Runx3 prevents spontaneous colitis by directing the differentiation of anti-inflammatory mononuclear phagocytes

Area of Science:

• Immunology
• Gastroenterology
• Molecular Biology

Background:

• Mice lacking the transcription factor Runx3 exhibit immune system defects and early-onset colitis.
• Runx3 expression is identified in colonic mononuclear phagocytes (MNP), including resident macrophages (RM) and dendritic cell subsets (cDC2).

Purpose of the Study:

• To investigate the role of Runx3 in colonic mononuclear phagocytes (MNP) and its impact on intestinal immune homeostasis.
• To elucidate the mechanisms by which Runx3 deficiency leads to colitis.

Main Methods:

• Analysis of Runx3 expression in colonic MNP subsets (RM and cDC2).
• Assessment of MNP maturation, gene expression profiles (pro-inflammatory and anti-inflammatory genes), and signaling pathways (TGF-β, β-catenin) in Runx3-deficient mice.
• Transcriptome and ChIP-seq analysis to identify direct Runx3 targets.

Main Results:

• Runx3 deletion in MNP results in impaired maturation and an imbalance of MNP subsets, causing early-onset colitis.
• Pro-inflammatory gene expression is upregulated, while anti-inflammatory/TGF-β-regulated genes and β-catenin signaling genes are downregulated in specific MNP subsets.
• A significant portion of genes affected by Runx3 loss are direct Runx3 targets, as indicated by transcriptome and ChIP-seq data.

Conclusions:

• Runx3 is essential for maintaining intestinal immune tolerance by regulating the maturation of colonic anti-inflammatory MNP.
• Runx3 deficiency disrupts MNP homeostasis, leading to gut inflammation and colitis.
• These findings support the role of RUNX3 as a risk gene for human gastrointestinal immune diseases like Crohn's disease and celiac disease.