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Uhrf1-Mediated Tnf-α Gene Methylation Controls Proinflammatory Macrophages in Experimental Colitis Resembling

Shanshan Qi1, Yongkui Li1, Zheng Dai1

  • 1Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.

Journal of Immunology (Baltimore, Md. : 1950)
|October 16, 2019
PubMed

Insights

The epigenetic regulator Uhrf1 controls macrophage function in inflammatory bowel diseases (IBD) by regulating Tnf-α. Uhrf1 deficiency exacerbates colitis, suggesting new therapeutic targets for IBD.

Area of Science:

  • Immunology
  • Epigenetics
  • Gastroenterology

Background:

  • Macrophages are key drivers of inflammatory bowel diseases (IBD) through pro-inflammatory cytokine secretion.
  • Epigenetic modifications are linked to macrophage function, but specific mechanisms in IBD are unclear.

Purpose of the Study:

  • To investigate the role of the epigenetic regulator Uhrf1 in regulating macrophage function in the context of intestinal inflammation.
  • To determine if Uhrf1 influences susceptibility to dextran sodium sulfate-induced colitis.

Main Methods:

  • Utilized transgenic mouse models with Uhrf1 deficiency in macrophages or at its DNA methylation site.
  • Assessed colitis susceptibility and analyzed cytokine production from macrophages stimulated with LPS.
  • Investigated the impact of pro-inflammatory cytokines on Uhrf1 expression.

Main Results:

  • Uhrf1 deficiency and mutation led to severe colitis in mice.
  • Macrophages lacking functional Uhrf1 showed hypomethylation of the Tnf-α promoter and increased Tnf-α expression.
  • Anti-Tnf-α therapy indicated Tnf-α's critical role in aggravated colitis.
  • Exogenous Tnf-α destabilized Uhrf1 protein, activating macrophages.

Conclusions:

  • Uhrf1-mediated DNA methylation is crucial for controlling Tnf-α expression in macrophages during experimental colitis.
  • These findings highlight epigenetic mechanisms in macrophage activation as potential therapeutic targets for IBD.

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