title: Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy.
abstract: Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra(-/-) mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/MΦ) cardiac infiltrates. Depletion of Ly6Chi MO/MΦ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/MΦ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A-fibroblast-GM-CSF-MO/MΦ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Lei
authors.initials: L
authors.lastname: Wu
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: SuFey
authors.initials: S
authors.lastname: Ong
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Monica V
authors.initials: MV
authors.lastname: Talor
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Jobert G
authors.initials: JG
authors.lastname: Barin
authors.affiliation: Department of Parasitology, US Naval Medical Research Unit Six (NAMRU-6), Lima 34031, Peru.
authors.forename: G Christian
authors.initials: GC
authors.lastname: Baldeviano
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Djahida
authors.initials: D
authors.lastname: Bedja
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Asfandyar
authors.initials: A
authors.lastname: Sheikh
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Joseph B
authors.initials: JB
authors.lastname: Margolick
authors.affiliation: Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba 278-0022, Japan.
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Noel R
authors.initials: NR
authors.lastname: Rose
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Department of Pathology, and Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors.forename: Daniela
authors.initials: D
authors.lastname: Ciháková
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology*; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000473:pathology; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D009504:Neutrophils / Q000276:immunology / Q000473:pathology
chemical_list: C098680:Il17a protein, mouse; D020381:Interleukin-17; D016178:Granulocyte-Macrophage Colony-Stimulating Factor