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

• Verfasst von: Bockstahler, Mariella [VerfasserIn]
• Verfasst von: Fischer, Andrea [VerfasserIn]
• Verfasst von: Goetzke, Carl Christoph [VerfasserIn]
• Verfasst von: Neumaier, Hannah Louise [VerfasserIn]
• Verfasst von: Sauter, Martina [VerfasserIn]
• Verfasst von: Kespohl, Meike [VerfasserIn]
• Verfasst von: Müller, Anna-Maria [VerfasserIn]
• Verfasst von: Meckes, Christin [VerfasserIn]
• Verfasst von: Salbach, Christian [VerfasserIn]
• Verfasst von: Schenk, Mirjam [VerfasserIn]
• Verfasst von: Heuser, Arnd [VerfasserIn]
• Verfasst von: Landmesser, Ulf [VerfasserIn]
• Verfasst von: Weiner, January [VerfasserIn]
• Verfasst von: Meder, Benjamin [VerfasserIn]
• Verfasst von: Lehmann, Lorenz [VerfasserIn]
• Verfasst von: Kratzer, Adelheid [VerfasserIn]
• Verfasst von: Klingel, Karin [VerfasserIn]
• Verfasst von: Katus, Hugo [VerfasserIn]
• Verfasst von: Kaya, Ziya [VerfasserIn]
• Verfasst von: Beling, Antje [VerfasserIn]
• Titel: Heart-specific immune responses in an animal model of autoimmune-related myocarditis mitigated by an immunoproteasome inhibitor and genetic ablation
• Verf.angabe: Mariella Bockstahler, Andrea Fischer, Carl Christoph Goetzke, Hannah Louise Neumaier, Martina Sauter, Meike Kespohl, Anna-Maria Mueller, Christin Meckes, Christian Salbach, Mirjam Schenk, Arnd Heuser, Ulf Landmesser, January Weiner, Benjamin Meder, Lorenz Lehmann, Adelheid Kratzer, Karin Klingel, Hugo A. Katus, Ziya Kaya, Antje Beling
• E-Jahr: 2020
• Jahr: June 9, 2020
• Umfang: 18 S.
• Teil: volume:141
• Teil: year:2020
• Teil: number:23
• Teil: pages:1885-1902
• Teil: extent:18
• Fussnoten: Gesehen am 05.10.2020
• Titel Quelle: Enthalten in: Circulation
• Ort Quelle: Philadelphia, Pa. : Lippincott, Williams & Wilkins, 1950
• Jahr Quelle: 2020
• Band/Heft Quelle: 141(2020), 23, Seite 1885-1902
• ISSN Quelle: 1524-4539
• DOI: doi:10.1161/CIRCULATIONAHA.119.043171
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: autoimmunity
• Sach-SW: cardiac troponin-i
• Sach-SW: cardio-oncology
• Sach-SW: deficiency
• Sach-SW: dexamethasone
• Sach-SW: dilated cardiomyopathy
• Sach-SW: failure
• Sach-SW: induction
• Sach-SW: inflammation
• Sach-SW: models
• Sach-SW: myocarditis
• Sach-SW: pd-1
• Sach-SW: proteasome
• Sach-SW: selective inhibitor
• Sach-SW: tumor-necrosis-factor
• K10plus-PPN: 1734636912

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 (programmed cell death protein 1), control the threshold of self-antigen responses directed against cardiac TnI (troponin I). We aimed to identify how the immunoproteasome, the main proteolytic machinery in immune cells harboring 3 distinct protease activities in the LMP2 (low-molecular-weight protein 2), LMP7 (low-molecular-weight protein 7), and MECL1 (multicatalytic endopeptidase complex subunit 1) 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 3 immunoproteasome subunits (triple-ip(-/-)) or lacking either the gene encoding LMP2 and LMP7 by immunization with a cardiac TnI peptide. Alternatively, before induction of TnI-AM or after establishment of autoimmune myocarditis, mice were treated with the immunoproteasome inhibitor ONX 0914. Immune parameters defining heart-specific autoimmunity were investigated in experimental TnI-AM and in 2 cases of ICI-related myocarditis. Results: All immunoproteasome-deficient strains showed mitigated autoimmune-related cardiac pathology with less inflammation, lower proinflammatory and chemotactic cytokines, less interleukin-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 (Toll-like receptor 2)-engaged and TLR7 (Toll-like receptor 7)/TLR8 (Toll-like receptor 8)-engaged CD14(+)monocytes with ONX 0914, diminished proinflammatory 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 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, immunoglobulin G deposition, interleukin-17 production in heart tissue, and TnI-directed humoral autoimmune responses, was also present in 2 cases of ICI-related myocarditis, 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 patients with ICI-related heart-specific autoimmunity.