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Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation.

Thromb. Haemost. 115, 781-788 (2016)
Postprint DOI
Open Access Green
as soon as is submitted to ZB.
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 pretreatment 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Instant Blood-mediated Inflammatory Reaction (ibmir) ; Developmental Endothelial Locus 1 (del-1) ; Coagulation ; Platelet-monocyte Aggregates ; Islet Transplantation ; Gpib ; Mac-1 Integrin; Glycoprotein Ib-alpha; Leukocyte Integrin Mac-1; Cell Recruitment; Tissue Factor; Whole-blood; Mice; Del-1; Expression; Disease; Type-1
Reviewing status
Institute(s) Institute for Pancreatic Beta Cell Research (IPI)