title: Chloroquine inhibits HMGB1 inflammatory signaling and protects mice from lethal sepsis.
abstract: Sepsis is caused by an overwhelming immune response to bacterial infection. The discovery of high mobility group box 1 (HMGB1) as a late mediator of lethal sepsis has prompted investigation into the development of new therapeutics which specifically target this protein. Here, we show that chloroquine, an anti-malarial drug, prevents lethality in mice with established endotoxemia or sepsis. This effect is still observed even if administration of chloroquine is delayed. The protective effects of chloroquine were mediated through inhibition of HMGB1 release in macrophages, monocytes, and endothelial cells, thereby preventing its cytokine-like activities. As an inhibitor of autophagy, chloroquine specifically inhibited HMGB1-induced Iκ-B degradation and NF-κB activation. These findings define a novel mechanism for the anti-inflammatory effects of chloroquine and also suggest a new potential clinical use for this drug in the setting of sepsis.
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan 410008, People's Republic of China.
authors.forename: Minghua
authors.initials: M
authors.lastname: Yang
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.forename: Liangchun
authors.initials: L
authors.lastname: Yang
authors.forename: Mingyi
authors.initials: M
authors.lastname: Zhao
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000627:therapeutic use*; D002460:Cell Line; D002738:Chloroquine / Q000627:therapeutic use*; D024243:HMGB1 Protein / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018836:Inflammation Mediators / Q000627:therapeutic use*; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018805:Sepsis / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D015996:Survival Rate
chemical_list: D000962:Antimalarials; D024243:HMGB1 Protein; C582808:HMGB1 protein, mouse; D018836:Inflammation Mediators; D002738:Chloroquine
keywords: Autophagy; Beclin 1; Chloroquine; HMGB1; NF-κB; Sepsis