Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells

Elife. 2014 Nov 19;3:e04631. doi: 10.7554/eLife.04631.

Abstract

Epigenetic modifiers are an emerging class of anti-tumor drugs, potent in multiple cancer contexts. Their effect on spontaneously developing autoimmune diseases has been little explored. We report that a short treatment with I-BET151, a small-molecule inhibitor of a family of bromodomain-containing transcriptional regulators, irreversibly suppressed development of type-1 diabetes in NOD mice. The inhibitor could prevent or clear insulitis, but had minimal influence on the transcriptomes of infiltrating and circulating T cells. Rather, it induced pancreatic macrophages to adopt an anti-inflammatory phenotype, impacting the NF-κB pathway in particular. I-BET151 also elicited regeneration of islet β-cells, inducing proliferation and expression of genes encoding transcription factors key to β-cell differentiation/function. The effect on β cells did not require T cell infiltration of the islets. Thus, treatment with I-BET151 achieves a 'combination therapy' currently advocated by many diabetes investigators, operating by a novel mechanism that coincidentally dampens islet inflammation and enhances β-cell regeneration.

Keywords: NF-KB; autoimmune diabetes; bromodomain inhibitor; immunology; mouse.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / drug effects
  • CD4-Positive T-Lymphocytes / immunology
  • Diabetes Mellitus, Type 1 / drug therapy
  • Diabetes Mellitus, Type 1 / genetics*
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / prevention & control
  • Epigenesis, Genetic* / drug effects
  • Female
  • Heterocyclic Compounds, 4 or More Rings / pharmacology
  • Heterocyclic Compounds, 4 or More Rings / therapeutic use
  • Inflammation / pathology
  • Insulin-Secreting Cells / drug effects
  • Insulin-Secreting Cells / metabolism
  • Insulin-Secreting Cells / pathology*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Macrophages / pathology*
  • Mice, Inbred NOD
  • Monocytes / cytology
  • Monocytes / drug effects
  • NF-kappa B / metabolism
  • Phenotype
  • Regeneration / drug effects
  • Signal Transduction / drug effects
  • Transcription, Genetic / drug effects

Substances

  • GSK1210151A
  • Heterocyclic Compounds, 4 or More Rings
  • NF-kappa B