Download PDF
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

Ioannis Kourtzelis   *
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Klara Kotlabova   *
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Jong-Hyung Lim
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Ioannis Mitroulis
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
2   Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Anaisa Ferreira
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Lan-Sun Chen
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Bettina Gercken
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Anja Steffen
3   Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZDGerman Centre for Diabetes Research, Dresden, Germany
4   Department of Medicine III, Technische Universität Dresden, Dresden, Germany
,
Elisabeth Kemter
5   Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
,
Anne Klotzsche-von Ameln
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
,
Claudia Waskow
6   Institute of Immunology, Medical Faculty, Technische Universität Dresden, Dresden, Germany;
,
Kavita Hosur
7   University of Pennsylvania, Penn Dental Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA
,
Antonios Chatzigeorgiou
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
2   Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
,
Barbara Ludwig
3   Paul Langerhans Institute Dresden of Helmholtz Centre Munich at University Clinic Carl Gustav Carus of TU Dresden and DZDGerman Centre for Diabetes Research, Dresden, Germany
4   Department of Medicine III, Technische Universität Dresden, Dresden, Germany
,
Eckhard Wolf
5   Chair for Molecular Animal Breeding and Biotechnology, and Laboratory for Functional Genome Analysis, Gene Center, Ludwig-Maximilians-Universität München, Munich, Germany
,
George Hajishengallis
7   University of Pennsylvania, Penn Dental Medicine, Department of Microbiology, Philadelphia, Pennsylvania, USA
,
Triantafyllos Chavakis
1   Department of Clinical Pathobiochemistry, Medical Faculty, Technische Universität Dresden, Germany
2   Institute of Clinical Chemistry and Laboratory Medicine, Medical Faculty, Technische Universität Dresden, Dresden, Germany
› Author Affiliations
Further Information

Publication History

Received: 26 May 2015

Accepted after major revision: 25 November 2015

Publication Date:
28 November 2017 (online)

    Permissions and Reprints

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

* I. K. and K. K. contributed equally to this work.


 

