Institute for Clinical Chemistry and Laboratory Medicine, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
FASEB J. 2020 Feb;34(2):3336-3346. doi: 10.1096/fj.201900125RR. Epub 2020 Jan 9.
In Type 1 Diabetes Mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta cells precede hyperglycemia and clinical disease symptoms. In this context, the role of the pancreatic endothelium as a barrier for autoimmunity- and inflammation-related destruction of the islets is not well studied. Here, we identified Robo4, expressed on endothelial cells, as a regulator of pancreatic vascular endothelial permeability during autoimmune diabetes. Circulating levels of Robo4 were upregulated in mice subjected to the Multiple Low-Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4-deficiency resulted in increased pancreatic vascular permeability, leukocyte infiltration to the islets and islet apoptosis, associated with reduced insulin levels and faster diabetes development. On the contrary, in vivo administration of Slit2 in mice modestly delayed the emergence of hyperglycaemia and ameliorated islet inflammation in MLDS-induced diabetes. Thus, Robo4-mediated endothelial barrier integrity reduces insulitis and islet destruction in autoimmune diabetes. Our findings highlight the importance of the endothelium as gatekeeper of pancreatic inflammation during T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.
在 1 型糖尿病（T1DM）中，胰岛的白细胞浸润以及由此导致的β细胞免疫介导性破坏先于高血糖和临床疾病症状出现。在这种情况下，胰腺内皮作为自身免疫和炎症相关胰岛破坏的屏障的作用尚未得到很好的研究。在这里，我们确定了 Robo4，它在胰岛自身免疫性疾病中表达于内皮细胞上，是调节胰岛血管内皮通透性的一个因子。在多发性低剂量链脲佐菌素（MLDS）诱导的糖尿病小鼠中，循环 Robo4 水平上调。在 MLDS 诱导后，Robo4 缺陷导致胰腺血管通透性增加、白细胞浸润胰岛和胰岛细胞凋亡，与胰岛素水平降低和更快的糖尿病发展相关。相反，在 MLDS 诱导的糖尿病小鼠中，Slit2 的体内给药可适度延迟高血糖的出现，并改善胰岛炎症。因此，Robo4 介导的内皮屏障完整性可减少自身免疫性糖尿病中的胰岛炎症和胰岛破坏。我们的研究结果强调了内皮作为 T1DM 发展过程中胰腺炎症的守门员的重要性，可能为自身免疫性糖尿病的新型 Robo4 相关治疗方法铺平道路。
