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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.

SUBMITTER: Althof N

PROVIDER: S-EPMC5801517 | biostudies-other | 2018 Feb

REPOSITORIES: biostudies-other

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

Althof Nadine N Goetzke Carl Christoph CC Kespohl Meike M Voss Karolin K Heuser Arnd A Pinkert Sandra S Kaya Ziya Z Klingel Karin K Beling Antje A

EMBO molecular medicine 20180201 2

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 reduc ...[more]

PMID: 29295868

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Project description:Immune checkpoint inhibitors (ICIs), antibodies targeting PD-1/PD-L1 or CTLA4 have revolutionized cancer management but are associated with devastating immune-related adverse events (irAEs) including myocarditis. The main risk factor for ICI myocarditis is the use of combination PD-1 and CTLA4 inhibition. ICI-myocarditis is often fulminant and is pathophysiologically characterized by myocardial infiltration of T lymphocytes and macrophages. While much has been learned regarding the role of T-cells in ICI-myocarditis, little is understood regarding the identity, transcriptional diversity, and functions of infiltrating macrophages. We employed an established murine ICI myocarditis model (Ctla4+/-Pdcd1-/- mice) to explore the cardiac immune landscape using single-cell RNA-sequencing, immunostaining, and molecular imaging. We observed marked increases in CCR2+ monocyte-derived macrophages and CD8+ T-cells in this model. The macrophage compartment was heterogeneous and displayed marked enrichment in an inflammatory CCR2+ subpopulation expressing Cxcl9, Cxcl10, Gbp2b, and Fcgr4 that originated from CCR2+ monocytes. Importantly, a similar macrophage population expressing CXCL9, CXCL10, and CD16α (human homologue of mouse FcgR4) were found selectively in patients with ICI myocarditis compared to other forms of heart failure and myocarditis. In silico prediction of cell-cell communication suggested interactions between T-cells and Cxcl9+Cxcl10+ macrophages via IFN-γ and CXCR3 signaling pathways. Depleting CD8+T-cells and blockade of IFN-γ signaling blunted the emergence of Cxcl9+Cxcl10+ macrophages in the heart and attenuated myocarditis suggesting that this interaction was necessary for disease pathogenesis. Collectively, these data demonstrate that ICI-myocarditis is associated with the emergence of a specific population of inflammatory macrophages and suggest the possibility that IFN-γ blockade may serve as an effective treatment for this devastating condition.

Dataset Information

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

Publications

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

Similar Datasets

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