Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
- University of California, San Diego, United States
- Harvard Medical School, United States
- Massachusetts General Hospital, Harvard Medical School, United States
- GlaxoSmithKline, United Kingdom
- Pfizer, United States
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.
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Ethics
Animal experimentation: NOD/Lt mice were bred under specific-pathogen-free conditions in our animal facility at the New Research Building of Harvard Medical School, cared for in accordance with the ethical guidelines of the Institutional Animal Care and Use Committee (#02954). Relevant studies were also conducted in accordance with GSK's Policy on the Care, Welfare and Treatment of Laboratory Animals. NOD.Cg-Rag1<tm1mom> mice were maintained in our lab's colony at Jackson Laboratory.
Copyright
© 2014, Fu et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
eLife 3:e04631.
https://doi.org/10.7554/eLife.04631
