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In this context, the role of the pancreatic endothelium as a barrier for autoimmunity\u2010 and inflammation\u2010related 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\u2010Dose Streptozotocin (MLDS) model of diabetes. Upon MLDS induction, Robo4\u2010deficiency 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\u2010induced diabetes. Thus, Robo4\u2010mediated 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\u2010related therapeutic approaches for autoimmune diabetes.<\/jats:p>","DOI":"10.1096\/fj.201900125rr","type":"journal-article","created":{"date-parts":[[2020,1,9]],"date-time":"2020-01-09T06:01:32Z","timestamp":1578549692000},"page":"3336-3346","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Robo4\u2010mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes"],"prefix":"10.1096","volume":"34","author":[{"given":"Maria","family":"Troullinaki","sequence":"first","affiliation":[{"name":"Institute for Clinical Chemistry and Laboratory Medicine University Clinic Carl Gustav Carus Technische Universit\u00e4t Dresden Dresden 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Laboratory Medicine University Clinic Carl Gustav Carus Technische Universit\u00e4t Dresden Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bettina","family":"Gercken","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Laboratory Medicine University Clinic Carl Gustav Carus Technische Universit\u00e4t Dresden Dresden Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Koutsilieris","sequence":"additional","affiliation":[{"name":"Department of Physiology Medical School National and Kapodistrian University of Athens Athens Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Triantafyllos","family":"Chavakis","sequence":"additional","affiliation":[{"name":"Institute for Clinical Chemistry and Laboratory Medicine University Clinic Carl Gustav Carus Technische Universit\u00e4t Dresden Dresden Germany"},{"name":"Paul Langerhans Institute Dresden of the Helmholtz 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