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

心肌炎及其后遗症，炎性心肌病，是导致心力衰竭和猝死的主要原因。病毒感染是西方世界心肌炎症最常见的诱因。导致免疫细胞浸润心肌的心脏定向免疫应答激活的幅度是导致不良结局的急性病毒介导疾病的衰弱性后遗症的独立预测因子。在某些个体中，我们发现免疫锚定表型导致压倒性的免疫反应激活，要么针对病毒感染的细胞并涉及免疫病理学，要么导致自身耐受性丧失并诱导心脏定向自身免疫。在此背景下，我们定义了免疫细胞中主要的细胞蛋白水解机制-免疫蛋白酶体的病理功能。这种多催化酶复合物的肽酶能力影响病毒性和自身免疫性心肌炎小鼠模型的疾病表现。在A/J小鼠中，免疫蛋白酶体促进全身和局部促炎细胞因子/趋化因子的产生，这是免疫细胞浸润心脏的先决条件。由于受损的免疫蛋白酶体蛋白水解逆转了急性心脏定向免疫病理学和自身免疫的易感性，我们提出了针对免疫蛋白酶体的特异性抑制剂作为持续性炎症性心脏病的新治疗方法。我们的目的是调查是否免疫蛋白酶体选择性抑制剂能够减轻一旦浸润或各自的后遗症已经出现的炎性损伤。毒性和免疫相关的不良事件可能是这种具有广泛功能的目标的重大障碍。因此，我们建议进一步研究，以确定信号，转录和转录后机制，免疫蛋白酶体抑制导致免疫细胞活化，增殖，分化和细胞因子分泌的变化。因此，这项提案的努力将是至关重要的，以提供最佳的方式来调节免疫蛋白酶体影响的途径和推定的不良事件的持续患者的利益的见解。

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.