The endothelial receptor Robo4 protects from islet inflammation during MLDS–Induced Diabetes in Mice

1) Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden, Dresden, Germany,

2) Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece

Background: In type 1 diabetes mellitus (T1DM), leukocyte infiltration of the pancreatic islets and the resulting immune-mediated destruction of beta-cells precedes hyperglycemia and the clinical symptoms of the disease. Nevertheless, the role of pancreatic endothelium as a regulating barrier during autoimmune tissue destruction remains scarce. Signalling through Robo4 (an endothelial-specific receptor of the Robo family) is known to promote vascular stability under inflammatory conditions by reducing endothelial permeability. The aim of this study was to determine whether Robo4-deficiency induces endothelial hyper-permeability in pancreas leading to increased inflammatory response during T1DM development. Methods: The Multiple Low Dose Streptozotocin (MLDS) model of autoimmune diabetes was performed in Robo4-deficient and sufficient mice. Blood glucose and insulin levels were monitored at specific intervals up to 15 days upon starting MLDS induction. Insulitis development and pancreatic islet leukocyte infiltration were evaluated by histological studies, while vascular permeability was evaluated by an in vivo permeability assay. Results: Robo4 was expressed in the pancreatic endothelium. Robo4-deficient mice displayed increased permeability of the pancreatic endothelium and increased leukocyte infiltration of the pancreatic islets leading to exacerbated hyperglycaemia, reduced insulin levels and faster diabetes development upon MLDS as compared to the Robo4-sufficient mice. Together, Robo4 is a gatekeeper of the pancreatic endothelium ameliorating islet inflammation during MLDS–induced Diabetes.