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Troullinaki, M. ; Chen, L.-S.* ; Witt, A.* ; Pyrina, I.* ; Phieler, J.* ; Kourtzelis, I.* ; Chmelar, J.* ; Sprott, D.* ; Gercken, B.* ; Koutsilieris, M.* ; Chavakis, T. ; Chatzigeorgiou, A.*

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

FASEB J. 34, 3336-3346 (2020)
Forschungsdaten DOI PMC
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Endothelium ; Insulitis ; Leukocyte Infiltration ; Pancreatic Islets ; Type 1 Diabetes Mellitus (t1dm); Beta-cell Death; Gene-expression; Adhesion Molecules; Adipose-tissue; Real-time; Robo4; Angiogenesis; Receptor; Growth; Disruption
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 0892-6638
e-ISSN 1530-6860
Zeitschrift FASEB Journal
Quellenangaben Band: 34, Heft: 2, Seiten: 3336-3346 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort Bethesda, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Pancreatic Islet Research (IPI)
Institute of Diabetes and Cancer (IDC)
POF Topic(s) 90000 - German Center for Diabetes Research
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-502600-008
G-501900-251
DOI 10.1096/fj.201900125RR
WOS ID WOS:000506442300001
Scopus ID 85078677283
PubMed ID 31916652
Erfassungsdatum 2020-03-09
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