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ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury

Author

Listed:
  • 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
    University of 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)
    University of Heidelberg)

  • 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
    University of Tübingen)

  • Harald F. Langer

    (University Heart Center
    Partner Site Hamburg/Lübeck/Kiel)

  • Dominik Rath

    (University Hospital Tübingen, Eberhard Karls University Tübingen)

  • Meinrad Gawaz

    (University Hospital Tübingen, Eberhard Karls University Tübingen)

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.

Suggested Citation

  • 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 Kre, 2022. "ACKR3 regulates platelet activation and ischemia-reperfusion tissue injury," Nature Communications, Nature, vol. 13(1), pages 1-20, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29341-1
    DOI: 10.1038/s41467-022-29341-1
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