Cardioimmunology

Heart-specific inflammation or myocarditis is a common cause of remodeling and heart failure, i.e. dilated cardiomyopathy (iDCM). We study mechanistic aspects of virus triggered and autoimmune inflammation and its progression to end stage heart failure characterized by ventricular dilation and tissue fibrosis, which further impairs cardiac function.

Using Coxsackie B3 viruses, we induce acute myocarditis in the mouse, which turns into an autoimmune chronic inflammation and end stage heart failure. Alternatively, we use an autoimmune model where myocarditis is induced by heart-specific self-peptides either by injection with an adjuvant, or by vaccination of with self-peptide-loaded activated dendritic cells. The resulting phenotype closely resembles the typical histology observed in the failing human heart. Thus, our experimental models allow to study mechanisms of cardiac inflammation and pathological remodeling in vivo, and – using gene-targeted mice – at the genetic level.

abb2.jpgFig. 1 sFRP2 prevents from development of postinflammatory fibrosis in EAM. a-MyHC/CFA immunized BALB/c treated with secreted Frizzled-related proteins (sFRP) – a natural inhibitors of Wnt signalling during acute myocarditis are protected from development of postinflammatory fibrosis in the heart.

We identified heart-infiltrating CD133+ progenitor cells as the key compartment of remodeling in inflammatory heart disease pointing to a critical role of epigenetic factors. We delineated the mechanisms of the differentiation of CD133+ progenitors and identified TGF-β-mediated pathways promoting fibrogenesis (Fig. 1 and 2). Similarly, we studied the role of angiotensin mediated pathways.

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Fig. 2 Graphical presentation of molecular mechanism of TGF-β-mediated activation of canonical Wnt pathway during progression of myocarditis into myocardial fibrosis phenotype in Experimental Autoimmune Myocarditis (EAM)

In parallel we investigated heart-specific autoreactive CD4+ T cells and the dual role of the cytokine Interferon in cardiac autoimmunity. This cytokine exerts is involved in the priming process of autoreactive pathogenic T cells and up-regulation of endothelial MHC class II molecules, but also protects from exaggerated autoimmunity via a NO-mediated negative feedback loop, which confines T cell expansion.

Knowledge of the mechanisms involved in iDCM is the basis for the development of novel treatment strategies. We envisage that our pathogenic insights are generalizable also to ischemic heart disease in the future.


Publications
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. Circulation 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.