Robo4-mediated pancreatic endothelial integrity decreases inflammation and islet destruction in autoimmune diabetes.
Type 1 Diabetes Mellitus (T1DM)
endothelium
insulitis
leukocyte infiltration
pancreatic islets
Journal
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
ISSN: 1530-6860
Titre abrégé: FASEB J
Pays: United States
ID NLM: 8804484
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
14
01
2019
revised:
23
12
2019
accepted:
24
12
2019
pubmed:
10
1
2020
medline:
7
10
2020
entrez:
10
1
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31916652
doi: 10.1096/fj.201900125RR
doi:
Substances chimiques
Receptors, Cell Surface
0
Robo4 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3336-3346Informations de copyright
© 2020 Federation of American Societies for Experimental Biology.
Références
van Belle TL, Coppieters KT, von Herrath MG. Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol Rev. 2011;91:79-118.
Pugliese A. Insulitis in the pathogenesis of type 1 diabetes. Pediatr Diabetes. 2016;17 Suppl 22:31-36.
Goddard LM, Iruela-Arispe ML. Cellular and molecular regulation of vascular permeability. Thromb Haemost. 2013;109:407-415.
Orlova VV, Chavakis T. Regulation of vascular endothelial permeability by junctional adhesion molecules (JAM). Thromb Haemost. 2007;98:327-332.
Ley K, Laudanna C, Cybulsky MI, Nourshargh S. Getting to the site of inflammation: the leukocyte adhesion cascade updated. Nat Rev Immunol. 2007;7:678-689.
Zanone MM, Favaro E, Camussi G. From endothelial to beta cells: insights into pancreatic islet microendothelium. Curr Diabetes Rev. 2008;4:1-9.
Nyman LR, Wells KS, Head WS, et al. Real-time, multidimensional in vivo imaging used to investigate blood flow in mouse pancreatic islets. J Clin Invest. 2008;118:3790-3797.
Eberhard D, Kragl M, Lammert E. ‘Giving and taking’: endothelial and beta-cells in the islets of Langerhans. Trends Endocrinol Metab. 2010;21:457-463.
In't Veld P, Lammert E. The dark side of islet vasculature. Diabetologia. 2015;58:4-6.
Blockus H, Chedotal A. Slit-Robo signaling. Development. 2016;143:3037-3044.
Okada Y, Yano K, Jin E, et al. A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. Circ Res. 2007;100:1712-1722.
Park KW, Morrison CM, Sorensen LK, et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev Biol. 2003;261:251-267.
Koch AW, Mathivet T, Larrivee B, et al. Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev Cell. 2011;20:33-46.
Jones CA, London NR, Chen H, et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat Med. 2008;14:448-453.
London NR, Zhu W, Bozza FA, et al. Targeting Robo4-dependent Slit signaling to survive the cytokine storm in sepsis and influenza. Sci Transl Med. 2010;2:23ra19.
Chia JS, McRae JL, Thomas HE, et al. The protective effects of CD39 overexpression in multiple low-dose streptozotocin-induced diabetes in mice. Diabetes. 2013;62:2026-2035.
Garcia-Martin R, Alexaki VI, Qin N, et al. Adipocyte-specific hypoxia-inducible factor 2alpha deficiency exacerbates obesity-induced brown adipose tissue dysfunction and metabolic dysregulation. Mol Cell Biol. 2015;36:376-393.
Chung KJ, Chatzigeorgiou A, Economopoulou M, et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol. 2017;18:654-664.
Kourtzelis I, Kotlabova K, Lim JH, et al. Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation. Thromb Haemost. 2016;115:781-788.
Masjkur J, Arps-Forker C, Poser SW, et al. Hes3 is expressed in the adult pancreatic islet and regulates gene expression, cell growth, and insulin release. J Biol Chem. 2014;289:35503-35516.
Mellado-Gil J, Rosa TC, Demirci C, et al. Disruption of hepatocyte growth factor/c-Met signaling enhances pancreatic beta-cell death and accelerates the onset of diabetes. Diabetes. 2011;60:525-536.
Flodstrom M, Tyrberg B, Eizirik DL, Sandler S. Reduced sensitivity of inducible nitric oxide synthase-deficient mice to multiple low-dose streptozotocin-induced diabetes. Diabetes. 1999;48:706-713.
Pejnovic NN, Pantic JM, Jovanovic IP, et al. Galectin-3 deficiency accelerates high-fat diet-induced obesity and amplifies inflammation in adipose tissue and pancreatic islets. Diabetes. 2013;62:1932-1944.
Pavlovic S, Petrovic I, Jovicic N, et al. IL-33 prevents MLD-STZ induction of diabetes and attenuate insulitis in prediabetic NOD mice. Front Immunol. 2018;9:2646.
Choi EY, Lim JH, Neuwirth A, et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry. 2015;20:880-888.
