β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes
β-Cell DNA Damage Response Promotes Islet Inflammation in Type 1 Diabetes
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DOI：
10.2337/db17-1006
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发表时间：
2018-11-01
期刊：
影响因子：
7.7
通讯作者：
Dor, Yuval
中科院分区：
文献类型：
--
作者：
Horwitz, Elad;Krogvold, Lars;Dor, Yuval
1型糖尿病（T1 D）是一种自身免疫性疾病，其中胰腺β细胞被胰岛浸润T细胞破坏。虽然β细胞缺陷的作用已被怀疑，但β细胞异常很难证明。我们显示了一种β细胞DNA损伤反应（DDR），由53 BP 1蛋白的激活和p53的积累，在活检和尸检材料从最近诊断的T1 D患者以及人类T1 D的大鼠模型。β细胞DDR在CD 45（+）免疫细胞浸润的胰岛中更常见，表明与胰岛炎症有关。β-细胞毒素链脲佐菌素（STZ）在体内和离体两种情况下均增强胰岛中的DDR，并导致促炎分子IL-1 β和Cxcl 10升高。STZ处理的小鼠中主要DNA修复基因共济失调毛细血管扩张突变（ATM）的β细胞特异性失活降低了胰岛中促炎细胞因子的表达并减弱了高血糖症的发展。总之，这些数据表明β细胞DDR是T1 D的早期事件，可能有助于自身免疫。
Type 1 diabetes (T1D) is an autoimmune disease where pancreatic beta-cells are destroyed by islet-infiltrating T cells. Although a role for beta-cell defects has been suspected, beta-cell abnormalities are difficult to demonstrate. We show a beta-cell DNA damage response (DDR), presented by activation of the 53BP1 protein and accumulation of p53, in biopsy and autopsy material from patients with recently diagnosed T1D as well as a rat model of human T1D. The beta-cell DDR is more frequent in islets infiltrated by CD45(+) immune cells, suggesting a link to islet inflammation. The beta-cell toxin streptozotocin (STZ) elicits DDR in islets, both in vivo and ex vivo, and causes elevation of the proinflammatory molecules IL-1 beta and Cxcl10. beta-Cell-specific inactivation of the master DNA repair gene ataxia telangiectasia mutated (ATM) in STZ-treated mice decreases the expression of proinflammatory cytokines in islets and attenuates the development of hyperglycemia. Together, these data suggest that beta-cell DDR is an early event in T1D, possibly contributing to autoimmunity.