Periodic Reporting for period 2 - CardiacStroma (Tissue Cytokines at the Nexus of Immune Cell-Cardiac Stromal Cell Interaction)
Reporting period: 2023-07-01 to 2024-12-31
Myocarditis is a prototypical inflammatory heart disease that results in cardiomyocyte loss and often leads to fibrotic remodeling of the myocardium, culminating in heart failure. Currently, treatments for acute and chronic myocardial inflammation have limited efficacy and vary from physical activity restriction, anti-inflammatory treatment in patients with pericardial involvement, general heart failure management to off-label use of immunosuppressive medications. Despite the identification of a number of pathways leading to myocardial inflammation, the elucidation of effective therapeutic intervention remains incomplete because the overarching molecular mechanisms that govern the balance between myocardial homeostasis and inflammation are incompletely understood.
Selective restoration of cellular homeostasis in the inflamed heart is therefore critical to facilitate treatment of myocardial inflammation, reduce cardiac fibrosis and ultimately prevent heart failure. The main goals of this project are to thoroughly dissect the pathological principles underlying cardiac inflammation and to target those molecular pathways that are at the core of the inflammatory process. The planned work will provide a detailed analysis of the molecular pathways that drive T cell-mediated myocarditis and inflammatory cardiomyopathy and delineate a straightforward path towards therapeutic intervention for these diseases.
Selective restoration of cellular homeostasis in the inflamed heart is therefore critical to facilitate treatment of myocardial inflammation, reduce cardiac fibrosis and ultimately prevent heart failure. The main goals of this project are to thoroughly dissect the pathological principles underlying cardiac inflammation and to target those molecular pathways that are at the core of the inflammatory process. The planned work will provide a detailed analysis of the molecular pathways that drive T cell-mediated myocarditis and inflammatory cardiomyopathy and delineate a straightforward path towards therapeutic intervention for these diseases.
Tissue cytokines such as bone morphogenetic proteins (BMPs) are important for cardiac tissue homeostasis and function. Here, we used single cell transcriptomics of inflamed human and murine cardiac tissue to investigate whether and to what extent dysregulation of BMPs is associated with myocardial inflammation and cardiac tissue integrity. We found that the BMP4-Gremlin (GREM)1/2 axis is a key pathway involved in the maintenance of homeostatic cardiac function. Antibody-mediated neutralization of the BMP4 inhibitors GREM1 and GREM2 restored BMP signaling in the inflamed myocardium, thereby attenuating immune cell activity, reducing fibrotic remodeling, and preserving cardiomyocyte integrity.
To gain further insight into the processes underlying myocardial inflammation in humans, prospective cohorts of patients with acute or chronic myocardial inflammation have been established. The ImmpathCarditis study is currently recruiting patients with myocarditis and chronic inflammatory cardiomyopathy including cardiac sarcoidosis at the University Hospital Zurich and the Cantonal Hospital of St. Gallen. In addition, we have established a second clinical study to elucidate the immunological processes underlying heart transplant rejection using single-cell transcriptome analysis.
To gain further insight into the processes underlying myocardial inflammation in humans, prospective cohorts of patients with acute or chronic myocardial inflammation have been established. The ImmpathCarditis study is currently recruiting patients with myocarditis and chronic inflammatory cardiomyopathy including cardiac sarcoidosis at the University Hospital Zurich and the Cantonal Hospital of St. Gallen. In addition, we have established a second clinical study to elucidate the immunological processes underlying heart transplant rejection using single-cell transcriptome analysis.
The work in this project combines sophisticated mouse models of cardiac inflammation with high-resolution molecular and immunological analysis and validation in human patient cohorts to guide the development of improved diagnostic and prognostic markers in inflammatory heart disease. The development of immunotherapeutic therapies targeting stromal-immune cell interactions in the inflamed heart will strengthen European research competitiveness by fostering the establishment of a promising new field of research.