4E-BP3 deficiency impairs dendritic cell activation and CD4+ T cell differentiation and attenuates α-myosin-specific T cell-mediated myocarditis in mice
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引用次数: 0
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.
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