TY - JOUR
T1 - AMPK regulates immunometabolism in sepsis
AU - Huang, Jun
AU - Liu, Ke
AU - Zhu, Shan
AU - Xie, Min
AU - Kang, Rui
AU - Cao, Lizhi
AU - Tang, Daolin
N1 - Funding Information:
We thank Christine Heiner (Department of Surgery, University of Pittsburgh) for her critical reading of the manuscript. This work was supported by grants from the US National Institutes of Health ( R01GM115366 , R01CA160417 , and R01CA211070 ), the Natural Science Foundation of Guangdong Province ( 2016A030308011 ), the American Cancer Society (Research Scholar Grant RSG-16-014-01-CDD ), the National Natural Science Foundation of China ( 31671435 , 81402247 , 81400132 , and 81772508 ), and Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2017). This project partly utilized University of Pittsburgh Cancer Institute shared resources supported by award P30CA047904 .
Publisher Copyright:
© 2017 Elsevier Inc.
PY - 2018/8
Y1 - 2018/8
N2 - Sepsis and septic shock remain challenging for intensive care units worldwide and have limited treatment options; therefore, identification of targetable key players in systemic inflammation and multiple organ failure is urgently needed. Here, we show that AMP-activated protein kinase (AMPK) is a negative regulator of bioenergetic reprogramming in immune cells and suppresses sepsis development in vivo. Mechanistically, AMPK deficiency increases pyruvate kinase isozyme M2 (PKM2)-dependent aerobic glycolysis, which leads to the release of high mobility group box 1 (HMGB1, a late mediator of lethal systemic inflammation) in macrophages and monocytes. Consequently, activation of AMPK by A-769662 protects whereas depletion of AMPKα in myeloid cells promotes endotoxic shock and polymicrobial sepsis in mice. Additionally, administration of the PKM2 inhibitor shikonin reduces lactate production, HMGB1 release, and septic death in AMPKα-deficient mice. These findings suggest that disruption of the AMPK-dependent immunometabolism pathway may contribute to sepsis development and hence constitute a target for therapeutic intervention.
AB - Sepsis and septic shock remain challenging for intensive care units worldwide and have limited treatment options; therefore, identification of targetable key players in systemic inflammation and multiple organ failure is urgently needed. Here, we show that AMP-activated protein kinase (AMPK) is a negative regulator of bioenergetic reprogramming in immune cells and suppresses sepsis development in vivo. Mechanistically, AMPK deficiency increases pyruvate kinase isozyme M2 (PKM2)-dependent aerobic glycolysis, which leads to the release of high mobility group box 1 (HMGB1, a late mediator of lethal systemic inflammation) in macrophages and monocytes. Consequently, activation of AMPK by A-769662 protects whereas depletion of AMPKα in myeloid cells promotes endotoxic shock and polymicrobial sepsis in mice. Additionally, administration of the PKM2 inhibitor shikonin reduces lactate production, HMGB1 release, and septic death in AMPKα-deficient mice. These findings suggest that disruption of the AMPK-dependent immunometabolism pathway may contribute to sepsis development and hence constitute a target for therapeutic intervention.
KW - AMPK
KW - DAMP
KW - HMGB1
KW - Sepsis
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U2 - 10.1016/j.bbi.2017.11.003
DO - 10.1016/j.bbi.2017.11.003
M3 - Article
C2 - 29109024
AN - SCOPUS:85032885042
SN - 0889-1591
VL - 72
SP - 89
EP - 100
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -