Next Article in Journal
Clinical Outcomes and Risk Factors of Heart Transplantation Patients Experiencing Gastrointestinal Bleeding
Next Article in Special Issue
Variability of Mitochondrial DNA Heteroplasmy: Association with Asymptomatic Carotid Atherosclerosis
Previous Article in Journal
Upholding or Breaking the Law of Superposition in Pharmacokinetics
Previous Article in Special Issue
Thymus in Cardiometabolic Impairments and Atherosclerosis: Not a Silent Player?
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Biomedicines
Volume 12
Issue 8
10.3390/biomedicines12081844
biomedicines-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

T-Cell Metabolic Reprogramming in Atherosclerosis

by
Shuye Chang
†,
Zhaohui Wang
† and
Tianhui An
*
Department of Geriatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
*
Author to whom correspondence should be addressed.
†
The first two authors contributed equally to this work.
Biomedicines 2024, 12(8), 1844; https://doi.org/10.3390/biomedicines12081844
Submission received: 13 July 2024 / Revised: 5 August 2024 / Accepted: 10 August 2024 / Published: 14 August 2024
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of CVD: Focus on Atherosclerosis (Volume II))
Browse Figures
Versions Notes

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.

1. Introduction

Ischemic cardiovascular and cerebrovascular diseases, such as coronary heart disease, myocardial infarction, and stroke, are among the leading causes of death and disability in China [1]. Atherosclerosis (AS) serves as the primary pathological basis for these conditions [2]. It is well-established that AS is both a metabolic and a chronic inflammatory disease [3,4]. Helper T-cells (Th) and regulatory T-cells (Treg) play crucial roles in mediating the inflammatory response associated with AS [5]. Specifically, Th1 and Th17 cells exhibit pro-inflammatory effects, whereas Th2 and Treg cells demonstrate anti-inflammatory effects [6,7]. Research indicates that the balance between pro-inflammatory and anti-inflammatory responses, particularly between Th1/Th2 and Th17/Treg, dictates the progression or regression of AS.
In atherosclerosis (AS), T-cells demonstrate significant phenotypic plasticity. T-cell differentiation into pro-inflammatory (Th1, Th17) or anti-inflammatory (Th2, Treg) phenotypes depends on microenvironmental conditions, such as hyperlipidemia, hyperglycemia, hypoxia, oxidative stress, and the presence of apoptotic and necrotic cells [8,9]. Recent studies show [9] that hypoxia and high glucose levels activate T-cells’ glycolytic pathways, promoting differentiation into Th1 and Th17 phenotypes. Conversely, environments with ample oxygen and high lipid levels promote oxidative phosphorylation and fatty acid oxidation, leading to a preference for Th2 and Treg differentiation [10]. This change in crucial metabolic pathways, namely glycolysis, oxidative phosphorylation, and fatty acid oxidation, is known as “metabolic reprogramming” in immunometabolism [11,12]. This metabolic reprogramming alters the balance between Th1/Th2 and Th17/Treg differentiation in T-cells [13]. For example, transgenic mice overexpressing the glucose transporter 1 gene consume more glucose than their wild-type counterparts, leading to increased T-cell differentiation into Th1 and Th17 and reduced Treg differentiation [14]. Additionally, diets high in short-chain fatty acids promote more Treg differentiation and reduce inflammation [15]. Essentially, metabolic reprogramming is the key driver of the differentiation of plaque-resident T-cells (a specific subset of T-cells located within or near atherosclerotic plaques) into pro-inflammatory or anti-inflammatory phenotypes, shaping their fate and function and influencing AS progression or regression. This article discusses the roles of pro-inflammatory and anti-inflammatory T-cells in AS, emphasizing the crucial role of T-cell metabolic reprogramming in controlling AS development and its molecular mechanisms. It also reviews the burgeoning field of immunometabolism, exploring novel therapeutic advances for treating AS. We have synthesized and summarized the main findings of relevant studies in a comprehensive table (Table 1).

