Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
Christian Perez‐Shibayama, Cristina Gil‐Cruz, Nadine Cadosch, Mechthild Lütge, Hung‐Wei Cheng, Angelina De Martin, Kira Frischmann, Anna Joachimbauer, Lucas Onder, Iliana Papadopoulou, Chrysa Papadopoulou, Sandra S. Ring, Philippe Krebs, Vivian Vu, Matthias P. Nägele, Valentina A. Rossi, Danaë Parianos, Valentin W. Zsilavecz, Leslie T. Cooper, Andreas J. Flammer, Frank Ruschitzka, Peter P. Rainer, Dörthe Schmidt, Burkhard Ludewig
Abstract
Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.