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

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

The Hull York Medical School

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	781-8
Number of pages	8
Journal	Thrombosis and haemostasis
Volume	115
Issue number	4
DOIs	https://doi.org/10.1160/TH15-05-0429
Publication status	Published - Apr 2016

Keywords

Animals
Blood Coagulation/genetics
Blood Platelets/physiology
Carrier Proteins/genetics
Cells, Cultured
Humans
Inflammation/genetics
Islets of Langerhans/metabolism
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

Access to Document

10.1160/TH15-05-0429

Cite this

Kourtzelis, I., Kotlabova, K., Lim, J.-H., Mitroulis, I., Ferreira, A., Chen, L.-S., Gercken, B., Steffen, A., Kemter, E., Klotzsche-von Ameln, A., Waskow, C., Hosur, K., Chatzigeorgiou, A., Ludwig, B., Wolf, E., Hajishengallis, G., & Chavakis, T. (2016). Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation. Thrombosis and haemostasis, 115(4), 781-8. https://doi.org/10.1160/TH15-05-0429

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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. ",

keywords = "Animals, Blood Coagulation/genetics, Blood Platelets/physiology, Carrier Proteins/genetics, Cells, Cultured, Humans, Inflammation/genetics, Islets of Langerhans/metabolism, 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",

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

year = "2016",

month = apr,

doi = "10.1160/TH15-05-0429",

language = "English",

volume = "115",

pages = "781--8",

journal = "Thrombosis and haemostasis",

issn = "0340-6245",

publisher = "Schattauer GmbH",

number = "4",

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Kourtzelis, I, Kotlabova, K, Lim, J-H, Mitroulis, I, Ferreira, A, Chen, L-S, Gercken, B, Steffen, A, Kemter, E, Klotzsche-von Ameln, A, Waskow, C, Hosur, K, Chatzigeorgiou, A, Ludwig, B, Wolf, E, Hajishengallis, G & Chavakis, T 2016, 'Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation', Thrombosis and haemostasis, vol. 115, no. 4, pp. 781-8. https://doi.org/10.1160/TH15-05-0429

TY - JOUR

T1 - Developmental endothelial locus-1 modulates platelet-monocyte interactions and instant blood-mediated inflammatory reaction in islet transplantation

AU - Kourtzelis, Ioannis

AU - Kotlabova, Klara

AU - Lim, Jong-Hyung

AU - Mitroulis, Ioannis

AU - Ferreira, Anaisa

AU - Chen, Lan-Sun

AU - Gercken, Bettina

AU - Steffen, Anja

AU - Kemter, Elisabeth

AU - Klotzsche-von Ameln, Anne

AU - Waskow, Claudia

AU - Hosur, Kavita

AU - Chatzigeorgiou, Antonios

AU - Ludwig, Barbara

AU - Wolf, Eckhard

AU - Hajishengallis, George

AU - Chavakis, Triantafyllos

PY - 2016/4

Y1 - 2016/4

N2 - 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.

AB - 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.

KW - Animals

KW - Blood Coagulation/genetics

KW - Blood Platelets/physiology

KW - Carrier Proteins/genetics

KW - Cells, Cultured

KW - Humans

KW - Inflammation/genetics

KW - Islets of Langerhans/metabolism

KW - Islets of Langerhans Transplantation

KW - Macrophage-1 Antigen/metabolism

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Transgenic

KW - Monocytes/physiology

KW - Platelet Aggregation/genetics

KW - Platelet Glycoprotein GPIb-IX Complex/metabolism

KW - Thrombosis/genetics

U2 - 10.1160/TH15-05-0429

DO - 10.1160/TH15-05-0429

M3 - Article

C2 - 26676803

SN - 0340-6245

VL - 115

SP - 781

EP - 788

JO - Thrombosis and haemostasis

JF - Thrombosis and haemostasis

IS - 4

ER -