2. The Role of Pro-Inflammatory and Anti-Inflammatory T-Cells in Atherosclerosis

2.1. Pro-Inflammatory T-Cells Promote as Progression

Th1 cells, prevalent in the plaques, accelerate atherosclerosis progression by secreting pro-inflammatory cytokines [16], including interferon gamma (IFN-γ) and interleukin 2 (IL-2), (although IL-2 plays a role in the differentiation of Tregs, it can promote T-cell proliferation, activate NK cells, and increase their toxicity, exhibiting strong pro-inflammatory properties) [17,18,19]. Th1 cells and their pro-inflammatory secretions exacerbate plaque instability by inhibiting vascular smooth muscle cell proliferation and inducing macrophage differentiation into the pro-inflammatory M1 phenotype [20,21]. Clinical studies indicate a higher prevalence of Th1 cells in the plaques of patients post-stroke compared to those with asymptomatic atherosclerosis, implying that Th1 cells may facilitate plaque progression and potential rupture [16,22].
Th17 cells also play a pro-inflammatory and pro-AS role, mainly through the secretion of their characteristic cytokines IL-17 (interleukin-17, IL-17) and IL-6 (interleukin-6, IL-6) [5,6,8,9]. The number of Th17 cells is increased in patients with unstable angina or myocardial infarction compared to patients with stable angina and healthy subjects [19].

2.2. Anti-Inflammatory T-Cells Delay or Even Reverse Progression

Th2 cells, known for their anti-inflammatory properties, can delay or potentially reverse atherosclerosis progression, primarily via the secretion of cytokines like interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 13 (IL-13) [23]. Research suggests that a lower presence of Th2 cells in individuals correlates with an increased likelihood of developing atherosclerotic formations [24].
Regulatory T-cells (Tregs) secrete anti-inflammatory cytokines like IL-10 and transforming growth factor-beta (TGF-β) [25], providing a comprehensive protective effect against atherosclerosis. Tregs regulate the differentiation of M1 to M2 macrophages, reduce monocyte infiltration, and enhance smooth muscle and collagen fiber proliferation, thereby stabilizing plaques and decelerating atherosclerosis progression through lipid reduction [26,27]. Preliminary and collaborative research confirms that patients with acute coronary syndrome exhibit reduced Treg cell counts, which are inversely associated with AS plaque stability [5]. Additionally, a large cohort study suggests that a lower blood ratio of Treg cells indicates a higher incidence of cardiovascular events.
Although some scholars recognize that Th2 cells may exhibit pro-inflammatory effects and Th17 cells may display anti-inflammatory effects [90,91,92], the majority of the literature supports the view that Th2 cells predominantly have anti-inflammatory properties, whereas Th17 cells are primarily pro-inflammatory.
Other studies have shown that certain biomarkers related to plaque stability, such as soluble suppressor of tumorigenicity (sST)-2, interleukin 33 (IL-33), and soluble fibrinogen-like protein 2 (sFgl2), can increase the differentiation of Treg cells within plaques, promote the shift from Th1 to Th2 cells, delay the progression of atherosclerosis, and exert a protective effect [93,94,95,96].
The roles of T helper cell subpopulations, like Th9, Th22, T follicular helper (Tfh)cells, and cytotoxic T-cells in atherosclerosis, are less studied compared to Th1, Th2, and Th17 cells [6]. Given the emerging nature of T-cell metabolic reprogramming research, we focused our manuscript on the more extensively studied T-cell subtypes—Th1, Th2, Th17, and Treg cells—and their roles in atherosclerosis.
To enhance clarity, we have created a figure that provides a detailed depiction of the relationship between pro-inflammatory T-cells, anti-inflammatory T-cells, and the progression of atherosclerosis (Figure 1).

3. T-Cell Metabolic Reprogramming in Regulating Atherosclerosis Progression

3.1. Main Metabolic Pathways of Immune Cells

Like other cells, the metabolism of immune cells is essential for their survival and function. Common metabolic pathways in immune cells encompass glycolysis, oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway (PPP), fatty acid oxidation (FAO), fatty acid synthesis (FAS), and amino acid metabolism. Glycolysis and oxidative phosphorylation (OXPHOS) are the primary mechanisms through which immune cells generate ATP [97,98]. In oxygen-rich conditions, cells primarily metabolize glucose via oxidative phosphorylation (OXPHOS), while glycolysis is favored under hypoxic conditions [99]. Interestingly, activated T-cells intensify aerobic glycolysis, even in oxygen-rich environments [100]; this process, though less energy-efficient, is advantageous for synthesizing critical biochemical intermediates [101]. A key glycolytic product, glucose-6-phosphate, is converted into fructose-6-phosphate, which either contributes to glycogen synthesis or enters the pentose phosphate pathway (PPP) [102]. The pentose phosphate pathway (PPP) supplies raw materials for nucleic acid synthesis and produces nicotinamide adenine dinucleotide phosphate (NADPH), essential for driving metabolic reactions [103].

