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

Maria Troullinaki; Lan-Sun Chen; Anke Witt; Iryna Pyrina; Julia Phieler; Ioannis Kourtzelis; Jindrich Chmelar; David Sprott; Bettina Gercken; Michael Koutsilieris; Triantafyllos Chavakis; Antonios Chatzigeorgiou

doi:10.1096/fj.201900125RR

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

Maria Troullinaki, Lan-Sun Chen, Anke Witt, Iryna Pyrina, Julia Phieler, Ioannis Kourtzelis, Jindrich Chmelar, David Sprott, Bettina Gercken, Michael Koutsilieris, Triantafyllos Chavakis, Antonios Chatzigeorgiou

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

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 T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.

Original language	English
Number of pages	11
Journal	The FASEB Journal
Early online date	9 Jan 2020
DOIs	https://doi.org/10.1096/fj.201900125RR
Publication status	Published - 2020

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10.1096/fj.201900125RR

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title = "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 T1DM development and may pave the way for novel Robo4-related therapeutic approaches for autoimmune diabetes.",

author = "Maria Troullinaki and Lan-Sun Chen and Anke Witt and Iryna Pyrina and Julia Phieler and Ioannis Kourtzelis and Jindrich Chmelar and David Sprott and Bettina Gercken and Michael Koutsilieris and Triantafyllos Chavakis and Antonios Chatzigeorgiou",

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T1 - Robo4-mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes

AU - Troullinaki, Maria

AU - Chen, Lan-Sun

AU - Witt, Anke

AU - Pyrina, Iryna

AU - Phieler, Julia

AU - Kourtzelis, Ioannis

AU - Chmelar, Jindrich

AU - Sprott, David

AU - Gercken, Bettina

AU - Koutsilieris, Michael

AU - Chavakis, Triantafyllos

AU - Chatzigeorgiou, Antonios

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

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DO - 10.1096/fj.201900125RR

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SN - 0892-6638

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