4E-BP3 deficiency impairs dendritic cell activation and CD4+ T cell differentiation and attenuates α-myosin-specific T cell-mediated myocarditis in mice

IF 7.5 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Siqi Li, Kazuko Tajiri, Zixun Yuan, Yoshiko Murakata, Zonghu Song, Seiya Mizuno, Dongzhu Xu, Nobuyuki Murakoshi
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Abstract

Immune checkpoint inhibitor (ICI)-associated myocarditis is a rare but potentially fatal immune-related adverse event. Previously, we reported a case of ICI-associated myocarditis with elevated autoantibodies to 4E-binding protein 3 (4E-BP3). Recent studies have suggested that 4E-BP3 may play an important role in tumor development. However, its role in cardiac diseases including myocarditis is unknown. We investigated the role of 4E-BP3 in an autoimmune myocarditis mouse model. Myocarditis was induced in wild-type and 4E-BP3 knockout mice by immunization with murine α-myosin peptide. 4E-BP3 gene expression was upregulated in the heart of myocarditis mouse. We found that genetic deletion of 4E-BP3 attenuated myocardial inflammation, reduced fibrosis area, and improved cardiac function in myocarditis mice. Studies in bone marrow-chimeric mice demonstrated that immune cell-derived 4E-BP3 plays a pivotal role in the pathogenesis of myocarditis. Immune cell transfer experiments revealed that 4E-BP3 deficiency in dendritic cells and CD4+ T cells decreased disease severity in recipient mice. Furthermore, dendritic cells that were deficient in 4E-BP3 exhibited a diminished capacity to produce IL-6 and IL-1β. Naive CD4+ T cells lacking 4E-BP3 had a reduced ability to differentiate into T-helper (Th)1 and Th17 cells. These findings suggest that 4E-BP3 in dendritic cells and CD4+ T cells may be critically involved in the pathogenesis of α-myosin-specific T cell-mediated myocarditis. Thus, 4E-BP3 could be a possible therapeutic target for myocarditis.

Abstract Image

4E-BP3 缺乏会损害树突状细胞活化和 CD4+ T 细胞分化,并减轻 α 肌球蛋白特异性 T 细胞介导的小鼠心肌炎
免疫检查点抑制剂(ICI)相关心肌炎是一种罕见但可能致命的免疫相关不良事件。此前,我们曾报道过一例 ICI 相关性心肌炎患者,其 4E 结合蛋白 3(4E-BP3)自身抗体升高。最近的研究表明,4E-BP3 可能在肿瘤发生发展中扮演重要角色。然而,它在包括心肌炎在内的心脏疾病中的作用尚不清楚。我们研究了 4E-BP3 在自身免疫性心肌炎小鼠模型中的作用。用鼠α肌球蛋白肽免疫诱导野生型小鼠和4E-BP3基因敲除小鼠患心肌炎。4E-BP3基因在心肌炎小鼠心脏中表达上调。我们发现,基因缺失4E-BP3可减轻心肌炎小鼠的心肌炎症,减少纤维化面积,并改善其心脏功能。对骨髓嵌合小鼠的研究表明,免疫细胞衍生的4E-BP3在心肌炎的发病机制中起着关键作用。免疫细胞转移实验显示,树突状细胞和 CD4+ T 细胞缺乏 4E-BP3 会降低受体小鼠的疾病严重程度。此外,缺乏4E-BP3的树突状细胞产生IL-6和IL-1β的能力减弱。缺乏 4E-BP3 的幼稚 CD4+ T 细胞分化成 Thelper (Th)1 和 Th17 细胞的能力降低。这些研究结果表明,树突状细胞和CD4+ T细胞中的4E-BP3可能与α-肌球蛋白特异性T细胞介导的心肌炎的发病机制密切相关。因此,4E-BP3可能是心肌炎的治疗靶点。
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来源期刊
Basic Research in Cardiology
Basic Research in Cardiology 医学-心血管系统
CiteScore
16.30
自引率
5.30%
发文量
54
审稿时长
6-12 weeks
期刊介绍: Basic Research in Cardiology is an international journal for cardiovascular research. It provides a forum for original and review articles related to experimental cardiology that meet its stringent scientific standards. Basic Research in Cardiology regularly receives articles from the fields of - Molecular and Cellular Biology - Biochemistry - Biophysics - Pharmacology - Physiology and Pathology - Clinical Cardiology
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