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Myocardial healing requires Reg3β-dependent accumulation of macrophages in the ischemic heart

Nature Medicine volume 21, pages 353–362 (2015)Cite this article

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Abstract

Cardiac healing after myocardial ischemia depends on the recruitment and local expansion of myeloid cells, particularly macrophages. Here we identify Reg3β as an essential regulator of macrophage trafficking to the damaged heart. Using mass spectrometry–based secretome analysis, we found that dedifferentiating cardiomyocytes release Reg3β in response to the cytokine OSM, which signals through Jak1 and Stat3. Loss of Reg3β led to a large decrease in the number of macrophages in the ischemic heart, accompanied by increased ventricular dilatation and insufficient removal of neutrophils. This defect in neutrophil removal in turn caused enhanced matrix degradation, delayed collagen deposition and increased susceptibility to cardiac rupture. Our data indicate that OSM, acting through distinct intracellular pathways, regulates both cardiomyocyte dedifferentiation and cardiomyocyte-dependent regulation of macrophage trafficking. Release of OSM from infiltrating neutrophils and macrophages initiates a positive feedback loop in which OSM-induced production of Reg3β in cardiomyocytes attracts additional OSM-secreting macrophages. The activity of the feedback loop controls the degree of macrophage accumulation in the heart, which is instrumental in myocardial healing.

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Figure 1: Genetic inactivation of OSMR reduces the accumulation of leukocytes in the damaged heart after MI.
Figure 2: OSM stimulates the expression and secretion of Reg proteins from cardiomyocytes.
Figure 3: Upregulation of Reg3β expression in ischemic hearts depends on activation of the OSMR–Jak1–Stat3 pathway.
Figure 4: Reg3β exerts chemokinetic and chemotactic effects on macrophages.
Figure 5: Genetic inactivation of Reg3β prevents accumulation of macrophages in the heart after MI.
Figure 6: Inactivation of Reg3β prevents cardiac healing after MI, leading to decreased survival, impaired cardiac function and disturbed scar formation.

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Acknowledgements

We thank J. Wetzel, K. Richter, B. Matzke, U. Hofmann and S. Thomas for excellent technical assistance. We are indebted to A. Miyajima (University of Tokyo, Tokyo, Japan) and S. Hunt (University College London, London, UK) for the generous gifts of OSMR-deficient and Reg3β-deficient mice, respectively. This work was supported by the Foundation Leducq, the Excellence Initiative “Cardiopulmonary System,” the Cell and Gene Therapy Center (CGT) and the German Center for Cardiovascular Research (DZHK).

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  1. Holger Lörchner and Jochen Pöling: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cardiac Development and Remodeling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany

    Holger Lörchner, Jochen Pöling, Praveen Gajawada, Yunlong Hou, Viktoria Polyakova, Sawa Kostin, Juan M Adrian-Segarra, Thomas Boettger, Astrid Wietelmann, Thomas Kubin & Thomas Braun

  2. Department of Cardiac Surgery, Schüchtermann-Clinic, Bad Rothenfelde, Germany

    Jochen Pöling & Henning Warnecke

  3. Department of Cardiac Surgery, Kerckhoff-Klinik, Bad Nauheim, Germany

    Manfred Richter

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Contributions

H.L., J.P., P.G. and T.K. conducted experiments; Y.H. carried out experimental LAD ligations; V.P. and S.K. performed immunohistological analysis; J.M.A.-S. conducted data analyses; T.B. performed Genechip-based transcriptional profiling; A.W. performed and interpreted MRI analysis; H.W. supervised the project; M.R. provided biopsies of human ischemic cardiomyopathy samples; and H.L., J.P. and T.B. developed the concept, designed experimental studies, analyzed the data and wrote the manuscript.

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Correspondence to Jochen Pöling or Thomas Braun.

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Lörchner, H., Pöling, J., Gajawada, P. et al. Myocardial healing requires Reg3β-dependent accumulation of macrophages in the ischemic heart. Nat Med 21, 353–362 (2015). https://doi.org/10.1038/nm.3816

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