Cyclophilin A is a ligand for RAGE in thrombo-inflammation

Peter Seizer; Saskia N I von Ungern-Sternberg; Verena Haug; Valerie Dicenta; Annabelle Rosa; Elke Butt; Moritz Nöthel; Anne-Katrin Rohlfing; Manuel Sigle; Peter P Nawroth; Claudia Nussbaum; Markus Sperandio; Charly Kusch; Mara Meub; Markus Sauer; Patrick Münzer; Kristin Bieber; Anna Stanger; Andreas F Mack; René Huber; Korbinian Brand; Moritz Lehners; Robert Feil; Antti Poso; Konstantin Krutzke; Tilman E Schäffer; Bernhard Nieswandt; Oliver Borst; Andreas E May; Alma Zernecke; Meinrad Gawaz; David Heinzmann

doi:10.1093/cvr/cvad189

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Cyclophilin A is a ligand for RAGE in thrombo-inflammation

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Cyclophilin A is a ligand for RAGE in thrombo-inflammation

Peter Seizer, Saskia N I von Ungern-Sternberg, Verena Haug, Valerie Dicenta, Annabelle Rosa, Elke Butt, Moritz Nöthel, Anne-Katrin Rohlfing, Manuel Sigle, Peter P Nawroth, …

Cardiovascular research, Vol.120(4), pp.385-402

30/03/2024

DOI: https://doi.org/10.1093/cvr/cvad189

PMID: 38175781

Résumé

Animals

Basigin - metabolism

Cyclophilin A - genetics

Cyclophilin A - metabolism

Glycation End Products, Advanced

Humans

Inflammation

Ligands

Mice

Thrombosis - genetics

Cyclophilin A (CyPA) induces leucocyte recruitment and platelet activation upon release into the extracellular space. Extracellular CyPA therefore plays a critical role in immuno-inflammatory responses in tissue injury and thrombosis upon platelet activation. To date, CD147 (EMMPRIN) has been described as the primary receptor mediating extracellular effects of CyPA in platelets and leucocytes. The receptor for advanced glycation end products (RAGE) shares inflammatory and prothrombotic properties and has also been found to have similar ligands as CD147. In this study, we investigated the role of RAGE as a previously unknown interaction partner for CyPA. Confocal imaging, proximity ligation, co-immunoprecipitation, and atomic force microscopy were performed and demonstrated an interaction of CyPA with RAGE on the cell surface. Static and dynamic cell adhesion and chemotaxis assays towards extracellular CyPA using human leucocytes and leucocytes from RAGE-deficient Ager-/- mice were conducted. Inhibition of RAGE abrogated CyPA-induced effects on leucocyte adhesion and chemotaxis in vitro. Accordingly, Ager-/- mice showed reduced leucocyte recruitment and endothelial adhesion towards CyPA in vivo. In wild-type mice, we observed a downregulation of RAGE on leucocytes when endogenous extracellular CyPA was reduced. We furthermore evaluated the role of RAGE for platelet activation and thrombus formation upon CyPA stimulation. CyPA-induced activation of platelets was found to be dependent on RAGE, as inhibition of RAGE, as well as platelets from Ager-/- mice showed a diminished activation and thrombus formation upon CyPA stimulation. CyPA-induced signalling through RAGE was found to involve central signalling pathways including the adaptor protein MyD88, intracellular Ca2+ signalling, and NF-κB activation. We propose RAGE as a hitherto unknown receptor for CyPA mediating leucocyte as well as platelet activation. The CyPA-RAGE interaction thus represents a novel mechanism in thrombo-inflammation.

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Détails

Titre: Cyclophilin A is a ligand for RAGE in thrombo-inflammation
Créateurs - sans rôle: Peter Seizer - Department of Cardiology and Angiology, Ostalbklinikum Aalen, Aalen, Germany
Saskia N I von Ungern-Sternberg - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Verena Haug - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Valerie Dicenta - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Annabelle Rosa - Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Elke Butt - Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Moritz Nöthel - Department of Internal Medicine II, Cardiology, Pneumology, Angiology, University Hospital Bonn, Bonn, Germany
Anne-Katrin Rohlfing - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Manuel Sigle - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Peter P Nawroth - Joint Heidelberg-ICD Translational Diabetes Program, Helmholtz-Zentrum, Munich, Germany
Claudia Nussbaum - Division of Neonatology, Department of Pediatrics, Dr. von Hauner Children's Hospital, LMU University Hospital, LMU Munich, Munich, Germany
Markus Sperandio - German Centre for Cardiovascular Research (Deutsches Zentrum für Herz-Kreislauf-Forschung, DZHK), Munich Heart Alliance Partner Site, Munich, Germany
Charly Kusch - Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Mara Meub - Department of Biotechnology und Biophysics, Julius-Maximilians University, Würzburg, Germany
Markus Sauer - Department of Biotechnology und Biophysics, Julius-Maximilians University, Würzburg, Germany
Patrick Münzer - DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Tübingen, Germany
Kristin Bieber - Department of Hematology, Oncology, Immunology und Pulmonology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
Anna Stanger - Department of Hematology, Oncology, Immunology und Pulmonology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
Andreas F Mack - Institute of Clinical Anatomy and Cell Analytics, Eberhard Karls University Tübingen, Tübingen, Germany
René Huber - Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
Korbinian Brand - Institute of Clinical Chemistry, Hannover Medical School, Hannover, Germany
Moritz Lehners - Interfakultäres Institut für Biochemie, Eberhard Karls University Tübingen, Tübingen, Germany
Robert Feil - Interfakultäres Institut für Biochemie, Eberhard Karls University Tübingen, Tübingen, Germany
Antti Poso - Excellence Cluster 'Controlling Microbes to Fight Infections' (CMFI), Tübingen, Germany
Konstantin Krutzke - Institute of Applied Physics, Eberhard Karls University Tübingen, Tübingen, Germany
Tilman E Schäffer - Institute of Applied Physics, Eberhard Karls University Tübingen, Tübingen, Germany
Bernhard Nieswandt - Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
Oliver Borst - DFG Heisenberg Group Cardiovascular Thromboinflammation and Translational Thrombocardiology, University of Tübingen, Tübingen, Germany
Andreas E May - Department of Cardiology, Innere Medizin I, Klinikum Memmingen, Memmingen, Germany
Alma Zernecke - Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany
Meinrad Gawaz - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
David Heinzmann - Department of Cardiology and Angiology, Universitätsklinikum Tübingen, Eberhard Karls University Tübingen, Otfried-Müller-Str. 10, 72076 Tübingen, Germany
Détails de publication: Cardiovascular research, Vol.120(4), pp.385-402
Note de subvention: German Center for Diabetes Research Deutsche Stiftung für Herzforschung DFG #374031971-TRR 240 CRU-240 / German Research Foundation
Identifiants: 99154049009311
Unité académique: Institut de Génétique Moléculaire de Montpellier - IGMM
Langue: English
Type de ressource: Journal article