Schoch HJ, Fischer S, Marti HH. Hypoxia-induced vascular endothelial growth factor expression causes vascular leakage in the brain. Brain. 2002;125:2549-2557.
Pfeil U, Aslam M, Paddenberg R, et al. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability. Am J Physiol Lung Cell Mol Physiol. 2009;297:L837-L845.
Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25:402-408.
Kouadjo KE, Nishida Y, Cadrin-Girard JF, Yoshioka M, St-Amand J. Housekeeping and tissue-specific genes in mouse tissues. BMC Genom. 2007;8:127.
Pi L, Shenoy AK, Liu J, et al. CCN2/CTGF regulates neovessel formation via targeting structurally conserved cystine knot motifs in multiple angiogenic regulators. FASEB J. 2012;26:3365-3379.
Kaliberov SA, Kaliberova LN, Hong Lu Z, et al. Retargeting of gene expression using endothelium specific hexon modified adenoviral vector. Virology. 2013;447:312-325.
Tanno T, Fujiwara A, Sakaguchi K, Tanaka K, Takenaka S, Tsuyama S. Slit3 regulates cell motility through Rac/Cdc42 activation in lipopolysaccharide-stimulated macrophages. FEBS Lett. 2007;581:1022-1026.
Gohrig A, Detjen KM, Hilfenhaus G, et al. Axon guidance factor SLIT2 inhibits neural invasion and metastasis in pancreatic cancer. Cancer Res. 2014;74:1529-1540.
Burke-Gaffney A, Svermova T, Mumby S, Finney SJ, Evans TW. Raised plasma Robo4 and cardiac surgery-associated acute kidney injury. PLoS ONE. 2014;9:e111459.
Yang YH, Manning Fox JE, Zhang KL, MacDonald PE, Johnson JD. Intraislet SLIT-ROBO signaling is required for beta-cell survival and potentiates insulin secretion. Proc Natl Acad Sci U S A. 2013;110:16480-16485.
Jones CA, Nishiya N, London NR, et al. Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat Cell Biol. 2009;11:1325-1331.
Sherchan P, Huang L, Akyol O, Reis C, Tang J, Zhang JH. Recombinant Slit2 reduces surgical brain injury induced blood brain barrier disruption via Robo4 dependent Rac1 activation in a rodent model. Sci Rep. 2017;7:746.
Quan W, Jo EK, Lee MS. Role of pancreatic beta-cell death and inflammation in diabetes. Diabetes Obes Metab. 2013;15 Suppl 3:141-151.
Maedler K, Sergeev P, Ris F, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest. 2002;110:851-860.
Bluher M, Unger R, Rassoul F, Richter V, Paschke R. Relation between glycaemic control, hyperinsulinaemia and plasma concentrations of soluble adhesion molecules in patients with impaired glucose tolerance or Type II diabetes. Diabetologia. 2002;45:210-216.
Gustavsson C, Agardh CD, Zetterqvist AV, Nilsson J, Agardh E, Gomez MF. Vascular cellular adhesion molecule-1 (VCAM-1) expression in mice retinal vessels is affected by both hyperglycemia and hyperlipidemia. PLoS ONE. 2010;5:e12699.
Xie J, Gong Q, Liu X, et al. Transcription factor SP1 mediates hyperglycemia-induced upregulation of roundabout4 in retinal microvascular endothelial cells. Gene. 2017;616:31-40.
Coleman HA, Labrador JP, Chance RK, Bashaw GJ. The Adam family metalloprotease Kuzbanian regulates the cleavage of the roundabout receptor to control axon repulsion at the midline. Development. 2010;137:2417-2426.
Zhao H, Anand AR, Ganju RK. Slit2-Robo4 pathway modulates lipopolysaccharide-induced endothelial inflammation and its expression is dysregulated during endotoxemia. J Immunol. 2014;192:385-393.
Suchting S, Heal P, Tahtis K, Stewart LM, Bicknell R. Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J. 2005;19:121-123.
Rama N, Dubrac A, Mathivet T, et al. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat Med. 2015;21:483-491.
Kaur S, Samant GV, Pramanik K, et al. Silencing of directional migration in roundabout4 knockdown endothelial cells. BMC Cell Biol. 2008;9:61.
Sheldon H, Andre M, Legg JA, et al. Active involvement of Robo1 and Robo4 in filopodia formation and endothelial cell motility mediated via WASP and other actin nucleation-promoting factors. FASEB J. 2009;23:513-522.
Nirantharakumar K, Mohammed N, Toulis KA, Thomas GN, Narendran P. Clinically meaningful and lasting HbA1c improvement rarely occurs after 5 years of type 1 diabetes: an argument for early, targeted and aggressive intervention following diagnosis. Diabetologia. 2018;61:1064-1070.
Al-Awar A, Kupai K, Veszelka M, et al. Experimental diabetes mellitus in different animal models. J Diabetes Res. 2016;2016:9051426.