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
Affiliations
Xuezhou Hou
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Guobao Chen
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
William Bracamonte-Baran
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Hee Sun Choi
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Nicola L. Diny
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Jungeun Sung
Institute of Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
David Hughes
Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
Taejoon Won
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Megan Kay Wood
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Monica V. Talor
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
David Joel Hackam
Division of General Pediatric Surgery, Johns Hopkins University and Bloomberg Children’s Center, Johns Hopkins Hospital, Baltimore, MD 21218, USA
Karin Klingel
Cardiopathology, Institute for Pathology and Neuropathology, University of Tübingen, 72076 Tübingen, Germany
Giovanni Davogustto
Department of Internal Medicine, Division of Cardiovascular Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Heinrich Taegtmeyer
Department of Internal Medicine, Division of Cardiovascular Medicine, McGovern Medical School at The University of Texas Health Science Center at Houston, Houston, TX 77030, USA
Isabelle Coppens
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA
Jobert G. Barin
Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA
Daniela Čiháková
W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA; Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA; Corresponding author
Summary: 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. Keywords: monocytes, macrophages, heart, myocarditis, Ly6C, MerTK
