Metabolic reprogramming orchestrates CD4+ T-cell immunological status and restores cardiac dysfunction in autoimmune induced-dilated cardiomyopathy mice

Abstract

Cellular autoimmune responses, especially those mediated by T-cells, play vital roles in the immunopathogenesis of dilated cardiomyopathy (DCM). Metabolic reprogramming directly controls T-cell function, imprinting distinct functional fates. However, its contribution to T-cell dysfunction and the immunopathogenesis of DCM is unknown. Here, we found that in DCM patients, CD4 + T-cells exhibited immune dysfunction and glycolytic metabolic reprogramming based on extracellular acidification and oxygen consumption rates. Similar results were observed in splenic and cardiac CD4 + T-cells from autoimmune-induced DCM mice. In vitro, the glycolysis inhibitor 2-deoxy-D-glucose (2-DG) reversed T-cell dysfunction; thus, heightened metabolic activity directly controls CD4 + T-cell immunological status. Adoptive transfer of CD4 + T-cells from DCM mice to normal recipients induced cardiac remodeling and cardiac T-cell dysfunction. Strikingly, these effects were abolished by preconditioning cells with 2-DG, indicating that CD4 + T-cell dysfunction partially induced by metabolic reprogramming contributes to cardiac remodeling. Moreover, the microRNA let-7i modulated the metabolism and function of T-cells from DCM mice by directly targeting Myc. Collectively, our results show that metabolic reprogramming occurs in T-cells of autoimmune-induced DCM mice and patients. Further, our findings highlight that glycolytic metabolism is a critical contributor to T-cell dysfunction and DCM immunopathogenesis. Our data position the modulation of the metabolism as a central integrator for T-cell function, representing a promising strategy against autoimmune-mediated DCM progression.

Immune Mechanism, Gene Module, and Molecular Subtype Identification of Astragalus Membranaceus in the Treatment of Dilated Cardiomyopathy: An Integrated Bioinformatics Study

“…Evidence-Based Complementary and Alternative Medicine directly controls the immune status of CD4+ T cells. e adoptive transfer of CD4+ T cells from DCM mice to normal receptors causes cardiac remodeling and cardiac T cell dysfunction [62]. Inflammation is crucial in the early development and progression of many cardiovascular diseases involving congenital and adaptive immune responses.…”

“…The TREG cells play an essential role in inducing and maintaining immune homeostasis and tolerance. The generation or dysfunction of Treg cells can trigger abnormal immune responses and lead to pathology [ 62 ]. Myocardial diseases, such as DCM, are characterized by chronic inflammation, mainly mediated by T lymphocytes, and associated enhanced reactive fibrosis [ 21 ].…”

Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis

“…9,10 Previous studies have demonstrated that glycolytic metabolic reprogramming is essential for EAM-induced cardiac remodeling. 11 Furthermore, the T cell immunological and metabolic status is associated with the course of EAM progression. [11][12][13][14] Recently, the critical involvement of cell-cell communication has been suggested in a variety of pathophysiological processes, resulting in novel interventional targets.…”

“…11 Furthermore, the T cell immunological and metabolic status is associated with the course of EAM progression. [11][12][13][14] Recently, the critical involvement of cell-cell communication has been suggested in a variety of pathophysiological processes, resulting in novel interventional targets. 15 Exosomes are one example of this.…”

Amino Acid-Mediated Metabolism: A New Power to Influence Properties of Stem Cells

“…The status of cancer cells can be reprogrammed through metabolic remodeling while their dedifferentiation ability for the induced stem-like phenotype is maintained [20–22]. This capability of switching between differentiated somatic and stem cell states is called cell plasticity [23].…”