Published online before print September 17, 2009, doi: 10.1161/CIRCRESAHA.109.199802
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on April 24, 2009
Revised on September 2, 2009
Accepted on September 3, 2009
Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy
Przemyslaw Blyszczuk *;
From the Department of Cardiology (P.B., G.K., R.R.M., A.V., C.T.B., C.M.M., T.F.L., U.E.), University Hospital, Zurich, Switzerland; and Cardiovascular Research, Zurich Center for Integrative Human Physiology, University of Zurich, Switzerland; Clinical Cardiology (T.D.), Department of Internal Medicine; and Institute of Pathology (C.B., T.P.), University Hospital, Basle, Switzerland; Department of Medicine (S.D.), University of Lausanne Medical School, Lausanne, Switzerland; and Institute for Molecular Biotechnology of the Austrian Academy of Sciences (J.M.P.), Vienna, Austria.
* To whom correspondence should be addressed. E-mail: przemyslaw.blyszczuk{at}access.uzh.ch.
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 
-myosin heavy chain peptide (MyHC-)–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-/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.
Key words: autoimmune myocarditis • heart failure • fibrosis • innate immunity