3.2. Metabolic Reprogramming of Pro-Inflammatory and Anti-Inflammatory T-Cells in Atherosclerosis Progression

We have depicted the characteristics of metabolic reprogramming in CD4 T-cells in the model diagram (Figure 2).

3.2.1. Pro-Inflammatory T-Cells

Glucose Metabolic Reprogramming

The glucose metabolic reprogramming of pro-inflammatory T-cells plays a critical role in the pathophysiology of atherosclerosis (AS), attracting significant research attention. In atherosclerosis, Th1 and Th17 cells increase glucose uptake and utilization to satisfy the elevated energy demands of their activated state [28]. Research shows that [29] inflammatory stimuli significantly boost the glycolysis rate in these cells. Lactate dehydrogenase A (LDHA), essential for aerobic glycolysis, plays a pivotal role in sustaining this metabolic pathway [30]. LDHA activity directly impacts glucose consumption and lactate production [31]. Th1 and Th17 cells deficient in LDHA show decreased glucose consumption and lactate production, alongside an increase in oxidative phosphorylation (OXPHOS) [32,33]. This shift likely results from increased pyruvate input into the mitochondrial tricarboxylic acid (TCA) cycle, shifting their metabolic focus from rapid glycolysis to sustained energy production via OXPHOS, impacting their pro-inflammatory capabilities and, thus, influencing AS progression.

Lipid Metabolic Reprogramming

In the context of atherosclerosis (AS), the reprogramming of lipid metabolism in pro-inflammatory T-cells is pivotal to both the initiation and progression of the disease. Specifically, Th1 and Th17 cell subsets augment fatty acid synthesis pathways, supplying essential lipids for cellular biosynthesis and energy metabolism, and playing a significant role in regulating cell differentiation and function [34,35].
Under hypercholesterolemic conditions, the metabolic reprogramming of immune cells can result in an enhanced differentiation of pro-inflammatory Th1 and Th17 cells, while concurrently inhibiting the differentiation of regulatory T-cells (Tregs) [36]. This shift is particularly critical in the pathogenesis of atherosclerosis, as an increase in Th1 cells intensifies inflammatory responses, whereas a reduction in Tregs weakens immunosuppressive capabilities.
Furthermore, excessive cholesterol intake has been shown to promote Th17 cell differentiation [37,38], while excessive intake of long-chain fatty acids may enhance the differentiation and proliferation of pathogenic Th1 and Th17 cells [38,39,40]. Statins, by reducing blood cholesterol levels, have demonstrated the capacity to limit Th17 cell differentiation, thus playing a crucial role in immune regulation [41].
Acetyl-CoA Carboxylase (ACC) is a critical regulatory enzyme in fatty acid synthesis, catalyzing the conversion of Acetyl-CoA to Malonyl-CoA, thereby initiating the fatty acid synthesis process [42]. During T-cell activation and proliferation, cholesterol and its derivatives serve as vital components for cell membrane construction and also participate in the regulation of intracellular signaling and gene expression through interactions with specific transcription factors [43].
Notably, the activity of ACC1 is essential for Th17 cell differentiation. T-cells deficient in ACC1 are predisposed to differentiate into regulatory T-cells (Tregs) rather than Th17 cells [44]. Moreover, studies in mice have corroborated that inhibition of ACC1 activity results in a decreased production of Th17 cells, thereby modulating the balance of immune responses [44].
These findings underscore the pivotal role of ACC1 in T-cell differentiation and elucidate the potential implications of the fatty acid synthesis pathway in immune regulation.

