Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.
Epigenetic modulation of type-1 diabetes via a dual effect on pancreatic macrophages and β cells.
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DOI：
10.7554/elife.04631
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发表时间：
2014-11-19
期刊：
影响因子：
7.7
通讯作者：
Mathis D
中科院分区：
文献类型：
--
作者：
Fu W;Farache J;Clardy SM;Hattori K;Mander P;Lee K;Rioja I;Weissleder R;Prinjha RK;Benoist C;Mathis D
表观遗传修饰剂是一类新兴的抗肿瘤药物，在多种癌症中均有效。它们对自发性自身免疫性疾病的影响很少被研究。我们报告说，I-BET151（一种含溴结构域转录调节因子家族的小分子抑制剂）的短期治疗可不可逆地抑制 NOD 小鼠 1 型糖尿病的发展。该抑制剂可以预防或清除胰岛炎，但对浸润和循环 T 细胞的转录组影响很小。相反，它诱导胰腺巨噬细胞采取抗炎表型，尤其影响 NF-κB 通路。 I-BET151 还引发胰岛 β 细胞再生，诱导编码对 β 细胞分化/功能至关重要的转录因子的基因的增殖和表达。对 β 细胞的影响不需要 T 细胞浸润胰岛。因此，I-BET151 治疗实现了许多糖尿病研究人员目前提倡的“联合疗法”，其通过一种新机制进行操作，同时抑制胰岛炎症并增强 β 细胞再生。 DOI：http://dx.doi.org/10.7554/eLife.04631.001 细胞内的 DNA 通常紧紧包裹在蛋白质周围，形成称为染色质的紧凑结构。添加到染色质中的化学基团可以促使附近的基因打开或关闭；一些酶和其他蛋白质有助于读取、添加或去除染色质上的这些标记。如果这些染色质修饰（或相关的酶和蛋白质）受到干扰，可能会导致癌症等疾病。还有人提出，类似的变化可能会影响自身免疫性疾病，即免疫系统攻击人体自身组织。目前正在开发针对读取、添加或删除这些染色质修饰的蛋白质的药物来治疗癌症。例如，抑制这些蛋白质家族（BET）的药物有助于治疗患有血液癌或淋巴结癌的小鼠的肿瘤。然而，由于这些药物针对涉及免疫系统的途径，因此它们也可能可用于治疗自身免疫性疾病。现在傅等人。测试了 BET 抑制剂是否可能有效治疗 1 型糖尿病。在 1 型糖尿病患者中，胰腺中产生胰岛素激素的细胞被免疫系统杀死。如果没有足够的胰岛素水平，1 型糖尿病患者的血糖水平可能会出现危险的高低水平，必须服用胰岛素，有时还必须服用其他药物。 Fu 等人使用在相对年轻时自发患上 1 型糖尿病的小鼠。测试了如果小鼠在生命早期接受 BET 抑制剂两周会发生什么。接受治疗的小鼠在余生中都不会患上 1 型糖尿病。具体来说，该治疗保护了胰岛素产生细胞并允许它们继续产生胰岛素。该药物减少了胰腺的炎症，并增加了促进胰岛素生成细胞再生的基因的表达。糖尿病研究人员一直在寻找能够保护胰岛素生成细胞并促进其再生的药物组合。因此，Fu 等人。表明这些发现证明了进一步研究的合理性，以确定 BET 抑制剂是否有助于治疗或预防人类 1 型糖尿病。 DOI：http://dx.doi.org/10.7554/eLife.04631.002
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. DOI: http://dx.doi.org/10.7554/eLife.04631.001 The DNA inside a cell is often tightly wrapped around proteins to form a compact structure called chromatin. Chemical groups added to the chromatin can encourage nearby genes to either be switched on or off; and several enzymes and other proteins help to read, add, or remove these marks from the chromatin. If these chromatin modifications (or the related enzymes and proteins) are disturbed it can lead to diseases like cancer. It has also been suggested that similar changes may influence autoimmune diseases, in which the immune system attacks the body's own tissues. Drugs that target the proteins that read, add, or remove these chromatin modifications are currently being developed to treat cancer. For example, drugs that inhibit one family of these proteins called BET have helped to treat tumors in mice that have cancers of the blood or lymph nodes. However, because these drugs target pathways involved in the immune system they may also be useful for treating autoimmune diseases. Now Fu et al. have tested whether a BET inhibitor might be a useful treatment for type-1 diabetes. In patients with type-1 diabetes, the cells in the pancreas that produce the insulin hormone are killed off by the immune system. Without adequate levels of insulin, individuals with type-1 diabetes may experience dangerous highs and lows in their blood sugar levels and must take insulin and sometimes other medications. Using mice that spontaneously develop type-1 diabetes when still relatively young, Fu et al. tested what would happen if the mice received a BET inhibitor for just 2 weeks early on in life. Treated mice were protected from developing type-1 diabetes for the rest of their lives. Specifically, the treatment protected the insulin-producing cells and allowed them to continue producing insulin. The drug reduced inflammation in the pancreas and increased the expression of genes that promote the regeneration of insulin-producing cells. Diabetes researchers have been searching for drug combinations that protect the insulin-producing cells and boost their regeneration. As such, Fu et al. suggest that these findings justify further studies to see if BET inhibitors may help to treat or prevent type-1 diabetes in humans. DOI: http://dx.doi.org/10.7554/eLife.04631.002