title: Plumbagin Protects Mice from Lethal Sepsis by Modulating Immunometabolism Upstream of PKM2.
abstract: Sepsis is characterized by dysregulated systemic inflammation with release of early (for example, interleukin (IL)-1β) and late (for example, HMGB1) proinflammatory mediators from macrophages. Plumbagin, a medicinal plant-derived naphthoquinone, has been reported to exhibit antiinflammatory activity, but the underling mechanisms remain unclear. Here, we have demonstrated that plumbagin inhibits the inflammatory response through interfering with the immunometabolism pathway in activated macrophages. Remarkably, plumbagin inhibited lipopolysaccharide (LPS)-induced aerobic glycolysis by downregulating the expression of pyruvate kinase M2 (PKM2), a protein kinase responsible for the final and rate-limiting reaction step of the glycolytic pathway. Moreover, the NADPH oxidase 4 (NOX4)-mediated oxidative stress was required for LPS-induced PKM2 expression, because pharmacologic or genetic inhibition of NOX4 by plumbagin or RNA interference limited LPS-induced PKM2 expression, lactate production and subsequent proinflammatory cytokine (IL-1β and HMGB1) release in macrophages. Finally, plumbagin protected mice from lethal endotoxemia and polymicrobial sepsis induced by cecal ligation and puncture. These findings identify a new approach for inhibiting the NOX4/PKM2-dependent immunometabolism pathway in the treatment of sepsis and inflammatory diseases.
authors.affiliation: Department of Pediatrics, The Second Affiliated Hospital of Jinan University, Shenzhen People's Hospital, Shenzhen, Guangdong, People's Republic of China.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Wenjun
authors.initials: W
authors.lastname: Deng
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Rui
authors.initials: R
authors.lastname: Kang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xie
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Billiar
authors.affiliation: Laboratory of Emergency Medicine, The Feinstein Institute for Medical Research, Manhasset, New York, United States of America.
authors.forename: Haichao
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China.
authors.forename: Lizhi
authors.initials: L
authors.lastname: Cao
authors.affiliation: Department of Surgery, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.|Center for DAMP Biology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, People's Republic of China.
authors.forename: Daolin
authors.initials: D
authors.lastname: Tang