AMPK regulates immunometabolism in sepsis

Jun Huang, Ke Liu, Shan Zhu, Min Xie, Rui Kang, Lizhi Cao, Daolin Tang

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)89-100
Number of pages12
JournalBrain, Behavior, and Immunity
Volume72
DOIs
StatePublished - Aug 2018
Externally publishedYes

Keywords

  • AMPK
  • DAMP
  • HMGB1
  • Sepsis

ASJC Scopus subject areas

  • Immunology
  • Endocrine and Autonomic Systems
  • Behavioral Neuroscience

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