Article: article from journal or magazin.
Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.
Publication types: Journal Article ; Research Support, Non-U.S. Gov'tPublication Status: ppublish
RATIONALE: The myeloid differentiation factor (MyD)88/interleukin (IL)-1 axis activates self-antigen-presenting cells and promotes autoreactive CD4(+) T-cell expansion in experimental autoimmune myocarditis, a mouse model of inflammatory heart disease. OBJECTIVE: The aim of this study was to determine the role of MyD88 and IL-1 in the progression of acute myocarditis to an end-stage heart failure. METHODS AND RESULTS: Using alpha-myosin heavy chain peptide (MyHC-alpha)-loaded, activated dendritic cells, we induced myocarditis in wild-type and MyD88(-/-) mice with similar distributions of heart-infiltrating cell subsets and comparable CD4(+) T-cell responses. Injection of complete Freund's adjuvant (CFA) or MyHC-alpha/CFA into diseased mice promoted cardiac fibrosis, induced ventricular dilation, and impaired heart function in wild-type but not in MyD88(-/-) mice. Experiments with chimeric mice confirmed the bone marrow origin of the fibroblasts replacing inflammatory infiltrates and showed that MyD88 and IL-1 receptor type I signaling on bone marrow-derived cells was critical for development of cardiac fibrosis during progression to heart failure. CONCLUSIONS: Our findings indicate a critical role of MyD88/IL-1 signaling in the bone marrow compartment in postinflammatory cardiac fibrosis and heart failure and point to novel therapeutic strategies against inflammatory cardiomyopathy.
Animals, Autoimmunity, Bone Marrow Transplantation, CD4-Positive T-Lymphocytes/immunology, Cardiomyopathy, Dilated/immunology, Cardiomyopathy, Dilated/pathology, Cells, Cultured, Dendritic Cells/immunology, Dendritic Cells/transplantation, Disease Models, Animal, Disease Progression, Fibroblasts/immunology, Fibrosis, Freund's Adjuvant, Green Fluorescent Proteins/genetics, Heart Failure/immunology, Heart Failure/pathology, Immunity, Innate, Interleukin-1beta/metabolism, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Myeloid Differentiation Factor 88/deficiency, Myeloid Differentiation Factor 88/genetics, Myocarditis/complications, Myocarditis/immunology, Myocardium/immunology, Myocardium/pathology, Myosin Heavy Chains/immunology, Phenotype, Receptors, Interleukin-1 Type I/genetics, Receptors, Interleukin-1 Type I/metabolism, Signal Transduction, Transplantation Chimera
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