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

Ioannis Kourtzelis; Klara Kotlabova; Jong-Hyung Lim; Ioannis Mitroulis; Anaisa Ferreira; Lan-Sun Chen; Bettina Gercken; Anja Steffen; Elisabeth Kemter; Anne Klotzsche-von Ameln; Claudia Waskow; Kavita Hosur; Antonios Chatzigeorgiou; Barbara Ludwig; Eckhard Wolf; George Hajishengallis; Triantafyllos Chavakis

doi:10.1160/TH15-05-0429

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2016; 115(04): 781-788
DOI: 10.1160/TH15-05-0429

Blood Cells, Inflammation and Infection

Schattauer GmbH

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

Authors

Ioannis Kourtzelis^*

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Klara Kotlabova^*

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Jong-Hyung Lim

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Ioannis Mitroulis

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany

²Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
Anaisa Ferreira

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Lan-Sun Chen

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Bettina Gercken

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Anja Steffen

³Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZDGerman Centre for Diabetes Research, Dresden, Germany

⁴Department of Medicine III, Technische Universität Dresden, Dresden, Germany
Elisabeth Kemter

⁵Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
Anne Klotzsche-von Ameln

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
Claudia Waskow

⁶Institute of Immunology, Medical Faculty, Technische Universität Dresden, Dresden, Germany;
Kavita Hosur

⁷University of Pennsylvania, Penn Dental Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA
Antonios Chatzigeorgiou

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany

²Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
Barbara Ludwig

³Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZDGerman Centre for Diabetes Research, Dresden, Germany

⁴Department of Medicine III, Technische Universität Dresden, Dresden, Germany
Eckhard Wolf

⁵Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
George Hajishengallis

⁷University of Pennsylvania, Penn Dental Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA
Triantafyllos Chavakis

¹Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany

²Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany

Abstract

Summary

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.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

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

Full Text

References

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