  • References

  • 1 Hajishengallis G, Chavakis T. Endogenous modulators of inflammatory cell recruitment. Trends Immunol 2013; 34: 1-6.
    CrossrefPubMedGoogle Scholar
  • 2 Mitroulis I, Alexaki VI, Kourtzelis I. et al. Leukocyte integrins: role in leukocyte recruitment and as therapeutic targets in inflammatory disease. Pharmacol Ther 2015; 147: 123-135.
    CrossrefPubMedGoogle Scholar
  • 3 Langer HF, Chavakis T. Leukocyte-endothelial interactions in inflammation. J Cell Mol Med 2009; 13: 1211-1220.
    CrossrefPubMedGoogle Scholar
  • 4 Simon DI, Chen Z, Xu H. et al. Platelet glycoprotein ibalpha is a counterreceptor for the leukocyte integrin Mac-1 (CD11b/CD18). J Exp Med 2000; 192: 193-204.
    CrossrefPubMedGoogle Scholar
  • 5 Ehlers R, Ustinov V, Chen Z. et al. Targeting platelet-leukocyte interactions: identification of the integrin Mac-1 binding site for the platelet counter receptor glycoprotein Ibalpha. J Exp Med 2003; 198: 1077-1088.
    CrossrefPubMedGoogle Scholar
  • 6 Chavakis T, Santoso S, Clemetson KJ. et al. High molecular weight kininogen regulates platelet-leukocyte interactions by bridging Mac-1 and glycoprotein Ib. J Biol Chem 2003; 278: 45375-45381.
    CrossrefPubMedGoogle Scholar
  • 7 Santoso S, Sachs UJH, Kroll H. et al. The junctional adhesion molecule 3 (JAM-3) on human platelets is a counterreceptor for the leukocyte integrin Mac-1. J Exp Med 2002; 196: 679-691.
    CrossrefPubMedGoogle Scholar
  • 8 Weber C, Springer TA. Neutrophil accumulation on activated, surface-adherent platelets in flow is mediated by interaction of Mac-1 with fibrinogen bound to alphaIIbbeta3 and stimulated by platelet-activating factor. J Clin Invest 1997; 100: 2085-2093.
    CrossrefPubMedGoogle Scholar
  • 9 Huo Y, Schober A, Forlow SB. et al. Circulating activated platelets exacerbate atherosclerosis in mice deficient in apolipoprotein E. Nat Med 2003; 09: 61-67.
    CrossrefPubMedGoogle Scholar
  • 10 Wang Y, Sakuma M, Chen Z. et al. Leukocyte engagement of platelet glycoprotein Ibalpha via the integrin Mac-1 is critical for the biological response to vascular injury. Circulation 2005; 112: 2993-3000.
    PubMedGoogle Scholar
  • 11 Langer HF, Choi EY, Zhou H. et al. Platelets contribute to the pathogenesis of experimental autoimmune encephalomyelitis. Circ Res 2012; 110: 1202-1210.
    CrossrefPubMedGoogle Scholar
  • 12 Chavakis E, Choi EY, Chavakis T. Novel aspects in the regulation of the leukocyte adhesion cascade. Thromb Haemost 2009; 102: 191-197.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 13 Choi EY, Chavakis E, Czabanka MA. et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science 2008; 322: 1101-1104.
    CrossrefPubMedGoogle Scholar
  • 14 Mitroulis I, Kang Y-Y, Gahmberg CG. et al. Developmental endothelial locus-1 attenuates complement-dependent phagocytosis through inhibition of Mac-1-integrin. Thromb Haemost 2014; 111: 1004-1006.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Eskan MA, Jotwani R, Abe T. et al. The leukocyte integrin antagonist Del-1 inhibits IL-17-mediated inflammatory bone loss. Nat Immunol 2012; 13: 465-473.
    CrossrefPubMedGoogle Scholar
  • 16 Choi EY, Lim J-H, Neuwirth A. et al. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination. Mol Psychiatry 2014; 20: 880-888.
    PubMedGoogle Scholar
  • 17 Kang Y-Y, Kim D-Y, Lee S-H. et al. Deficiency of developmental endothelial locus-1 (Del-1) aggravates bleomycin-induced pulmonary fibrosis in mice. Bio-chem Biophys Res Commun 2014; 445: 369-374.
    CrossrefPubMedGoogle Scholar
  • 18 Kanczkowski W, Chatzigeorgiou A, Grossklaus S. et al. Role of the endothelial-derived endogenous anti-inflammatory factor Del-1 in inflammation-mediated adrenal gland dysfunction. Endocrinology 2013; 154: 1181-1189.
    CrossrefPubMedGoogle Scholar
  • 19 Cnop M, Welsh N, Jonas J-C. et al. Mechanisms of pancreatic beta-cell death in type 1 and type 2 diabetes: many differences, few similarities. Diabetes 2005; 54 (Suppl. 02) S97-107.
    PubMedGoogle Scholar
  • 20 Orchard TJ, Costacou T, Kretowski A. et al. Type 1 diabetes and coronary artery disease. Diabetes Care 2006; 29: 2528-2538.
    CrossrefPubMedGoogle Scholar
  • 21 Bruni A, Gala-Lopez B, Pepper AR. et al. Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges. Diabetes Metab Syndr Obes 2014; 07: 211-223.
    PubMedGoogle Scholar
  • 22 Luan NM, Iwata H. Long-term allogeneic islet graft survival in prevascularized subcutaneous sites without immunosuppressive treatment. Am J Transplant 2014; 14: 1533-1542.
    CrossrefPubMedGoogle Scholar
  • 23 Reichart B, Niemann H, Chavakis T. et al. Xenotransplantation of porcine islet cells as a potential option for the treatment of type 1 diabetes in the future. Horm Metab Res 2015; 47: 31-35.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 van der Windt DJ, Echeverri GJ, Ijzermans JNM. et al. The choice of anatomical site for islet transplantation. Cell Transplant 2008; 17: 1005-1014.
    CrossrefPubMedGoogle Scholar
  • 25 Nilsson B, Ekdahl KN, Korsgren O. Control of instant blood-mediated inflammatory reaction to improve islets of Langerhans engraftment. Curr Opin Organ Transplant 2011; 16: 620-626.
    CrossrefPubMedGoogle Scholar
