T-Cell Metabolic Reprogramming in Atherosclerosis

Abstract

Atherosclerosis is a key pathological basis for cardiovascular diseases, significantly influenced by T-cell-mediated immune responses. T-cells differentiate into various subtypes, such as pro-inflammatory Th1/Th17 and anti-inflammatory Th2/Treg cells. The imbalance between these subtypes is critical for the progression of atherosclerosis (AS). Recent studies indicate that metabolic reprogramming within various microenvironments can shift T-cell differentiation towards pro-inflammatory or anti-inflammatory phenotypes, thus influencing AS progression. This review examines the roles of pro-inflammatory and anti-inflammatory T-cells in atherosclerosis, focusing on how their metabolic reprogramming regulates AS progression and the associated molecular mechanisms of mTOR and AMPK signaling pathways.

Keywords: T-cells; atherosclerosis; inflammations; metabolic reprogramming.

Figure 1

Simplified schematic of T-cell subsets and their roles in atherosclerosis. T-cells are broadly categorized into two major subsets: pro-inflammatory (Th1 and Th17 cells) and anti-inflammatory (Th2 and Treg cells). Th1 cells secrete pro-inflammatory cytokines, such as IFN-γ and IL-2, while Th17 cells contribute to inflammation by secreting IL-17 and IL-6. Conversely, Th2 cells produce anti-inflammatory cytokines, including IL-4, IL-5, and IL-13, and Treg cells secrete IL-10 and TGF-β, exerting anti-inflammatory effects. Pro-inflammatory T-cells are implicated in promoting the progression of atherosclerosis, whereas anti-inflammatory T-cells play a role in mitigating this progression. Abbreviations: Th cells, T-helper-cells; Treg, regulatory T-cells; IFN-γ, interferon-γ; IL, interleukin; TGF-β, transforming growth factor beta.

Figure 2

Metabolic characteristics of CD4 T-Cells in atherosclerosis. T-cells undergo significant metabolic reprogramming in the context of atherosclerosis. Pro-inflammatory T-cells, such as type 1 helper T-cells (Th1) and type 17 helper T-cells (Th17), exhibit a metabolic preference for glycolysis, fatty acid synthesis (FAS), and glutamine amino acid metabolism. This metabolic reprogramming provides these T-cells with energy and biosynthetic precursors necessary for their effector functions. The key enzymes involved in glycolysis and fatty acid synthesis are shown in the diagram. In contrast, regulatory T-cells (Tregs) and type 2 helper T-cells (Th2), which possess anti-inflammatory and atheroprotective properties, display metabolic characteristics marked by oxidative phosphorylation (OXPHOS), fatty acid oxidation (FAO), and glycolysis, with increased metabolism of arginine and kynurenine. These metabolic features support the suppressive functions of Tregs and Th2 cells, aiding in the maintenance of immune tolerance and the reduction of atherosclerotic inflammation. The key molecules involved in glycolysis and fatty acid oxidation are illustrated in the diagram. Abbreviations: LDHA, Lactate Dehydrogenase A; PDK1, Pyruvate Dehydrogenase Kinase 1; ACC, Acetyl-CoA Carboxylase; GLUT 1/3, glucose transporter 1/3; CPT1, Carnitine Palmitoyl transferase I; PPAR-γ, peroxisome proliferator-activated receptor γ.