Extracellular histone H3 induces macrophage inflammation in acute liver failure via HDAC2 activation and PKM2...

Area of Science:

• Immunology
• Cell Biology
• Hepatology

Background:

• Acute liver failure (ALF) is a severe condition with limited treatments, often requiring liver transplantation.
• Extracellular histones act as damage-associated molecular patterns (DAMPs), contributing to cellular damage and immune activation.
• The specific role of extracellular histone H3 in macrophage dysfunction during ALF requires further elucidation.

Purpose of the Study:

• To investigate the impact of extracellular histone H3 on macrophage function in acute liver failure.
• To explore the molecular mechanisms underlying histone H3-induced macrophage activation and inflammation.
• To assess the therapeutic potential of targeting histone H3-mediated pathways in ALF.

Main Methods:

• In vivo and in vitro models of acute liver failure.
• Macrophage treatment with extracellular histone H3.
• Analysis of macrophage phenotype, phagocytic capacity, and inflammatory markers.
• Investigation of PKM2 nuclear translocation, glycolytic activity, and HDAC2 expression.
• Pharmacological inhibition of HDAC2 and molecular docking studies.

Main Results:

• Extracellular histone H3 stimulation significantly increased inflammation in vivo.
• In vitro, histone H3 induced a proinflammatory macrophage phenotype with impaired phagocytosis.
• Histone H3 promoted PKM2 nuclear translocation, enhanced glycolysis, and upregulated HDAC2 in macrophages.
• HDAC2 inhibition partially reversed PKM2 nuclear localization and reduced inflammation.
• Direct interaction between HDAC2 and PKM2 was confirmed.

Conclusions:

• Extracellular histone H3 drives a proinflammatory macrophage phenotype in ALF.
• This phenotype is mediated by modulation of HDAC2 expression and PKM2 subcellular localization.
• Targeting the HDAC2-PKM2 interaction may represent a novel therapeutic approach for ALF.