The immunoproteasome‐specific inhibitor ONX 0914 reverses susceptibility to acute viral myocarditis

Abstract

Severe heart pathology upon virus infection is closely associated with the immunological equipment of the host. Since there is no specific treatment available, current research focuses on identifying new drug targets to positively modulate predisposing immune factors. Utilizing a murine model with high susceptibility to coxsackievirus B3‐induced myocarditis, this study describes ONX 0914—an immunoproteasome‐specific inhibitor—as highly protective during severe heart disease. Represented by reduced heart infiltration of monocytes/macrophages and diminished organ damage, ONX 0914 treatment reversed fulminant pathology. Virus‐induced immune response features like overwhelming pro‐inflammatory cytokine and chemokine production as well as a progressive loss of lymphocytes all being reminiscent of a sepsis‐like disease course were prevented by ONX 0914. Although the viral burden was only minimally affected in highly susceptible mice, resulting maintenance of immune homeostasis improved the cardiac output, and saved animals from severe illness as well as high mortality. Altogether, this could make ONX 0914 a potent drug for the treatment of severe virus‐mediated inflammation of the heart and might rank immunoproteasome inhibitors among drugs for preventing pathogen‐induced immunopathology.

Fibrosis Rescue Improves Cardiac Function in Dystrophin-Deficient Mice and Duchenne Patient–Specific Cardiomyocytes by Immunoproteasome Modulation

“…19,20 Of note, the potent inhibitor ONX-0914, originally named PR957 and specifically targeted toward the highly active subunit LMP7 (b5i) of the immunoproteasome, 21 was successfully used to treat a viral myocarditis by diminishing the expression of proinflammatory cytokines and chemokines, reducing infiltration of inflammatory cells, and leading to a general improvement of the cardiac output. 22 In line with this result, our previous work found that ONX-0914 treatment modulates dystrophic features in mdx mice by reducing the amount of infiltrating activated T cells, myofiber necrosis, and collagen deposition in skeletal muscle tissues. 23 The present study confirmed the possibility of using ONX-0914 for inhibiting the immunoproteasome function, therefore countervailing inflammatory cells and fibrosis in dilated cardiomyopathy of mdx mice and improving their hemodynamic performance.…”

“…6,7 Immunoproteasome functions are synergistically associated with the activity of most of the proteins that are involved in the development of the symptoms that will lead to dilated cardiomyopathy, such as cardiomyocyte necrosis, myocardial tissue degeneration, and fibrosis. 22,45,46 We found overexpression of immunoproteasome subunits in the hearts of mdx mice and suggest that immunoproteasome modulation is a valuable tool to counteract cardiac pathologic findings in mdx mice.…”

Immunoproteasome subunit β5i regulates diet‐induced atherosclerosis through altering MERTK‐mediated efferocytosis in Apoe knockout mice

“…It is well known that immune and inflammatory cells, including macrophages, T cells and dendritic cells, play an important role in the development and progression of atherosclerosis [23,24]. The immunoproteasome is expressed constitutively in immune cells, and can be induced in immune and non-immune cells upon exposure to pro-inflammatory stimuli such as viruses, angiotensin II and high salt, thus contributes to the regulation of immuno-inflammatory diseases, including viral myocarditis, hypertrophic remodeling, atrial fibrillation and vascular cell apoptosis [15,16,18,[25][26][27][28]. Here, the results presented showed that β5i was upregulated in the atherosclerotic plaques of eKO mice (Figure 1); genetic ablation or inhibition of β5i reduced lesional accumulation of apoptotic cells but enhanced MERTK-mediated efferocytosis, therefore inhibited necrotic core formation and atherosclerosis progression (Figures 2-4).…”

Regional astrocyte interferon-γ signaling regulates immunoproteasome-mediated protection during chronic autoimmunity

“…The best known function of the iP is its role in antigen processing; however, since astrocytes present little or no antigen (83-85), alternate functions of the iP were examined, namely, clearance of ROS and oxidatively damaged and poly-ubiquitinated proteins (86). To determine the role of the iP in astrocyte viability and ROS clearance, we treated regional human astrocytes with or without IFNγ and a specific inhibitor of the iP, ONX 0914 (87-89). Following iP inhibition, an increase in caspase activity was observed only in spinal cord astrocytes compared to media treatment, which was significantly enhanced compared to those from the brainstem (Figure 3A).…”