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

Thromb Haemost. 2016 Apr;115(4):781-8. doi: 10.1160/TH15-05-0429. Epub 2015 Dec 17.

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.

Keywords: Developmental endothelial locus 1 (Del-1); GPIb; Instant blood-mediated inflammatory reaction (IBMIR); Mac-1 integrin; coagulation; islet transplantation; platelet-monocyte aggregates.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blood Coagulation / genetics
  • Blood Platelets / physiology*
  • Calcium-Binding Proteins
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Cell Adhesion Molecules
  • Cells, Cultured
  • Humans
  • Inflammation / genetics*
  • Islets of Langerhans / metabolism*
  • Islets of Langerhans / pathology
  • Islets of Langerhans Transplantation*
  • Macrophage-1 Antigen / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Monocytes / physiology*
  • Platelet Aggregation / genetics
  • Platelet Glycoprotein GPIb-IX Complex / metabolism
  • Thrombosis / genetics*
  • Thrombosis / immunology

Substances

  • Calcium-Binding Proteins
  • Carrier Proteins
  • Cell Adhesion Molecules
  • EDIL3 protein, human
  • Macrophage-1 Antigen
  • Platelet Glycoprotein GPIb-IX Complex
  • adhesion receptor