Robo4‐mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes

Abstract

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

Recombinant ling zhi-8 enhances Tregs function to restore glycemic control in streptozocin-induced diabetic rats

“…Due to excessive inflammatory cytokines play a crucial role in the development and progression of diabetes, [ 24 ] we next to evaluate the effect of rLZ‐8 on the expressions of TNF‐α, IL‐1β and IL‐10. As shown in Figure 4, the levels of TNF‐α and IL‐1β in pancreas and serum were significantly increased after STZ treatment as compared to the control group, while the level of IL‐10 in STZ group was also markedly reduced (Figure 4).…”

Hepatic Senescence Accompanies the Development of NAFLD in Non-Aged Mice Independently of Obesity

“…The SsoFast EvaGreen Supermix (BioRad, Hercules, CA, USA) was used to perform qPCR on an iQ5 Bio-Rad cycler system. The calculation of the relative mRNA expression was performed according to the ∆∆Ct method [42] by using the expression of eukaryotic translation elongation factor 2 (ETEF2) for normalization among samples [43,44].…”

Vascular Leakage Prevention by Roundabout 4 under Pathological Conditions

“…Mice lacking Robo4 are viable and show slightly increased vascular permeability under basal conditions. 22,28,29) In several disease models, such as those of hypoxia-induced retinopathy, 22) cancer, 24) diabetes, 30) and endotoxemia, 29,31) studies have shown that lack of Robo4 leads to more severe vascular leakage. Robo4 stabilizes endothelial permeability by regulating both adherens junctions and tight junctions in endothelial cells.…”

“…Robo4 stabilizes endothelial permeability by regulating both adherens junctions and tight junctions in endothelial cells. 29,32,33) Adherens junctions are involved in the transmigration of cancer and immune cells, [34][35][36] and lack of Robo4 enhances lung metastasis of cancers 24,37) and diapedesis of immune cells. 29) In vitro studies have shown that Robo4 suppresses endothelial hyperpermeability induced by various stimuli such as vascular endothelial growth factor (VEGF), 22,38) interleukin-1β (IL-1β), 31) tumor necrosis factor α (TNF-α), 29,31) and histamine.…”

“…29,32,33) Adherens junctions are involved in the transmigration of cancer and immune cells, [34][35][36] and lack of Robo4 enhances lung metastasis of cancers 24,37) and diapedesis of immune cells. 29) In vitro studies have shown that Robo4 suppresses endothelial hyperpermeability induced by various stimuli such as vascular endothelial growth factor (VEGF), 22,38) interleukin-1β (IL-1β), 31) tumor necrosis factor α (TNF-α), 29,31) and histamine. 38) Recent evidence suggests that Robo4 regulates endothelial permeability through several distinct mechanisms.…”