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| Item Type: | Article |
|---|---|
| Title: | Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation |
| Creators Name: | Bockstahler, M., Fischer, A., Goetzke, C.C., Neumaier, H.L., Sauter, M., Kespohl, M., Müller, A.M., Meckes, C., Salbach, C., Schenk, M., Heuser, A., Landmesser, U., Weiner, J., Meder, B., Lehmann, L., Kratzer, A., Klingel, K., Katus, H.A., Kaya, Z. and Beling, A. |
| Abstract: | BACKGROUND: Immune checkpoint inhibitor (ICI) therapy is often accompanied by immune-related pathology, with an increasing occurrence of high-risk ICI-related myocarditis. Understanding the mechanisms involved in this side effect could enable the development of management strategies. In mouse models, immune checkpoints, such as PD-1, control the threshold of self-antigen responses directed against cardiac troponin I (TnI). Here, we aimed at identifying how the immunoproteasome, the main proteolytic machinery in immune cells harboring three distinct protease activities in the LMP2, LMP7 and MECL1 subunit, affects TnI-directed autoimmune pathology of the heart. METHODS: TnI-directed autoimmune myocarditis (TnI-AM), a CD4(+) T cell-mediated disease, was induced in mice lacking all three immunoproteasome subunits, triple-ip(-/-), or lacking either the LMP2 or LMP7 gene, by immunization with a cardiac TnI peptide. Alternatively, prior to induction of TnI-AM or after establishment of AM, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in both experimental TnI-AM and in two cases of ICI-related myocarditis. RESULTS: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower pro-inflammatory and chemotactic cytokines, less IL-17 production, and reduced fibrosis formation. Protection from TnI-directed autoimmune heart pathology with improved cardiac function in LMP7(-/-) mice involved a changed balance between effector and regulatory CD4(+) T cells in the spleen, with CD4(+) T cells from LMP7(-/-) mice showing a higher expression of inhibitory PD-1 molecules. Blocked immunoproteasome proteolysis, by treatment of TLR2 and TLR7/8-engaged CD14(+) monocytes with ONX 0914, diminished pro-inflammatory cytokine responses, thereby reducing the boost for the expansion of self-reactive CD4(+) T cells. Correspondingly, in mice, ONX 0914 treatment reversed cardiac autoimmune pathology, preventing both the induction and progression of TnI-AM, when self-reactive CD4+ T cells were primed. The autoimmune signature during experimental TnI-AM, with high immunoproteasome expression, immunoglobulinG deposition, IL-17 production in heart tissue and TnI-directed humoral autoimmune responses, was also present in two cases of ICI-related myocarditis, thus demonstrating the activation of heart-specific autoimmune reactions by ICI therapy. CONCLUSIONS: By reversing heart-specific autoimmune responses, immunoproteasome inhibitors applied to a mouse model demonstrate their potential to aid in the management of autoimmune myocarditis in humans, possibly including cases with ICI-related heart-specific autoimmunity. |
| Keywords: | Autoimmunity, Myocarditis, Immunoproteasome, Immune-Checkpoint Inhibitor, Animals, Mice |
| Source: | Circulation |
| ISSN: | 0009-7322 |
| Publisher: | American Heart Association |
| Volume: | 141 |
| Number: | 23 |
| Page Range: | 1885-1902 |
| Date: | 9 June 2020 |
| Official Publication: | https://doi.org/10.1161/CIRCULATIONAHA.119.043171 |
| PubMed: | View item in PubMed |
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