Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.


Autoria(s): Blyszczuk P.; Kania G.; Dieterle T.; Marty R.R.; Valaperti A.; Berthonneche C.; Pedrazzini T.; Berger C.T.; Dirnhofer S.; Matter C.M.; Penninger J.M.; Lüscher T.F.; Eriksson U.
Data(s)

2009

Resumo

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.

Identificador

http://serval.unil.ch/?id=serval:BIB_96039EB6D1D8

isbn:1524-4571[electronic]

pmid:19762681

doi:10.1161/CIRCRESAHA.109.199802

isiid:000271032300011

Idioma(s)

en

Fonte

Circulation research, vol. 105, no. 9, pp. 912-920

Palavras-Chave #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
Tipo

info:eu-repo/semantics/article

article