NK cells promote cardiac cell death and regulate myelopoiesis in myocardial infarction

Nature Communications, vol. 17

Abstract

Ischemic heart failure remains a major clinical challenge, underscoring the need to better understand post-infarction immune mechanisms and identify new therapeutic targets. Both innate and adaptive immunity contribute to adverse cardiac remodeling following myocardial infarction (MI), yet the role of cytotoxic cells such as natural killer (NK) cells remains poorly defined. Here, we show that after acute MI in mice, NK cells are recruited to the ischemic myocardium in a CCR2-dependent manner and become activated. Activated NK cells locally release granzyme B, promoting cardiomyocyte apoptosis, adverse ventricular remodeling, and impaired cardiac function. Genetic deletion or pharmacological depletion of NK cells reduces cardiomyocyte death, attenuates inflammation, limits myocardial injury, and improves cardiac function. In contrast, NK cell activation using an anti-NKG2A monoclonal antibody exacerbates ischemic heart failure. We further demonstrate that NK cells regulate bone marrow myelopoiesis through local GM-CSF production. Finally, we identify a distinct NK cellular and transcriptomic signature in human ischemic heart tissue at early stages. Together, these findings reveal a detrimental role for NK cells following acute MI and highlight NK cells as potential therapeutic targets to limit adverse cardiac remodeling.

Authors 33

1. Raphaël Cohen

   Inserm · Université Paris Cité · Paris Cardiovascular Research Center

   Affiliation as printed

   Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

2. Vincent Duval

   Inserm · Université Paris Cité · Paris Cardiovascular Research Center

   Affiliation as printed

   Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

3. Rida Al-Rifai

   Inserm · Université Paris Cité · Paris Cardiovascular Research Center

   Affiliation as printed

   Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

4. Sidrah Maryam Aachen Institute of Experimental Medicine and Systems Biology

   RWTH Aachen University

   Affiliation as printed

   Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany

5. Icía Santos‐Zas

   Instituto de Investigación Sanitaria de Santiago · Complejo Hospitalario Universitario de Santiago

   Affiliation as printed

   Laboratorio de Endocrinología Celular, Área de Endocrinología Molecular y Cellular Instituto de Investigación Sanitaria de Santiago, Complejo Hospitalario Universitario de Santiago (CHUS), Santiago de Compostela, Spain

6. Rayan Braik

   Inserm · Université Paris Cité · Paris Cardiovascular Research Center

   Affiliation as printed

   Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

7. Marc Diedisheim

   Inserm · Institut Necker Enfants Malades

   Affiliation as printed

   Clinique Saint Gatien Alliance (NCT + ), Saint-Cyr-sur-Loire, France, INSERM U1151, Necker Enfants Malades (INEM), IMMEDIAB Laboratory, Paris, France

8. Charlène Jouve

   Inserm · Université Paris Cité · Paris Cardiovascular Research Center

   Affiliation as printed

   Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

9. Simon Nicoletti

   Centre National de la Recherche Scientifique · Sorbonne Paris Cité · Inserm · Université Paris Cité · Institut des Maladies Génétiques Imagine

   Affiliation as printed

   Institut Imagine, INSERM U1163, CNRS ERL 8254, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Université Paris Cité, Paris, France

10. Sara Thietart

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

11. Théo Guyon

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

12. Luna Chetrit

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

13. Maria Kral

    Ludwig-Maximilians-Universität München · German Centre for Cardiovascular Research · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten

    Affiliation as printed

    German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany

    Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany

14. Yvonne Döring

    Ludwig-Maximilians-Universität München · German Centre for Cardiovascular Research · University of Bern · University Hospital of Bern · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten

    Affiliation as printed

    Department for BioMedical Research (DBMR), University of Bern, Bern, Switzerland

    Division of Angiology, Swiss Cardiovascular Center, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland

    German Centre for Cardiovascular Research (DZHK), Partner Site Munich Heart Alliance, Munich, Germany

    Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany

15. Christian Weber

    Ludwig-Maximilians-Universität München · Maastricht University · Maastricht University Medical Centre · Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten · Munich Cluster for Systems Neurology

    Affiliation as printed

    Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University Medical Centre, Maastricht, The Netherlands

    Institute for Cardiovascular Prevention (IPEK), Ludwig-Maximilians-University Munich (LMU), Munich, Germany

    Munich Cluster for Systems Neurology (SyNergy), Munich, Germany

16. Alexandre Loupy

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

17. Orianne Domengé

    Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou · Centre d'Investigation Clinique Hôpital Européen Georges Pompidou

    Affiliation as printed

    CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France

18. Marine Livrozet

    Assistance Publique – Hôpitaux de Paris · Hôpital Européen Georges-Pompidou · Centre d'Investigation Clinique Hôpital Européen Georges Pompidou

    Affiliation as printed

    CIC1418 and DMU CARTE, AP-HP, Hôpital Européen Georges-Pompidou, Paris, France

19. Jean‐Sébastien Hulot

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

20. Ecem T. Sakalli

    Universitätsklinikum Würzburg

    Affiliation as printed

    Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

21. Giuseppe Rizzo

    Universitätsklinikum Würzburg

    Affiliation as printed

    Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

22. Antoine‐Emmanuel Saliba

    University of Würzburg · Helmholtz Institute for RNA-based Infection Research

    Affiliation as printed

    Helmholtz Institute for RNA-based Infection Research (HIRI), Helmholtz-Center for Infection Research (HZI), Würzburg, Germany

    Institute of Molecular Infection Biology (IMIB), University of Würzburg, Würzburg, Germany

23. Marie Piollet

    Inserm · Université Paris Cité · Universitätsklinikum Würzburg · Paris Cardiovascular Research Center

    Affiliation as printed

    Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

24. Patrick Bruneval

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

25. Alain Tedgui

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

26. Soraya Taleb

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

27. Olivier Hermine

    Centre National de la Recherche Scientifique · Sorbonne Paris Cité · Inserm · Université Paris Cité · Institut des Maladies Génétiques Imagine

    Affiliation as printed

    Institut Imagine, INSERM U1163, CNRS ERL 8254, Sorbonne Paris-Cité, Laboratoire d'Excellence GR-Ex, Université Paris Cité, Paris, France

28. Ian P. Wicks

    The University of Melbourne · Walter and Eliza Hall Institute of Medical Research

    Affiliation as printed

    Walter and Eliza Hall Institute of Medical Research and Department of Medical Biology, University of Melbourne, Parkville, Melbourne, VIC, Australia

29. Jean‐Sébastien Silvestre

    Inserm · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

30. Sikander Hayat Aachen Institute of Experimental Medicine and Systems Biology

    RWTH Aachen University

    Affiliation as printed

    Institute of Experimental Medicine and Systems Biology, RWTH Aachen University, Aachen, Germany

31. Clément Cochain

    Inserm · Université Paris Cité · Universitätsklinikum Würzburg · Paris Cardiovascular Research Center

    Affiliation as printed

    Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France

32. Eric D. Vivier

    Centre National de la Recherche Scientifique · Aix-Marseille Université · Inserm · Centre d’Immunologie de Marseille-Luminy

    Affiliation as printed

    Aix Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, Marseille, France

33. Hafid Ait-Oufella corresponding

    Sorbonne Université · Inserm · Assistance Publique – Hôpitaux de Paris · Université Paris Cité · Paris Cardiovascular Research Center

    Affiliation as printed

    Sorbonne Université, Service de médecine intensive-Réanimation, Assistance Publique, Hôpitaux de Paris, Paris, France. hafid.aitoufella@inserm.fr

    Université Paris Cité, INSERM U970, Paris Cardiovascular Research Center, Paris, France. hafid.aitoufella@inserm.fr