IKZF1 exacerbates the inflammatory response by epigenetically modulating mitochondrial function following acute...

Area of Science:

• Immunology
• Molecular Biology
• Cellular Metabolism

Background:

• Macrophages are crucial for immune response but can cause tissue damage when overactivated.
• Acute peritonitis involves dysregulated macrophage inflammation.
• The role of transcription factor IKZF1 in peritonitis-induced macrophage activation is unknown.

Purpose of the Study:

• To investigate the molecular mechanism of IKZF1 in regulating inflammatory responses during acute peritonitis.
• To explore the potential of targeting IKZF1 for therapeutic intervention.

Main Methods:

• Murine cecal ligation and puncture (CLP) model of peritonitis.
• Analysis of IKZF1 expression, mitochondrial function (ROS, ATP, succinate), and SDHB acetylation.
• Use of lenalidomide (IKZF1 inhibitor) and acetate supplementation.
• Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) assays.

Main Results:

• IKZF1 expression increased in macrophages during CLP peritonitis.
• Lenalidomide treatment suppressed IKZF1, reduced inflammation, and mitigated lung injury.
• IKZF1 repressed SDHB expression via HDAC3 recruitment, causing mitochondrial dysfunction and inflammation.
• Acetate supplementation restored SDHB acetylation and counteracted inflammation.

Conclusions:

• IKZF1 exacerbates macrophage inflammation in peritonitis by epigenetically silencing SDHB through HDAC3-mediated deacetylation.
• This disrupts mitochondrial metabolism and amplifies pro-inflammatory signals.
• Targeting IKZF1 or enhancing acetylation presents novel therapeutic strategies for acute inflammatory conditions, with IKZF1 as a potential biomarker.