Molecular and therapeutic aspects of proteolytic machineries in immune cells for cardiac inflammation.

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Myocarditis and its sequela, inflammatory cardiomyopathy, are leading causes of heart failure and sudden death in young adults. Viral infections are the most common trigger of myocardial inflammation in the Western world. The magnitude of heart-directed immune response activation leading to infiltration of the heart muscle with immune cells is an independent predictor for debilitating sequela of acute virus-mediated disease leading to adverse outcome. In certain individuals, we find an immune-anchored phenotype leading to overwhelming immune response activation either directed against virus-infected cells and referred to immunopathology or resulting in a loss of self-tolerance and induction of heart-directed autoimmunity. Within this context, we have defined the pathological function the major cellular proteolytic machinery in immune cells – the immunoproteasome. The peptidase capacity of this multicatalytic enzymatic complex influences disease manifestation in a mouse model both of viral and autoimmune myocarditis. In A/J mice, the immunoproteasome facilitates systemic and local pro-inflammatory cytokine/chemokine production, which are a prerequisite for immune cell infiltration of the heart. Since impaired immunoproteasome proteolysis inverted the susceptibility for acute heart directed immunopathology and autoimmunity, we propose specific Inhibitors targeting the immunoproteasome as a novel therapeutic approach for ongoing inflammatory heart disease. We aim to investigate whether immunoproteasome-selective inhibitors are capable to mitigatemyocardial inflammatory injury once infiltration or respective sequela have emerged. Toxicity and immune-related adverse events may represent significant hurdles of such a target with wide-ranging functions. Therefore, we propose further research to identify the signaling, transcriptional, and posttranscriptional mechanisms by which immunoproteasome inhibition leads to changes in immune cell activation, proliferation, differentiation, and cytokine secretion. Thereby, efforts from this proposal will be essential to provide insights into optimal ways to modulate immunoproteasome-affected pathways and putative adverse events for sustained patients’ benefit.