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(Circulation Research. 2009;105:912.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Myeloid Differentiation Factor-88/Interleukin-1 Signaling Controls Cardiac Fibrosis and Heart Failure Progression in Inflammatory Dilated Cardiomyopathy

Przemyslaw Blyszczuk, Gabriela Kania, Thomas Dieterle, Rene R. Marty, Alan Valaperti, Corinne Berthonneche, Thierry Pedrazzini, Christoph T. Berger, Stephan Dirnhofer, Christian M. Matter, Josef M. Penninger, Thomas F. Lüscher, Urs Eriksson

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.

Correspondence to Przemyslaw Blyszczuk, PhD, Cardiovascular Research, Institute of Physiology, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland. 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