Heart-specific inflammation - myocarditis is a common cause of pathological tissue remodelling and heart failures, with the phenotype of inflammatory dilated cardiomyopathy (iDCM). In our projects, we study mechanistic aspects of the development of virus triggered and autoimmune cardiac inflammation and its progression to the end stage heart failure. The end stage heart failure phenotype following myocarditis in humans and experimental animal models is morphologically characterized by ventricular dilation and progressive tissue fibrosis, which further impairs cardiac function.
In our clinical projects we prospectively follow patients with heart failure, analysing subsets of activated peripheral T cells homeing to the heart. So far, we established a patient cohort and refined the methodology to perform efficient FACS analysis from human blood samples. Moreover, we set up an in vitro system to check the capacity of activated circulating T cells to promote transition from human cardiac fibroblast precursors into fibrotic myofibroblasts.
In our experimental projects we take advantage of mouse models. Using Coxsackie B3 viruses, it is possible to induce acute myocarditis in specific mouse strains, which turns into an ongoing, autoimmune chronic inflammation and later on into end stage heart failure. Alternatively, we use a model of Experimental Autoimmune Myocarditis. In this autoimmune model, myocarditis can be induced by immunization with heart-specific self- peptides either by injecting them together with a strong and non-specific adjuvant, or by vaccination of mice with self-peptide-loaded activated dendritic cells. Importantly, the resulting phenotype of the inflamed mouse heart closely resembles the typical histology observed in the failing human heart. Thus, our experimental models allow us to study mechanisms of cardiac inflammation and pathological remodelling in vivo, and – using gene-targeted mice – on the genetic level.
So far, we identified heart-infiltrating CD133+ progenitor cells as the key compartment of pathological remodelling in inflammatory heart disease and pointed to the critical role of epigenetic factors in this process. In our completed project we delineated the mechanisms affecting the differentiation of CD133+ progenitors and identified several TGF-beta mediated pathways promoting fibrogenesis in the chronically inflamed heart (see figures 1 and 2). Similarly, we studied the role of Angiotensin mediated pathways in this context.
In parallel we put great efforts in our understanding of mechanisms promoting priming of heart-specific autoreactive CD4+ T cells in our Experimental Autoimmune Myocarditis model. In this context, we greatly advanced our understanding of dual role of the cytokine Interferon gamma in cardiac autoimmunity. On one hand, this cytokine exerts a critical role in the initial priming process of autoreactive pathogenic T cells and up-regulation of endothelial MHC class II molecules in the target organ. On the other hand the same cytokine protects from exaggerated autoimmunity activating a negative nitric-oxide mediated feedback loop, which confines T cell expansion.
Knowledge of the mechanisms involved in iDCM is basic for the development of novel treatment strategies. We strongly believe that our pathogenic insights could be generalized to other heart diseases, such as ischemic heart disease in the future.
Ongoing research projects
- Wnt signalling in the myocardial fibrogenesis in inflammatory heart models (manuscript submitted).
- Role of Angiotensin/Rho kinases in transition from acute myocardial inflammation into chronic stages in iDCM (manuscript in preparation).
- Role of IFN-gamma in the sterile autoimmune myocarditis (manuscript in preparation).
- Identification of the cytokine profile produced by pathogenic autoreactive CD4+ T cells in autoimmune myocarditis (manuscript in preparation).
- Identification of activated T cells in patients with heart failure (ongoing clinical study).
Peer-reviewed original research (selection)
Valaperti A, Nishii M, Liu Y, Yang H, Naito K, Liu PP, Eriksson U. The adaptor protein c-Cbl-associated protein (CAP) protects from acute CVB3-mediated myocarditis through stabilization of type I interferon production and reduced cytotoxicity. Basic Res Cardiol 2014; 109:411
Valaperti A, Nishii M, Germano D, Liu PP, Eriksson U. Vaccination with Flt3L-induced CD8a+ dendritic cells prevents CD4+ T helper cell-mediated experimental autoimmune myocarditis. Vaccine 2013; 31:4802-4811.
Valaperti A, Nishii M, Liu Y, Naito K, Chan M, Zhang L, Skurk C, Schultheiss HP, Eriksson U, Liu PP. Innate Immune Interleukin-1 Receptor-Associated Kinase 4 (IRAK4) Exacerbates Viral Myocarditis by Reducing CCR5+CD11b+ Monocytes Migration and Impairing Interferon Production. Circulation 2013; 128:1542-1554.
Kania G, Siegert S, Behnke S, Prados-Rosales R, Casadevall A, Lüscher TF, Luther SA, Kopf M, Eriksson U*, Blyszczuk P*. Innate signalling promotes formation of regulatory nitric oxide-producing dendritic cells limiting T cell expansion in experimental autoimmune myocarditis.
2013; 127:2285 – 2295.
*shared last authorship
Heeswijk RB, De Blois J, Kania G, Gonzales C, Blyszczuk P, Stuber M, Eriksson U, Schwitter J. Selective in-vivo visualization of immune-cell infiltration in a mouse model of autoimmune myocarditis by fluorine-19 cardiac magnetic resonance. Circ Cardiovasc Imaging 2013; 6(2):277-284.
Blyszczuk P, Berthonneche C, Behnke S, Glönkler M, Moch H, Pedrazzini T, Lüscher TF, Eriksson U*, Kania G*. Nitric oxide synthase 2 is required for conversion of fibrogenic CD133+ progenitors into F4/80+ macrophages in experimental autoimmune myocarditis.