Amino Acid Metabolic Reprogramming

The reprogramming of amino acid metabolism plays a crucial role in the function of pro-inflammatory T-cells [45]. Subsets, such as Th1 and Th17 cells, rely on amino acid metabolism to provide essential precursors for the synthesis of cytokines and other biomolecules [46]. Under specific physiological or pathological conditions, alterations in the amino acid metabolism patterns of T-cells can significantly impact the progression of atherosclerosis (AS) [47].
In vitro studies have observed that glutamine deprivation leads to significant inhibition of activated T-cell growth, proliferation, and cytokine production [48]. Furthermore, in autoimmune mouse models, reduced expression of amino acid transporters has been associated with decreased differentiation of pro-inflammatory Th1 and Th17 cells [49]. This reduction in differentiation may lead to a diminished inflammatory response, providing strong evidence for the role of amino acid metabolism in regulating immune responses. Research indicates that insufficient leucine intake primarily restricts Th17 cell differentiation, with minimal impact on Th1 cell differentiation [50].

3.2.2. Anti-Inflammatory T-Cells

Glucose Metabolic Reprogramming

The differentiation of T-cells is highly dependent on glycolysis, with Th2 cells expressing the highest levels of glucose transporter 1 (GLUT1) and exhibiting the most robust glycolytic activity [51,52]. Although Treg cells primarily obtain energy through mitochondrial lipid oxidation, glucose metabolism is also essential for their differentiation, function, and migration [53,54]. In vitro studies have shown that during the differentiation of naive T-cells into Treg cells, the expression of glucose transporters GLUT1 and GLUT3 is upregulated, leading to increased glucose uptake and consumption [55,56].
This metabolic reprogramming enhances glycolysis and promotes an increase in Treg cell numbers. However, it has also been observed to decrease the expression of Foxp3, a key transcription factor for the immunosuppressive function of Treg cells. Therefore, increased glucose metabolism may partially inhibit the immunosuppressive function of Treg cells [55,57].
The dual-edged effect of glucose metabolic reprogramming suggests that the metabolic state of Treg cells has a complex and finely tuned impact on their function. In developing therapeutic strategies for atherosclerosis (AS), it is crucial to carefully balance Treg cell proliferation, migration, and immunosuppressive function to achieve optimal therapeutic outcomes.

Lipid Metabolic Reprogramming

Lipid metabolic reprogramming is crucial for the activation, proliferation, and growth of anti-inflammatory T-cells. The metabolic flexibility of Th2 cells and regulatory T-cells (Tregs) significantly influences their immunoregulatory functions and control of inflammatory responses. During Th2 cell differentiation, specific expression of peroxisome proliferator-activated receptor gamma (PPARγ) plays a pivotal role in regulating fatty acid metabolism [58]. Research indicates that statins [59], by reducing cholesterol levels, can enhance Th2 cell differentiation, potentially through impacts on membrane cholesterol content and signaling pathways. Additionally, administering squalene to mice increases membrane cholesterol enrichment and promotes Th2 differentiation by co-localizing signaling molecules within lipid rafts—namely interleukin-1 receptor antagonist (IL1Rα), IL2Rα, and IL4Rβ12—thereby enhancing the phosphorylation of the signal transducer and activator of transcription 4 and transcription activator 5 [43].
In Treg cells, mitochondrial fatty acid oxidation (FAO) serves as the primary energy source in their resting state, facilitated by oxidative phosphorylation (OXPHOS) [34,35,60]. This energy pathway not only sustains their regulatory functions but also enables rapid response during immune activation. Reprogramming of fatty acid synthesis and FAO during Treg cell differentiation is essential for preserving their immunosuppressive capabilities. Treg cells engage in de novo lipid synthesis via heightened expression of sterol regulatory element-binding protein (SREBP) [61] and fatty acid synthase (FASN), crucial for sustaining their immunosuppressive function.
Some research indicates that CPT1a, a key isoform of carnitine palmitoyltransferase I in lymphocytes, could influence Treg cell counts or Foxp3 expression levels, suggesting that Treg cell differentiation might rely on CPT1a-mediated fatty acid oxidation (FAO) [62]. This suggests that the metabolic flexibility of Treg cells is likely more complex than previously understood and could involve various metabolic pathways.

