AMPK regulates immunometabolism in sepsis

Brain Behav Immun. 2018 Aug:72:89-100. doi: 10.1016/j.bbi.2017.11.003. Epub 2017 Nov 3.

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.

Keywords: AMPK; DAMP; HMGB1; Sepsis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • AMP-Activated Protein Kinases / physiology
  • Animals
  • Biphenyl Compounds
  • Endotoxemia / metabolism
  • HMGB1 Protein / metabolism
  • Humans
  • Immunomodulation / immunology
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes
  • Myeloid Cells / metabolism
  • Pyrones / pharmacology
  • Pyruvate Kinase / metabolism
  • Sepsis / immunology*
  • Sepsis / metabolism*
  • THP-1 Cells
  • Thiophenes / pharmacology

Substances

  • Biphenyl Compounds
  • HMGB1 Protein
  • Pyrones
  • Thiophenes
  • Pyruvate Kinase
  • AMP-Activated Protein Kinases
  • 4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile