S100A1 is released from ischemic cardiomyocytes and signals myocardial damage via Toll-like receptor 4

Authors

  • David Rohde,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Christoph Schön,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Melanie Boerries,

    1. Institute of Molecular Medicine and Cell Research, Freiburg University, Freiburg, Germany
    2. German Consortium for Translational Cancer Research (DKTK), Partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Ieva Didrihsone,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Julia Ritterhoff,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Katharina F Kubatzky,

    1. Division for Microbiology and Hygiene, Department of Infectious Diseases, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Mirko Völkers,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Nicole Herzog,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Mona Mähler,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • James N Tsoporis,

    1. Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada
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  • Thomas G Parker,

    1. Division of Cardiology, Department of Medicine, Keenan Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Ontario, Canada
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  • Björn Linke,

    1. Division of Immunogenetics, Tumor Immunology Program, German Cancer Research Center (DKFZ), Heidelberg, Germany
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  • Evangelos Giannitsis,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Erhe Gao,

    1. Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
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  • Karsten Peppel,

    1. Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
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  • Hugo A Katus,

    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
    2. German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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  • Patrick Most

    Corresponding author
    1. Section of Molecular and Translational Cardiology, Department of Internal Medicine III, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
    2. Center for Translational Medicine, Department of Medicine, Thomas Jefferson University, Philadelphia, PA, USA
    3. German Centre for Cardiovascular Research (DZHK), Partner site Heidelberg/Mannheim, Heidelberg University Hospital, Heidelberg University, Heidelberg, Germany
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Abstract

Members of the S100 protein family have been reported to function as endogenous danger signals (alarmins) playing an active role in tissue inflammation and repair when released from necrotic cells. Here, we investigated the role of S100A1, the S100 isoform with highest abundance in cardiomyocytes, when released from damaged cardiomyocytes during myocardial infarction (MI). Patients with acute MI showed significantly increased S100A1 serum levels. Experimental MI in mice induced comparable S100A1 release. S100A1 internalization was observed in cardiac fibroblasts (CFs) adjacent to damaged cardiomyocytes. In vitro analyses revealed exclusive S100A1 endocytosis by CFs, followed by Toll-like receptor 4 (TLR4)-dependent activation of MAP kinases and NF-κB. CFs exposed to S100A1 assumed an immunomodulatory and anti-fibrotic phenotype characterized i.e. by enhanced intercellular adhesion molecule-1 (ICAM1) and decreased collagen levels. In mice, intracardiac S100A1 injection recapitulated these transcriptional changes. Moreover, antibody-mediated neutralization of S100A1 enlarged infarct size and worsened left ventricular functional performance post-MI. Our study demonstrates alarmin properties for S100A1 from necrotic cardiomyocytes. However, the potentially beneficial role of extracellular S100A1 in MI-related inflammation and repair warrants further investigation.

Synopsis

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S100A1 is a novel alarmin found released from ischemic cardiomyocytes of both patients and mice during heart attacks. Internalized by cardiac fibroblasts, S100A1 transiently signals via TLR4 to induce an immunomodulatory beneficial response and an anti-fibrotic phenotype.

  • In patients with acute ST-segment elevation myocardial infarction (STEMI), significantly elevated serum levels of S100A1 protein were found when compared to control patients without acute myocardial infarction (n = 12 patients in each group).
  • In C57B/6 mice, S100A1 from damaged cardiomyocytes was exclusively internalized by surrounding cardiac fibroblasts via fluid endocytosis.
  • In vitro, endocytosed S100A1 transiently activated intracellular Toll-like receptor 4 (TLR4) and evoked an immunomodulatory and anti-fibrotic phenotype transition of cardiac fibroblasts.
  • In mice, antibody-mediated neutralization of S100A1 during experimental myocardial infarction resulted in impaired infarct healing and significantly worsened heart function.