Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells
- Harvard Medical School, United States
- Massachusetts General Hospital, Harvard Medical School, United States
- GlaxoSmithKline, United Kingdom
- Harvard Medical School and Brigham and Women's Hospital, United States
Figures
Figure 1
I-BET151 inhibits diabetes and insulitis in NOD mice.
Female NOD mice were treated with I-BET151 in DMSO (10 mg/kg daily) or just DMSO from 3–5 weeks (A and D) or 12–14 weeks (B and E) of age. (A and B) Pre-diabetic mice. Hyperglycemia was monitored …
Figure 2
Little impact of BET-protein inhibition on CD4+ T cells in NOD mice.
(A) Microarray-based transcriptional profiling of TCR+CD4+ cells sorted from pancreata, pancreatic lymph nodes (PLNs) and inguinal lymph nodes (ILNs). Comparison plot of I-BET151- and DMSO-treated …
Figure 3
I-BET151 treatment promotes an MF-like, anti-inflammatory transcriptional program in pancreatic CD45+ cells.
(A and B) A volcano plot comparing the transcriptomes of pancreatic CD45+ cells from mice treated with I-BET151 or DMSO as per Figure 1B. Red: transcripts increased >twofold; blue: transcripts …
Figure 4
The NF-κB signaling pathway is a major focus of I-BET151's influence on NOD leukocytes.
(A) Upper panels: The inhibitor's effect on NF-κB-regulated genes—defined as per http://www.bu.edu/nf-kb/gene-resources/target-genes. Left, relevant transcripts from pancreatic CD45+ cells of NOD …
Figure 5
Effects of I-BET151 on human monocyte-derived MFs.
Cultures of human MFs were differentiated from peripheral-blood-derived CD14+ cells, pre-cultured for 30 min with I-BET151 (red bars) or just DMSO (blue bars), and stimulated for another 4 hr after …
Figure 6 with 2 supplements
BET-protein inhibition promotes regeneration of islet β cells.
(A) Pancreatic β cells were cytofluorometrically sorted from mice treated with I-BET151 or DMSO as per Figure 1B, and microarray-based transcriptional profiling performed. Red: transcripts increased …
Figure 6—figure supplement 1
Histologic analysis of β-cell proliferation in response to I-BET151 in NOD mice.
NOD mice were treated with I-BET151 or DMSO as in Figure 1B. EdU was administrated during the last 24 hr. Frozen sections of pancreas were stained for insulin and EdU. Left, representative islet …
Figure 6—figure supplement 2
Histologic analysis of β-cell proliferation in response to I-BET151 in NOD.Rag−/− mice.
NOD.Rag−/− mice were treated with I-BET151 or DMSO as in Figure 1B. EdU was administrated during the last 24 hr. Frozen sections of pancreas were stained for insulin and EdU. Left, representative …
Additional files
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Supplementary file 1
Genes over-represented in pancreatic CD45+ cells of NOD mice treated with I-BET151.
- https://doi.org/10.7554/eLife.04631.011
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Supplementary file 2
Genes under-represented in pancreatic CD45+ cells of NOD mice treated with I-BET151.
- https://doi.org/10.7554/eLife.04631.012
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Supplementary file 3
Expression of NF-κB target genes in pancreatic CD45+ cells of NOD mice treated with I-BET151.
- https://doi.org/10.7554/eLife.04631.013
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Supplementary file 4
Transcripts over-represented in β cells of NOD mice treated with I-BET151.
- https://doi.org/10.7554/eLife.04631.014
