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IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation

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Abstract

Inflammation resolution is important for scar formation following myocardial infarction (MI) and requires the coordinated actions of macrophages and fibroblasts. In this study, we hypothesized that exogenous interleukin-10 (IL-10), an anti-inflammatory cytokine, promotes post-MI repair through actions on these cardiac cell types. To test this hypothesis, C57BL/6J mice (male, 3- to 6-month old, n = 24/group) were treated with saline or IL-10 (50 μg/kg/day) by osmotic mini-pump infusion starting at day (d) 1 post-MI and sacrificed at d7 post-MI. IL-10 infusion doubled plasma IL-10 concentrations by d7 post-MI. Despite similar infarct areas and mortality rates, IL-10 treatment significantly decreased LV dilation (1.6-fold for end-systolic volume and 1.4-fold for end-diastolic volume) and improved ejection fraction 1.8-fold (both p < 0.05). IL-10 treatment attenuated inflammation at d7 post-MI, evidenced by decreased numbers of Mac-3-positive macrophages in the infarct (p < 0.05). LV macrophages isolated from d7 post-MI mice treated with IL-10 showed significantly elevated gene expression of M2 markers (Arg1, Ym1, and Tgfb1; all p < 0.05). We further performed RNA-seq analysis on post-MI cardiac macrophages and identified 410 significantly different genes (155 increased, 225 decreased by IL-10 treatment). By functional network analysis grouping, the majority of genes (133 out of 410) were part of the cellular assembly and repair functional group. Of these, hyaluronidase 3 (Hyal3) was the most important feature identified by p value. IL-10 treatment decreased Hyal3 by 28%, which reduced hyaluronan degradation and limited collagen deposition (all p < 0.05). In addition, in vivo IL-10 treatment increased fibroblast activation (proliferation, migration, and collagen production), an effect that was both directly and indirectly influenced by macrophage M2 polarization. Combined, our results indicate that in vivo infusion of IL-10 post-MI improves the LV microenvironment to dampen inflammation and facilitate cardiac wound healing.

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Acknowledgements

Research reported in this publication was supported by the American Heart Association under Award Number 15SDG22930009, by the National Heart, Lung, and Blood Institute and the National Institute of General Medical Sciences of the National Institutes of Health under Award Numbers HL075360, HL129823, HL051971, GM104357, GM114833, GM103476, GM103328, and GM115428, and from the Biomedical Laboratory Research and Development Service of the Veterans Affairs Office of Research and Development under Award Number 5I01BX000505. The content is solely the responsibility of the authors and does not necessarily represent the official views of the American Heart Association, the National Institutes of Health, or the Veterans Administration.

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  1. Department of Physiology and Biophysics, Mississippi Center for Heart Research, University of Mississippi Medical Center, 2500 North State St., Jackson, MS, 39216-4505, USA

    Mira Jung, Yonggang Ma, Rugmani Padmanabhan Iyer, Kristine Y. DeLeon-Pennell & Merry L. Lindsey

  2. Donald W. Reynolds Department of Geriatric Medicine, Reynolds Oklahoma Center on Aging, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Andriy Yabluchanskiy

  3. Department of Pharmacology and Toxicology, UMMC, Jackson, MS, USA

    Michael R. Garrett

  4. Research Service, G.V. (Sonny) Montgomery Veterans Affairs Medical Center, Jackson, MS, USA

    Kristine Y. DeLeon-Pennell & Merry L. Lindsey

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  1. Mira Jung
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Jung, M., Ma, Y., Iyer, R.P. et al. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol 112, 33 (2017). https://doi.org/10.1007/s00395-017-0622-5

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