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Mitigated viral myocarditis in A/J mice by the immunoproteasome inhibitor ONX 0914 depends on inhibition of systemic inflammatory responses in CoxsackievirusB3 infection
Basic Research in Cardiology ( IF 7.5 ) Pub Date : 2021-02-01 , DOI: 10.1007/s00395-021-00848-w
Carl Christoph Goetzke 1, 2, 3 , Nadine Althof 4 , Hannah Louise Neumaier 5 , Arndt Heuser 6 , Ziya Kaya 7, 8 , Meike Kespohl 5, 9 , Karin Klingel 10 , Antje Beling 5, 9
Affiliation  

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.



中文翻译:


免疫蛋白酶体抑制剂 ONX 0914 减轻 A/J 小鼠病毒性心肌炎的作用取决于对柯萨奇病毒 B3 感染中全身炎症反应的抑制



肌钙蛋白 I 诱导的心肌炎 (AM) 的临床前模型揭示了免疫蛋白酶体 (ip)(主要免疫细胞驻留蛋白酶体亚型)在心脏定向自身免疫中的重要作用。心脏的病毒感染是心脏自身免疫的已知触发因素,感染心肌柯萨奇病毒 B3 (CV) 后,腹腔注射会增强全身炎症反应。在这里,我们使用 ip 缺陷的 A/J-LMP7 −/−小鼠来研究 ip 介导的对 CV 引发的心肌炎适应性免疫的影响,发现与野生小鼠相比,炎症性心脏组织损伤或心脏功能没有改变。 -型控制。为了确定 CV 感染过程中 ip 蛋白水解控制下的全身炎症风暴的影响,我们在第一个感染周期后,当全身炎症已经开始时,用抑制剂 ONX 0914 靶向 A/J 小鼠的 ip心脏炎症。在急性心肌炎期间,ONX 0914 治疗组的心输出量与对照组相同,但心脏组织的炎症反应不受该化合物的影响。基于这些发现以及 ONX 0914 在 CV 感染中已知的抗炎作用,我们得出结论,ip 抑制剂对 A/J 小鼠中 CV 引发的心肌炎的疗效依赖于它们对全身炎症反应的免疫调节作用。

更新日期:2021-02-01
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