title: Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Cardiology, University Hospital, Zurich, Switzerland. przemyslaw.blyszczuk@access.uzh.ch
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Blyszczuk
authors.forename: Gabriela
authors.initials: G
authors.lastname: Kania
authors.forename: Thomas
authors.initials: T
authors.lastname: Dieterle
authors.forename: Rene R
authors.initials: RR
authors.lastname: Marty
authors.forename: Alan
authors.initials: A
authors.lastname: Valaperti
authors.forename: Corinne
authors.initials: C
authors.lastname: Berthonneche
authors.forename: Thierry
authors.initials: T
authors.lastname: Pedrazzini
authors.forename: Christoph T
authors.initials: CT
authors.lastname: Berger
authors.forename: Stephan
authors.initials: S
authors.lastname: Dirnhofer
authors.forename: Christian M
authors.initials: CM
authors.lastname: Matter
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Lüscher
authors.forename: Urs
authors.initials: U
authors.lastname: Eriksson
mesh_terms: D000818:Animals; D015551:Autoimmunity; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002311:Cardiomyopathy, Dilated / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000637:transplantation; D004195:Disease Models, Animal; D018450:Disease Progression; D005347:Fibroblasts / Q000276:immunology; D005355:Fibrosis; D005620:Freund's Adjuvant; D049452:Green Fluorescent Proteins / Q000235:genetics; D006333:Heart Failure / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D007113:Immunity, Innate; D053583:Interleukin-1beta / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D009205:Myocarditis / Q000150:complications / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000276:immunology* / Q000473:pathology; D018995:Myosin Heavy Chains / Q000276:immunology; D010641:Phenotype; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018183:Transplantation Chimera
chemical_list: D053583:Interleukin-1beta; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D053573:Receptors, Interleukin-1 Type I; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D005620:Freund's Adjuvant; D018995:Myosin Heavy Chains