Macrophage efferocytosis is controlled by epigenetic modifications mediated by RBPJ

Area of Science:

• Immunology
• Epigenetics
• Cell Biology

Background:

• Efferocytosis is vital for resolving inflammation and maintaining tissue homeostasis.
• The epigenetic mechanisms governing macrophage-mediated efferocytosis remain largely unknown.

Purpose of the Study:

• To investigate the role of epigenetic alterations in macrophage-mediated efferocytosis.
• To elucidate the function of Recombination Signal Binding Protein for Immunoglobulin Kappa J region (RBPJ) in regulating efferocytosis and inflammation.

Main Methods:

• Cleavage Under Targets and Release Using Nuclease (CUT&RUN) sequencing to identify genome-wide epigenetic changes.
• Utilized mouse and human primary macrophages from various tissues (atherosclerotic plaque, alveolar, peritoneal, bone marrow).
• Investigated the impact of Notch signaling inhibition and activation on efferocytosis.

Main Results:

• A genome-wide suppression of H3K9me3 (heterochromatin mark) was observed in macrophages during efferocytosis.
• RBPJ dampened H3K9me3, enhanced efferocytosis, and suppressed inflammation in multiple macrophage types.
• RBPJ upregulated Stard13 and Arsg by reducing H3K9me3 on their promoters, promoting efferocytosis via actin polymerization.
• Inhibition of SUV39H1/H2 methyltransferases augmented efferocytosis in RBPJ knockout macrophages.

Conclusions:

• Epigenetic regulation, specifically H3K9me3 suppression mediated by RBPJ, plays a critical role in efferocytosis.
• RBPJ-mediated epigenetic changes are crucial for efferocytosis and inflammation resolution in tissue macrophages.
• This study uncovers a novel mechanism of epigenetic control over efferocytosis, with implications for inflammatory diseases.