  • 26 van der Windt DJ, Bottino R, Casu A. et al. Rapid loss of intraportally transplanted islets: an overview of pathophysiology and preventive strategies. Xeno-transplantation 2007; 14: 288-297.
    CrossrefPubMedGoogle Scholar
  • 27 Shin J, Hosur KB, Pyaram K. et al. Expression and function of the homeostatic molecule Del-1 in endothelial cells and the periodontal tissue. Clin Dev Immunol 2013; 2013: 617809.
    PubMedGoogle Scholar
  • 28 Shin J, Maekawa T, Abe T. et al. DEL-1 restrains osteoclastogenesis and inhibits inflammatory bone loss in nonhuman primates. Sci Transl Med 2015; 07: 307ra155.
    CrossrefPubMedGoogle Scholar
  • 29 Moberg L, Johansson H, Lukinius A. et al. Production of tissue factor by pancreatic islet cells as a trigger of detrimental thrombotic reactions in clinical islet transplantation. Lancet 2002; 360: 2039-2045.
    CrossrefPubMedGoogle Scholar
  • 30 Johansson H, Goto M, Dufrane D. et al. Low molecular weight dextran sulfate: a strong candidate drug to block IBMIR in clinical islet transplantation. Am J Transplant 2006; 06: 305-312.
    CrossrefPubMedGoogle Scholar
  • 31 Bennet W, Sundberg B, Lundgren T. et al. Damage to porcine islets of Langerhans after exposure to human blood in vitro, or after intraportal transplantation to cynomologus monkeys: protective effects of sCR1 and heparin. Transplantation 2000; 69: 711-719.
    PubMedGoogle Scholar
  • 32 Ludwig B, Zimerman B, Steffen A. et al. A novel device for islet transplantation providing immune protection and oxygen supply. Horm Metab Res 2010; 42: 918-922.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Klymiuk N, van Buerck L, Bähr A. et al. Xenografted islet cell clusters from INS-LEA29Y transgenic pigs rescue diabetes and prevent immune rejection in humanized mice. Diabetes 2012; 61: 1527-1532.
    CrossrefPubMedGoogle Scholar
  • 34 Kourtzelis I, Markiewski MM, Doumas M. et al. Complement anaphylatoxin C5a contributes to hemodialysis-associated thrombosis. Blood 2010; 116: 631-639.
    CrossrefPubMedGoogle Scholar
  • 35 Ingalls RR, Arnaout MA, Golenbock DT. Outside-in signaling by lipopolysaccharide through a tailless integrin. J Immunol 1997; 159: 433-438.
    PubMedGoogle Scholar
  • 36 Sotiriou SN, Orlova VV, Al-Fakhri N. et al. Lipoprotein(a) in atherosclerotic plaques recruits inflammatory cells through interaction with Mac-1 integrin. FASEB J 2006; 20: 559-561.
    CrossrefPubMedGoogle Scholar
  • 37 Schlaeger TM, Bartunkova S, Lawitts JA. et al. Uniform vascular-endothelial-cell-specific gene expression in both embryonic and adult transgenic mice. Proc Natl Acad Sci USA 1997; 94: 3058-3063.
    CrossrefPubMedGoogle Scholar
  • 38 Amiri F, Virdis A, Neves MF. et al. Endothelium-restricted overexpression of human endothelin-1 causes vascular remodeling and endothelial dysfunction. Circulation 2004; 110: 2233-2240.
    CrossrefPubMedGoogle Scholar
  • 39 Nichol D, Shawber C, Fitch MJ. et al. Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7. Blood 2010; 116: 6133-6143.
    CrossrefPubMedGoogle Scholar
  • 40 Ray R, Murdoch CE, Wang M. et al. Endothelial Nox4 NADPH oxidase enhances vasodilatation and reduces blood pressure in vivo. Arterioscler Thromb Vasc Biol 2011; 31: 1368-1376.
    CrossrefPubMedGoogle Scholar
  • 41 Melzi R, Maffi P, Nano R. et al. Rapamycin does not adversely affect intrahepatic islet engraftment in mice and improves early islet engraftment in humans. Islets 2009; 01: 42-49.
    CrossrefPubMedGoogle Scholar
  • 42 Chatzigeorgiou A, Chung K-J, Garcia-Martin R. et al. Dual role of B7 costimu-lation in obesity-related nonalcoholic steatohepatitis and metabolic dysregulation. Hepatology 2014; 60: 1196-1210.
    CrossrefPubMedGoogle Scholar
  • 43 Kourtzelis I, Ferreira A, Mitroulis I. et al. Complement inhibition in a xenogeneic model of interactions between human whole blood and porcine endothelium. Horm Metab Res 2015; 47: 36-42.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 44 Maekawa T, Hosur K, Abe T. et al. Antagonistic effects of IL-17 and D-resolvins on endothelial Del-1 expression through a GSK-3β-C/EBPβ pathway. Nat Com-mun 2015; 06: 8272.
    CrossrefPubMedGoogle Scholar
  • 45 Totani L, Evangelista V. Platelet-leukocyte interactions in cardiovascular disease and beyond. Arterioscler Thromb Vasc Biol 2010; 30: 2357-2361.
    CrossrefPubMedGoogle Scholar
  • 46 Jensen MK, de Nully Brown P, Lund BV. et al. Increased circulating platelet-leukocyte aggregates in myeloproliferative disorders is correlated to previous thrombosis, platelet activation and platelet count. Eur J Haematol 2001; 66: 143-151.
    CrossrefPubMedGoogle Scholar
  • 47 Steiner S, Seidinger D, Huber K. et al. Effect of glycoprotein IIb/IIIa antagonist abciximab on monocyte-platelet aggregates and tissue factor expression. Arterioscler Thromb Vasc Biol 2003; 23: 1697-1702.
    CrossrefPubMedGoogle Scholar
  • 48 Barnard MR, Linden MD, Frelinger AL. et al. Effects of platelet binding on whole blood flow cytometry assays of monocyte and neutrophil procoagulant activity. J Thromb Haemost 2005; 03: 2563-2570.
    CrossrefPubMedGoogle Scholar
  • 49 Bennett JS. Structure and function of the platelet integrin alphaIIbbeta3. J Clin Invest 2005; 115: 3363-3369.
    CrossrefPubMedGoogle Scholar
  • 50 Humphries JD, Byron A, Humphries MJ. Integrin ligands at a glance. J Cell Sci 2006; 119: 3901-3903.
    PubMedGoogle Scholar