Mechanisms of Progression of Disease in Autoimmune Myocarditis

Date
2020
Authors
Herrera, Natalia
Journal Title
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Volume Title
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Abstract

Autoimmune myocarditis is an inflammatory disease of the myocardium with variable etiology and clinical manifestations. While myocarditis is self-limiting in most patients, it can progress to dilated cardiomyopathy (DCM). In DCM, the heart undergoes fibrotic remodeling that is associated with left ventricular dysfunction and heart failure, which may lead to a need for a heart transplant. Current treatments focus on supportive therapy rather than preventing the progression of disease; this is the case with glucocorticosteroids (GCs) such as Dexamethasone (Dex) which treat inflammation. It is known that Dex administration upregulates the cytokine macrophage migratory inhibition factor (MIF) which in turn can counteract the effect of GCs. Using the experimental autoimmune myocarditis (EAM) model in BALB/c mice, we demonstrated that Dex therapy in the absence of MIF ameliorated the severity of both acute phase EAM and chronic phase DCM. However, despite a decrease in inflammatory infiltrates and fibrotic remodeling, the autoimmune peripheral T cell response was comparable between groups, suggesting that progression towards DCM implicating some other mechanism driving progression. Additionally, qPCR for extracellular matrix and chemotactic genes among others showed a decrease in osteopontin (OPN) production in MIF-inhibited Dex treated mice. Subsequently, heart infiltrates were compared in Wt vs OPN knockout mice; though not statistically significant, they were decreased in OPN knockout mice. To determine a possible direct link between OPN and MIF, cardiac fibroblasts were treated with recombinant MIF and cytokine production evaluated by ELISA. Our findings reveal insights into the mechanisms driving progression of autoimmune myocarditis to DCM.

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Keywords
Autoimmune myocarditis, Dilated cardiomyopathy, Osteopontin
Citation
Department
Integrative Biology