Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection

Autor: Nadine Althof, Karin Klingel, Arndt Heuser, Hannah Louise Neumaier, Ziya Kaya, Antje Beling, Meike Kespohl, Carl Christoph Goetzke
Rok vydání: 2021
Předmět:
Male
0301 basic medicine
Proteasome Endopeptidase Complex
Viral Myocarditis
Myocarditis
Physiology
medicine.medical_treatment
Anti-Inflammatory Agents
Coxsackievirus Infections
Inflammation
030204 cardiovascular system & hematology
medicine.disease_cause
Systemic inflammation
Autoimmunity
03 medical and health sciences
0302 clinical medicine
Immune system
Physiology (medical)
Animals
Medicine
Myeloid Cells
Myocytes
Cardiac
Cytokine
Cells
Cultured
Mice
Knockout
Proteasome
business.industry
Original Contribution
Acquired immune system
medicine.disease
Enterovirus B
Human
Disease Models
Animal
030104 developmental biology
Host-Pathogen Interactions
Proteolysis
Immunology
Technology Platforms
medicine.symptom
Infection
Cardiology and Cardiovascular Medicine
business
Oligopeptides
Proteasome Inhibitors
600 Technik
Medizin
angewandte Wissenschaften::610 Medizin und Gesundheit::610 Medizin und Gesundheit
Zdroj: Basic Research in Cardiology
ISSN: 1435-1803
0300-8428
DOI: 10.1007/s00395-021-00848-w
Popis: A preclinical model of troponin I-induced myocarditis (AM) revealed a prominent role of the immunoproteasome (ip), the main immune cell-resident proteasome isoform, in heart-directed autoimmunity. Viral infection of the heart is a known trigger of cardiac autoimmunity, with the ip enhancing systemic inflammatory responses after infection with a cardiotropic coxsackievirusB3 (CV). Here, we used ip-deficient A/J-LMP7−/− mice to investigate the role of ip-mediated effects on adaptive immunity in CV-triggered myocarditis and found no alteration of the inflammatory heart tissue damage or cardiac function in comparison to wild-type controls. Aiming to define the impact of the systemic inflammatory storm under the control of ip proteolysis during CV infection, we targeted the ip in A/J mice with the inhibitor ONX 0914 after the first cycle of infection, when systemic inflammation has set in, well before cardiac inflammation. During established acute myocarditis, the ONX 0914 treatment group had the same reduction in cardiac output as the controls, with inflammatory responses in heart tissue being unaffected by the compound. Based on these findings and with regard to the known anti-inflammatory role of ONX 0914 in CV infection, we conclude that the efficacy of ip inhibitors for CV-triggered myocarditis in A/J mice relies on their immunomodulatory effects on the systemic inflammatory reaction.
Databáze: OpenAIRE
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