Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes
Role of uncoupling protein UCP2 in cell-mediated immunity: How macrophage-mediated insulitis is accelerated in a model of autoimmune diabetes
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DOI：
10.1073/pnas.0709557104
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发表时间：
2007-11-27
影响因子：
11.1
通讯作者：
Ricquier, Daniel
中科院分区：
文献类型：
--
作者：
Emre, Yalin;Hurtaud, Corinne;Ricquier, Daniel
炎症细胞浸润到胰岛和选择性破坏胰岛素分泌β细胞是1型糖尿病的特征。解偶联蛋白2（UCP 2）是在免疫细胞中表达的线粒体蛋白。UCP 2通过调节线粒体活性氧（ROS）的产生和MAPK信号传导来控制巨噬细胞活化。我们研究了UCP 2对UCP 2缺陷小鼠1型糖尿病免疫细胞活性的作用。使用多次低剂量链脲佐菌素（STZ）诱导的糖尿病模型，我们发现，与胰岛内淋巴细胞浸润增加的Ucp 2-WT小鼠相比，Ucp 2-KO小鼠的自身免疫性糖尿病强烈加速。与WT巨噬细胞相比，来自STZ处理的Ucp 2-KO小鼠的巨噬细胞增加了IL-1 β和一氧化氮（NO）的产生。此外，与Ucp 2-WT小鼠相比，STZ处理的Ucp 2-KO小鼠的胰岛中招募了更多的巨噬细胞。这一发现也伴随着增加NO/ROS诱导的损伤。总而言之，我们的数据表明，Ucp 2-KO小鼠和胰岛中的炎症更强，导致这些小鼠的疾病加重。我们的研究结果强调了线粒体蛋白UCP 2作为自身免疫性糖尿病的新参与者。
Infiltration of inflammatory cells into pancreatic islets of Langerhans and selective destruction of insulin-secreting beta-cells are characteristics of type 1 diabetes. Uncoupling protein 2 (UCP2) is a mitochondrial protein expressed in immune cells. UCP2 controls macrophage activation by modulating the production of mitochondrial reactive oxygen species (ROS) and MAPK signaling. We investigated the role of UCP2 on immune cell activity in type 1 diabetes in Ucp2-deficient mice. Using the model of multiple low-dose streptozotocin (STZ)-induced diabetes, we found that autoimmune diabetes was strongly accelerated in Ucp2-KO mice, compared with Ucp2-WT mice with increased intraislet lymphocytic infiltration. Macrophages from STZ-treated Ucp2-KO mice had increased IL-1 beta and nitric oxide (NO) production, compared with WT macrophages. Moreover, more macrophages were recruited in islets of STZ-treated Ucp2-KO mice, compared with Ucp2-WT mice. This finding also was accompanied by increased NO/ROS-induced damage. Altogether, our data show that inflammation is stronger in Ucp2-KO mice and islets, leading to the exacerbated disease in these mice. Our results highlight the mitochondrial protein UCP2 as a new player in autoimmune diabetes.