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Blocking the IL-1β signalling pathway prevents chronic viral myocarditis and cardiac remodeling

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Abstract

Coxsackieviruses of group B (CVB) are well-known causes of acute and chronic myocarditis. Chronic myocarditis can evolve into dilated cardiomyopathy (DCM) characterized by fibrosis and cardiac remodeling. Interleukin-1β (IL-1β) plays a decisive role in the induction of the inflammatory response as a consequence of viral replication. In this study, we analyzed the effects of IL-1β neutralization on the transition of acute to chronic myocarditis in a mouse model of CVB3 myocarditis. Mice were treated with an anti-murine IL-1β antibody as a surrogate for Canakinumab at different time points post CVB3 infection. Treatment was performed in the early phase (day 1–14 pi, day 3–14 pi) or at a later stage of myocarditis (day 14–28 pi). Subsequently, the hearts were examined histologically, immunohistochemically and by molecular biology. A significant reduction of viral replication, cardiac damage and inflammation was found after administration of the antibody in the early phase and in the later phase of infection. Furthermore, less collagen I deposition and a considerable reduction of fibrosis were found in antibody-treated mice. Using microarray analysis, a significant upregulation of various extracellular matrix and fibrosis-associated molecules was found in CVB3-infected mice, including TGF-β, TIMP-1 and MMP12, as well as diverse matricellular proteins, whereas, these molecules were significantly downregulated in all IL-1β antibody-treated infected mice. Neutralization of IL-1β at different stages of enteroviral infection prevents the development of chronic viral myocarditis by reducing inflammation, interstitial fibrosis and adverse cardiac remodeling. These findings are relevant for the treatment of patients with acute and chronic myocarditis.

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Acknowledgements

We acknowledge Sandra Bundschuh for excellent technical assistance and Hermann Gram (Novartis Pharma AG, Basel, Switzerland) for providing the murine IL-1β antibody.

Funding

This work was partially funded by the German Research Foundation (DFG) KL 595/2-3 to KK. TE was supported by a MD scholarship (Interdisziplinäres Zentrum für Klinische Forschung (IZKF)-Promotionskolleg) provided by the University Hospital Tübingen.

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  1. Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Liebermeisterstrasse 8, 72076, Tübingen, Germany

    Lisa Kraft, Tugs Erdenesukh, Martina Sauter & Karin Klingel

  2. Department of Cardiology, Berlin Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, Campus Virchow Klinikum, 13353, Berlin, Germany

    Carsten Tschöpe

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  1. Lisa Kraft
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Correspondence to Karin Klingel.

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KK received the IL-1β antibody as a gift and research funding from Novartis AG. The other authors declare that they have no conflict of interest.

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Lisa Kraft, Tugs Erdenesukh, Martina Sauter and Karin Klingel takes responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.

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Kraft, L., Erdenesukh, T., Sauter, M. et al. Blocking the IL-1β signalling pathway prevents chronic viral myocarditis and cardiac remodeling. Basic Res Cardiol 114, 11 (2019). https://doi.org/10.1007/s00395-019-0719-0

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