*shared last authorship
Bobbert P, Scheibenbogen C, Jenke A, Kania G, Wilk S, Krohn S, Stehr J, Kuehl U, Rauch U, Eriksson U, Schultheiss HP, Poller W, Skurk C. Adiponectin expression in patients with inflammatory cardiomyopathy indicates favourable outcome and inflammation control. Eur Heart J 2011; 32(9):1134-1147.
Rother M, Krohn S, Kania G, Vanhoutte D, Eisenreich A, Wang X, Westermann D, Savvatis K, Dannemann N, Skurk C, Hilfiker-Kleiner D, Cathomen T, Fechner H, Rauch U, Schultheiss HP, Heymans S, Eriksson U, Scheibenbogen C, Poller W. Matricellular Signaling Molecule CCN1 Attenuates Experimental Autoimmune Myocarditis by Acting as a Novel Immune Cell Migration Modulator. Circulation 2010; 122:2688-2698.
Blyszczuk P, Kania G, Dieterle T, Marty RR, Valaperti A, Bertonneche C, Pedrazzini T, Berger CT, Dirnhofer S, Matter CM, Penninger JM, Lüscher TF, Eriksson U. MyD88/IL-1 signaling controls cardiac fibrosis and heart failure progression in inflammatory dilated cardiomyopathy. Circ Res 2009; 105:912-920.
Kania G, Blyszczuk P, Stein MS, Valaperti A, Germano D, Dirnhofer S, Hunziker L, Matter CM, Eriksson U. Heart-infiltrating prominin-1+/CD133+ progenitor cells represent the cellular source of TGF-β-mediated cardiac fibrosis in experimental autoimmune myocarditis. Circ Res 2009; 105:462-470.
Kania G, Blyszczuk P, Valaperti A, Dieterle T, Leimenstoll B, Dirnhofer S, Zulewski H, Eriksson U. Prominin-1+/CD133+ bone marrow derived heart resident cells suppress experimental autoimmune myocarditis. Cardiovasc Res 2008; 80:236-245.
Valaperti A, Marty RR, Kania G, Germano D, Mauermann N, Dirnhofer S, Leimenstoll B, Blyszczuk P, Hunziker L, Eriksson U. CD11b+ monocytes abrogate Th17 CD4+ T cell mediated experimental autoimmune myocarditis. J Immunol 2008; 180:2686-2695.
Rangachari M, Mauermann N, Marty RR, Dirnhofer S, Kurrer MO, Komnenovic V, Penninger JM, Eriksson U. T-bet is a negative regulator of autoimmune heart disease. J Exp Med 2006; 203: 2009-2019.
Marty RR, Dirnhofer S, Mauermann N, Schweikert S, Akira S, Hunziker L, Penninger JM, Eriksson U. MyD88 signaling controls autoimmune myocarditis induction. Circulation 2006; 113:258-265.
Ricci R, Eriksson U, Oudit GY, Eferl R, Akhmedov A, Sumara I, Sumara G, Kassiri Z, David JP, Bakiri L, Sasse B, Idarraga MH, Rath M, Kurz D, Theussl HC, Perriard J, Backx P, Penninger JM, Wagner EF. Distinct function of junD in cardiac hypertrophy and heart failure. Gene Dev 2005; 19:208-213.
Ricci R, Sumara G, Sumara I, Rozenberg I, Kurrer MO, Akhmedov A, Hersberger M, Eriksson U, Eberli FR, Becher B, Boren J, Chen M, Cybulsky MI, Moore KJ, Freeman MW, Wagner EF, Matter CM, Luscher TF. Requirement of JNK2 for scavenger receptor A-mediated foam cell formation in atherogenesis. Science 2004; 306:1558-1561.
Eriksson U, Ricci R, Hunziker L, Kurrer MO, Oudit GY, Watts TH, Sonderegger I, Bachmaier K, Kopf M, Penninger JM. Dendritic cell-induced heart failure requires essential cooperation between adaptive and innate immunity. Nat Med 2003; 9:1484-1489.
Eriksson U, Kurrer MO, Sonderegger I, Iezzi G, Tafuri A, Hunziker L, Suzuki S, Bachmaier K, Bingisser RM, Penninger JM, Kopf M. Activation of dendritic cells through the IL-1 receptor 1 is essential for the induction of autoimmune myocarditis. J Exp Med 2003; 197(3):323-331.
Eriksson U, Kurrer MO, Schmitz N, Fontana A, Marsch SC, Eugster HP, Kopf M. IL-6 deficient mice resist development of autoimmune myocarditis associated with impaired upgulation of Complement C3. Circulation 2003; 107:320-325.
Eriksson U, Kurrer MO, Sebald W, Brombacher F, Kopf M. Dual role of the IL-12/IFN-γ axis in the development of myocarditis: induction by IL-12 and protection by IFN-γ. J Immunol 2001; 167:5464-5469.
Eriksson U, Kurrer MO, Bingisser RM, Eugster HP, Saremaslani P, Follath F, Marsch S, Widmer U. Lethal autoimmune myocarditis in Interferon-γ receptor deficient mice: enhanced disease severity by impaired inducible nitric oxide induction. Circulation 2001; 96:585-591.