ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury

Anne-Katrin Rohlfing, Kyra Kolb, Manuel Sigle, Melanie Ziegler, Alexander Bild, Patrick Münzer, Jessica Sudmann, Valerie Dicenta, Tobias Harm, Mailin-Christin Manke, Sascha Geue, Marcel Kremser, Madhumita Chatterjee, Chunguang Liang, Hendrik Eysmondt, Thomas Dandekar, David Heinzmann, Manina Günter, Saskia Ungern-Sternberg, Manuela Büttcher, Tatsiana Castor, Stine Mencl, Friederike Langhauser, Katharina Sies, Diyaa Ashour, Mustafa Caglar Beker, Michael Lämmerhofer, Stella E. Autenrieth, Tilman E. Schäffer, Stefan Laufer, Paulina Szklanna, Patricia Maguire, Matthias Heikenwalder, Karin Anne Lydia Müller, Dirk M. Hermann, Ertugrul Kilic, Ralf Stumm, Gustavo Ramos, Christoph Kleinschnitz, Oliver Borst, Harald F. Langer, Dominik Rath and Meinrad Gawaz ()
Additional contact information
Anne-Katrin Rohlfing: University Hospital Tübingen, Eberhard Karls University Tübingen
Kyra Kolb: University Hospital Tübingen, Eberhard Karls University Tübingen
Manuel Sigle: University Hospital Tübingen, Eberhard Karls University Tübingen
Melanie Ziegler: University Hospital Tübingen, Eberhard Karls University Tübingen
Alexander Bild: University Hospital Tübingen, Eberhard Karls University Tübingen
Patrick Münzer: University Hospital Tübingen, Eberhard Karls University Tübingen
Jessica Sudmann: University Hospital Tübingen, Eberhard Karls University Tübingen
Valerie Dicenta: University Hospital Tübingen, Eberhard Karls University Tübingen
Tobias Harm: University Hospital Tübingen, Eberhard Karls University Tübingen
Mailin-Christin Manke: University Hospital Tübingen, Eberhard Karls University Tübingen
Sascha Geue: University Hospital Tübingen, Eberhard Karls University Tübingen
Marcel Kremser: University Hospital Tübingen, Eberhard Karls University Tübingen
Madhumita Chatterjee: University Hospital Tübingen, Eberhard Karls University Tübingen
Chunguang Liang: Biocenter, University of Würzburg
Hendrik Eysmondt: University of Tübingen
Thomas Dandekar: Biocenter, University of Würzburg
David Heinzmann: University Hospital Tübingen, Eberhard Karls University Tübingen
Manina Günter: German Cancer Research Centre
Saskia Ungern-Sternberg: University Hospital Tübingen, Eberhard Karls University Tübingen
Manuela Büttcher: University Hospital Tübingen, Eberhard Karls University Tübingen
Tatsiana Castor: University Hospital Tübingen, Eberhard Karls University Tübingen
Stine Mencl: University Hospital Essen
Friederike Langhauser: University Hospital Essen
Katharina Sies: German Cancer Research Center (DKFZ)
Diyaa Ashour: Comprehensive Heart Failure Center (CHFC)
Mustafa Caglar Beker: Istanbul Medipol University
Michael Lämmerhofer: Pharmaceutical (Bio-)Analysis
Stella E. Autenrieth: German Cancer Research Centre
Tilman E. Schäffer: University of Tübingen
Stefan Laufer: University of Tübingen
Paulina Szklanna: University College Dublin
Patricia Maguire: University College Dublin
Matthias Heikenwalder: German Cancer Research Center (DKFZ)
Karin Anne Lydia Müller: University Hospital Tübingen, Eberhard Karls University Tübingen
Dirk M. Hermann: Department of Neurology
Ertugrul Kilic: Istanbul Medipol University
Ralf Stumm: Jena University Hospital
Gustavo Ramos: Comprehensive Heart Failure Center (CHFC)
Christoph Kleinschnitz: University Hospital Essen
Oliver Borst: University Hospital Tübingen, Eberhard Karls University Tübingen
Harald F. Langer: University Heart Center
Dominik Rath: University Hospital Tübingen, Eberhard Karls University Tübingen
Meinrad Gawaz: University Hospital Tübingen, Eberhard Karls University Tübingen

Nature Communications, 2022, vol. 13, issue 1, 1-20

Abstract: Abstract Platelet activation plays a critical role in thrombosis. Inhibition of platelet activation is a cornerstone in treatment of acute organ ischemia. Platelet ACKR3 surface expression is independently associated with all-cause mortality in CAD patients. In a novel genetic mouse strain, we show that megakaryocyte/platelet-specific deletion of ACKR3 results in enhanced platelet activation and thrombosis in vitro and in vivo. Further, we performed ischemia/reperfusion experiments (transient LAD-ligation and tMCAO) in mice to assess the impact of genetic ACKR3 deficiency in platelets on tissue injury in ischemic myocardium and brain. Loss of platelet ACKR3 enhances tissue injury in ischemic myocardium and brain and aggravates tissue inflammation. Activation of platelet-ACKR3 via specific ACKR3 agonists inhibits platelet activation and thrombus formation and attenuates tissue injury in ischemic myocardium and brain. Here we demonstrate that ACKR3 is a critical regulator of platelet activation, thrombus formation and organ injury following ischemia/reperfusion.

Date: 2022
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DOI: 10.1038/s41467-022-29341-1

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