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Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation

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. and Fischer, A. and Goetzke, C.C. and Neumaier, H.L. and Sauter, M. and Kespohl, M. and Müller, A.M. and Meckes, C. and Salbach, C. and Schenk, M. and Heuser, A. and Landmesser, U. and Weiner, J. and Meder, B. and Lehmann, L. and Kratzer, A. and Klingel, K. and Katus, H.A. and 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
Date:12 March 2020
Official Publication:https://doi.org/10.1161/CIRCULATIONAHA.119.043171
PubMed:View item in PubMed

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