1. Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.
- Author
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Fu W, Farache J, Clardy SM, Hattori K, Mander P, Lee K, Rioja I, Weissleder R, Prinjha RK, Benoist C, and Mathis D
- Subjects
- Animals, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, Diabetes Mellitus, Type 1 drug therapy, Diabetes Mellitus, Type 1 immunology, Diabetes Mellitus, Type 1 prevention & control, 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, Macrophages drug effects, Macrophages metabolism, Mice, Inbred NOD, Monocytes cytology, Monocytes drug effects, NF-kappa B metabolism, Phenotype, Regeneration drug effects, Signal Transduction drug effects, Transcription, Genetic drug effects, Diabetes Mellitus, Type 1 genetics, Epigenesis, Genetic drug effects, Insulin-Secreting Cells pathology, Macrophages pathology
- 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.
- Published
- 2014
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