Myeloid differentiation factor-88/interleukin-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy.
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.
Blyszczuk
Przemyslaw
P
Department of Cardiology, University Hospital, Zurich, Switzerland. przemyslaw.blyszczuk@access.uzh.ch
Kania
Gabriela
G
Dieterle
Thomas
T
Marty
Rene R
RR
Valaperti
Alan
A
Berthonneche
Corinne
C
Pedrazzini
Thierry
T
Berger
Christoph T
CT
Dirnhofer
Stephan
S
Matter
Christian M
CM
Penninger
Josef M
JM
Lüscher
Thomas F
TF
Eriksson
Urs
U
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
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