors.forename: Xuzhen
authors.initials: X
authors.lastname: Hu
authors.forename: Hua
authors.initials: H
authors.lastname: Zhou
authors.forename: Kent
authors.initials: K
authors.lastname: Doi
authors.forename: Richard
authors.initials: R
authors.lastname: Childs
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Peter S T
authors.initials: PS
authors.lastname: Yuen
authors.forename: Robert A
authors.initials: RA
authors.lastname: Star
mesh_terms: D000208:Acute Disease; D058186:Acute Kidney Injury / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001806:Blood Urea Nitrogen; D002738:Chloroquine / Q000627:therapeutic use*; D003404:Creatinine / Q000097:blood; D016207:Cytokines / Q000097:blood; D007668:Kidney / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018805:Sepsis / Q000150:complications* / Q000382:microbiology; D013154:Spleen / Q000473:pathology; D016019:Survival Analysis; D051217:Toll-Like Receptor 9 / Q000037:antagonists & inhibitors* / Q000235:genetics
chemical_list: D000962:Antimalarials; D016207:Cytokines; D051217:Toll-Like Receptor 9; D002738:Chloroquine; D003404:Creatinine