Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection
Modelling pancreatic β-cell inflammation in zebrafish identifies the natural product wedelolactone for human islet protection
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DOI：
10.1242/dmm.036004
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发表时间：
2019-01-01
影响因子：
4.3
通讯作者：
Ninov, Nikolay
中科院分区：
文献类型：
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作者：
Delgadillo-Silva, Luis Fernando;Tsakmaki, Anastasia;Ninov, Nikolay
胰岛炎症和细胞因子产生与胰腺β细胞功能障碍和糖尿病发病机制有关。然而，我们缺乏治疗方法来保护产生胰岛素的β细胞免受炎症损伤。填补这一临床空白需要建立胰岛炎症的新疾病模型，以促进旨在鉴定新保护剂的筛选工作。在这里，我们已经开发了一个遗传模型的白细胞介素-1 β（IL-1 β）驱动的胰岛炎症在斑马鱼，脊椎动物，允许非侵入性成像的β细胞和体内药物发现。我们模型中免疫细胞和β细胞的实时成像显示动态迁移、访问增加和巨噬细胞在胰岛中保留时间延长，以及β细胞中NF-κ B信号传导的强烈激活。我们发现IL-1 β介导的炎症不会导致β细胞破坏，而是损害β细胞的功能和特性。在体内，β-细胞表现出葡萄糖刺激的钙内流受损以及参与功能和成熟的基因表达降低。这些缺陷伴随着α细胞扩增、葡萄糖耐受不良和葡萄糖挑战后的高血糖症。值得注意的是，我们表明，药用植物衍生物（wedelolactone）是能够减少免疫细胞浸润，同时也改善我们的模型的高血糖表型。重要的是，斑马鱼中的这些抗糖尿病特性预测了wedelolactone在保护啮齿动物和人类胰岛免受苦参碱诱导的细胞凋亡中的功效。总之，这种糖尿病的新斑马鱼模型为研究体内免疫和β细胞之间的相互作用打开了一扇窗，同时也允许鉴定用于保护β细胞免受炎症的治疗剂。
Islet inflammation and cytokine production are implicated in pancreatic beta-cell dysfunction and diabetes pathogenesis. However, we lack therapeutics to protect the insulin-producing beta-cells from inflammatory damage. Closing this clinical gap requires the establishment of new disease models of islet inflammation to facilitate screening efforts aimed at identifying new protective agents. Here, we have developed a genetic model of Interleukin-1 beta (Il-1 beta)-driven islet inflammation in zebrafish, a vertebrate that allows for non-invasive imaging of beta-cells and in vivo drug discovery. Live imaging of immune cells and beta-cells in our model revealed dynamic migration, increased visitation and prolonged macrophage retention in the islet, together with robust activation of NF-kappa B signalling in beta-cells. We find that Il-1 beta-mediated inflammation does not cause beta-cell destruction but, rather, it impairs beta-cell function and identity. In vivo, beta-cells exhibit impaired glucose-stimulated calcium influx and reduced expression of genes involved in function and maturity. These defects are accompanied by alpha-cell expansion, glucose intolerance and hyperglycemia following a glucose challenge. Notably, we show that a medicinal plant derivative (wedelolactone) is capable of reducing the immune-cell infiltration while also ameliorating the hyperglycemic phenotype of our model. Importantly, these anti-diabetic properties in zebrafish are predictive of wedelolactone's efficacy in protecting rodent and human islets fromcytokine-induced apoptosis. Insummary, this newzebrafish model of diabetes opens a window to study the interactions between immune and beta-cells in vivo, while also allowing the identification of therapeutic agents for protecting beta-cells from inflammation.