The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis

Xuezhou Hou, Guobao Chen, William Bracamonte-Baran, Hee Sun Choi, Nicola L. Diny, Jungeun Sung, David Hughes, Taejoon Won, Megan Kay Wood, Monica V. Talor, David Joel Hackam, Karin Klingel, Giovanni Davogustto, Heinrich Taegtmeyer, Isabelle Coppens, Jobert G. Barin, Daniela Čiháková

Research output: Contribution to journalArticle

Abstract

Two types of monocytes, Ly6Chi and Ly6Clo, infiltrate the heart in murine experimental autoimmune myocarditis (EAM). We discovered a role for cardiac fibroblasts in facilitating monocyte-to-macrophage differentiation of both Ly6Chi and Ly6Clo cells, allowing these macrophages to perform divergent functions in myocarditis progression. During the acute phase of EAM, IL-17A is highly abundant. It signals through cardiac fibroblasts to attenuate efferocytosis of Ly6Chi monocyte-derived macrophages (MDMs) and simultaneously prevents Ly6Clo monocyte-to-macrophage differentiation. We demonstrated an inverse clinical correlation between heart IL-17A levels and efferocytic receptor expressions in humans with heart failure (HF). In the absence of IL-17A signaling, Ly6Chi MDMs act as robust phagocytes and are less pro-inflammatory, whereas Ly6Clo monocytes resume their differentiation into MHCII+ macrophages. We propose that MHCII+Ly6Clo MDMs are associated with the reduction of cardiac fibrosis and prevention of the myocarditis sequalae. Hou et al. show that cardiac fibroblasts facilitate infiltrating Ly6Chi and Ly6Clo monocytes to become macrophages. IL-17A trans-signaling through cardiac fibroblasts increases MerTK shedding and promotes a pro-inflammatory and pro-tissue remodeling gene expression profile in Ly6Chi monocyte-derived macrophages. Paradoxically, IL-17A signaling through cardiac fibroblasts can substantially inhibit Ly6Clo monocyte-to-macrophage differentiation.

Original languageEnglish (US)
Pages (from-to)172-189.e7
JournalCell Reports
Volume28
Issue number1
DOIs
StatePublished - Jul 2 2019

Keywords

  • Ly6C
  • MerTK
  • heart
  • macrophages
  • monocytes
  • myocarditis

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Hou, X., Chen, G., Bracamonte-Baran, W., Choi, H. S., Diny, N. L., Sung, J., Hughes, D., Won, T., Wood, M. K., Talor, M. V., Hackam, D. J., Klingel, K., Davogustto, G., Taegtmeyer, H., Coppens, I., Barin, J. G., & Čiháková, D. (2019). The Cardiac Microenvironment Instructs Divergent Monocyte Fates and Functions in Myocarditis. Cell Reports, 28(1), 172-189.e7. https://doi.org/10.1016/j.celrep.2019.06.007