title: Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.
abstract: Platelet-monocyte interactions are strongly implicated in thrombo-inflammatory injury by actively contributing to intravascular inflammation, leukocyte recruitment to inflamed sites, and the amplification of the procoagulant response. Instant blood-mediated inflammatory reaction (IBMIR) represents thrombo-inflammatory injury elicited upon pancreatic islet transplantation (islet-Tx), thereby dramatically affecting transplant survival and function. Developmental endothelial locus-1 (Del-1) is a functionally versatile endothelial cell-derived homeostatic factor with anti-inflammatory properties, but its potential role in IBMIR has not been previously addressed. Here, we establish Del-1 as a novel inhibitor of IBMIR using a whole blood-islet model and a syngeneic murine transplantation model. Indeed, Del-1 pre-treatment of blood before addition of islets diminished coagulation activation and islet damage as assessed by C-peptide release. Consistently, intraportal islet-Tx in transgenic mice with endothelial cell-specific overexpression of Del-1 resulted in a marked decrease of monocytes and platelet-monocyte aggregates in the transplanted tissues, relative to those in wild-type recipients. Mechanistically, Del-1 decreased platelet-monocyte aggregate formation, by specifically blocking the interaction between monocyte Mac-1-integrin and platelet GPIb. Our findings reveal a hitherto unknown role of Del-1 in the regulation of platelet-monocyte interplay and the subsequent heterotypic aggregate formation in the context of IBMIR. Therefore, Del-1 may represent a novel approach to prevent or mitigate the adverse reactions mediated through thrombo-inflammatory pathways in islet-Tx and perhaps other inflammatory disorders involving platelet-leukocyte aggregate formation.
authors.affiliation: Dr. Ioannis Kourtzelis, Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Fetscherstraße 74, 01307 Dresden, Germany, Tel.: +49 351 4586250, E-mail: Iannis.Kourtzelis@uniklinikum-dresden.de.
authors.forename: Ioannis
authors.initials: I
authors.lastname: Kourtzelis
authors.forename: Klara
authors.initials: K
authors.lastname: Kotlabova
authors.forename: Jong-Hyung
authors.initials: JH
authors.lastname: Lim
authors.forename: Ioannis
authors.initials: I
authors.lastname: Mitroulis
authors.forename: Anaisa
authors.initials: A
authors.lastname: Ferreira
authors.forename: Lan-Sun
authors.initials: LS
authors.lastname: Chen
authors.forename: Bettina
authors.initials: B
authors.lastname: Gercken
authors.forename: Anja
authors.initials: A
authors.lastname: Steffen
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kemter
authors.forename: Anne
authors.initials: A
authors.lastname: Klotzsche-von Ameln
authors.forename: Claudia
authors.initials: C
authors.lastname: Waskow
authors.forename: Kavita
authors.initials: K
authors.lastname: Hosur
authors.forename: Antonios
authors.initials: A
authors.lastname: Chatzigeorgiou
authors.forename: Barbara
authors.initials: B
authors.lastname: Ludwig
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.forename: George
authors.initials: G
authors.lastname: Hajishengallis
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Chavakis
mesh_terms: D000818:Animals; D001777:Blood Coagulation / Q000235:genetics; D001792:Blood Platelets / Q000502:physiology*; D002135:Calcium-Binding Proteins; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D007515:Islets of Langerhans / Q000378:metabolism* / Q000473:pathology; D016381:Islets of Langerhans Transplantation; D016177:Macrophage-1 Antigen / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009000:Monocytes / Q000502:physiology*; D010974:Platelet Aggregation / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism; D013927:Thrombosis / Q000235:genetics* / Q000276:immunology
chemical_list: D002135:Calcium-Binding Proteins; D002352:Carrier Proteins; D015815:Cell Adhesion Molecules; C110183:EDIL3 protein, human; D016177:Macrophage-1 Antigen; D019038:Platelet Glycoprotein GPIb-IX Complex; C094990:adhesion receptor
keywords: Developmental endothelial locus 1 (Del-1); GPIb; Instant blood-mediated inflammatory reaction (IBMIR); Mac-1 integrin; coagulation; islet transplantation; platelet-monocyte aggregates