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Interleukin-6-dependent phenotypic modulation of cardiac fibroblasts after acute myocardial infarction

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Abstract

Interleukin-6 (IL-6) is a multifunctional cytokine that orchestrates the immune response to a wide variety of pathophysiologic challenges but also contributes to tissue homeostasis. Furthermore, IL-6 is elevated in patients with acute myocardial infarction. Hyaluronan (HA) is an extracellular carbohydrate that has been implicated in wound healing and accumulates after acute myocardial infarction (AMI). Aim of this study was to investigate the involvement of IL-6 in the regulation of the HA-matrix in the early phase of infarct healing. In the present study, we show by the use of a blocking anti-IL-6 antibody, that endogenous IL-6 rapidly but transiently increased HA-synthase (HAS) 1 and 2 expression resulting in the formation of a HA-rich matrix acutely after AMI in mice. In vitro, IL-6 induced HAS1 and 2 via STAT3 phosphorylation in cardiac fibroblasts (CF) and supported a myofibroblastic phenotype in a HA-dependent manner. Furthermore, CCL5 and MCP1 expression were dependent on IL-6, HA-synthesis and the HA-receptor CD44 as shown in cultured CF derived from CD44 knockout mice. In vivo after AMI, blocking IL-6 decreased HA-matrix formation in the peri-infarct region and alpha-smooth muscle actin-positive myofibroblasts. Blocking IL-6 also reduced neutrophil infiltration in infarcted left ventricles. Moreover, treatment with the blocking IL-6 antibody reduced cardiac ejection fraction and increased infarct size 3 weeks after AMI. These findings support a functionally important role for IL-6 in CF by transiently inducing a HA-rich matrix that in turn promotes a myofibroblastic phenotype and inflammatory responses, and ultimately establishes a cardioprotective program after AMI.

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Abbreviations

HA:

Hyaluronan

HAS:

Hyaluronan synthase

HAbP:

Hyaluronan-binding protein

αSMA:

Alpha-smooth muscle actin

4-MU:

Soluble IL-6 receptor (sIL-6R), 4-methylumbelliferone

CF:

Cardiac fibroblasts

LAD:

Left anterior descending coronary artery

ECM:

Extracellular matrix

EF:

Ejection fraction

STEMI:

ST-segment elevation myocardial infarction

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Acknowledgments

The excellent technical assistance of Annika Zimmermann is greatly acknowledged.

Conflict of interest

No conflict of interest to be reported.

Author information

Authors and Affiliations

  1. Institut für Pharmakologie und Klinische Pharmakologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Germany

    Julia Müller, Simone Gorressen, Maria Grandoch, Kathrin Feldmann, Inga Kretschmer, Joachim P. Schmitt & Jens W. Fischer

  2. Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Simone Gorressen & Malte Kelm

  3. Institut für Klinische Biochemie u. Pathobiochemie, Deutsches Diabetes Zentrum, Auf’m Hennekamp 65, 40225, Düsseldorf, Germany

    Stefan Lehr

  4. Institut für Molekulare Kardiologie, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Zhaoping Ding & Jürgen Schrader

  5. Institut für Biochemie, Christian-Albrechts-Universität Kiel, Kiel, Germany

    Christoph Garbers

  6. Cardiovascular Research Institute Düsseldorf (CARID), Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Joachim P. Schmitt, Jürgen Schrader, Malte Kelm & Jens W. Fischer

  7. Institut für Pathophysiologie, Universität Duisburg-Essen, Essen, Germany

    Gerd Heusch

  8. Institut für Biochemie und Molekularbiologie II, Universitätsklinikum der Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany

    Jürgen Scheller

Authors
  1. Julia Müller
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  2. Simone Gorressen
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  3. Maria Grandoch
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  4. Kathrin Feldmann
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  7. Zhaoping Ding
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  11. Gerd Heusch
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  13. Jürgen Scheller
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  14. Jens W. Fischer
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Correspondence to Jens W. Fischer.

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C. Tschöpe, Berlin, Germany, served as guest editor for the manuscript and was responsible for all editorial decisions, including the selection of reviewers. The policy applies to all manuscripts with authors from the editor’s institution.

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Müller, J., Gorressen, S., Grandoch, M. et al. Interleukin-6-dependent phenotypic modulation of cardiac fibroblasts after acute myocardial infarction. Basic Res Cardiol 109, 440 (2014). https://doi.org/10.1007/s00395-014-0440-y

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