Amino Acid Metabolic Reprogramming

Amino acid metabolism is crucial for the differentiation and functionality of anti-inflammatory T-cells. Th2 cell differentiation and function are linked to the tryptophan metabolism pathway [63]. Tryptophan metabolites, notably kynurenine, influence Th2 cell activity and immune regulation via the aryl hydrocarbon receptor (AHR) signaling pathway [64]. Amino acid metabolic reprogramming in Th2 cells includes polyamine synthesis, particularly spermine and spermidine, which are vital for proliferation and function of the cells [104,105]. These polyamines regulate gene expression through effects on intracellular signaling and epigenetic modulation, thus influencing Th2 cell differentiation and effector functions.
Amino acid metabolism is essential for the differentiation and function of regulatory T-cells (Tregs). L-arginine and its metabolite putrescine significantly promote the differentiation of Treg cells, both in vitro and in vivo, enhancing their ability to secrete the anti-inflammatory cytokine IL-10 [106]. This process plays a pivotal role in maintaining immune homeostasis and suppressing inflammatory responses, particularly in chronic inflammatory diseases like atherosclerosis (AS).
Additionally, kynurenine, a byproduct of tryptophan catabolism, contributes to the differentiation of Treg cells. The accumulation of kynurenine promotes the differentiation of T-cells into Treg cells, which helps alleviate inflammatory responses in atherosclerosis (AS) and provides a protective effect [64]. This underscores the intricate role of amino acid metabolism in shaping the immune landscape, highlighting potential therapeutic targets to modulate immune responses in inflammatory diseases.

4. Key Molecular Mechanisms of Pro-Inflammatory and Anti-Inflammatory T-Cell Metabolic Reprogramming

The metabolic processes in cells involve various signaling pathways, with mTOR and AMPK being critical molecules in regulating the role of T-cell metabolic reprogramming in the progression of atherosclerosis (AS).

4.1. mTOR

mTOR (mammalian target of rapamycin) serves as a central regulatory factor in T-cell metabolic reprogramming, operating through two complexes, mTORC1 and mTORC2 [65]. During T-cell differentiation and maturation, mTORC1 activation enhances glycolytic metabolism, cell growth, and the cell cycle [66]. Following T-cell receptor (TCR) stimulation, mTORC1 collaborates with the transcription factor c-Myc to boost the expression of glucose transporters and CD98, thus facilitating the uptake of glucose and amino acids [67].
During the initial phases of T-cell activation, mitochondrial biogenesis is regulated by Pgc1α (peroxisome proliferator-activated receptor gamma coactivator 1-alpha). Concurrently, there is an increased cellular demand for serine, which is metabolized via the mitochondrial serine hydroxymethyl transferase pathway to support glutathione synthesis [68,69]. Glutathione is crucial in limiting the buildup of reactive oxygen species (ROS) [70,71,72], thus facilitating T-cell activation. CD4+ T-cells differentiate into subgroups with unique functions and metabolic requirements, with the mTOR signaling pathway playing a critical role in regulating their metabolic reprogramming. Specifically, pro-inflammatory T-cell subgroups such as Th1 and Th17 depend on selective regulation by mTOR complex 1 (mTORC1) [73,74], whereas the Th2 subgroup is regulated by mTOR complex 2 (mTORC2) [75]. Inhibiting mTOR can skew differentiation toward Treg cells expressing FoxP3, underscoring the critical role of mTOR in shaping the fate and function of various T-cell subtypes within the immune system [76].

4.2. AMPK

The AMP-activated protein kinase (AMPK) complex, a serine/threonine kinase, serves as an energy metabolism sensor in the body [77,78]. AMPK activation is triggered by T-cell receptor (TCR) signaling through two distinct pathways [79,80]. The first pathway depends on liver kinase B1 (LKB1) and activates AMPK when the intracellular AMP/ATP ratio increases. This activation promotes catabolic metabolism and inhibits anabolic processes, thereby replenishing ATP production [81]. The second pathway involves activation through calcium influx, which triggers calmodulin-dependent protein phosphatase and subsequent activation of calcium/calmodulin-dependent kinases [82].
AMPK activation is mediated by various upstream protein kinases. During early T-cell activation, an increase in intracellular calcium activates AMPK, which then limits mTOR signaling and curbs the early involvement of glycolytic synthetic metabolism by inhibiting downstream mediators [83]. T-cells deficient in AMPK demonstrate a reliance on glycolysis and fail to re-engage mitochondria during glucose consumption, underscoring this concept [84]. AMPK activation inhibits both glycolysis [85] and fatty acid synthesis [86]. Conversely, AMPK enhances fatty acid oxidation by upregulating the expression and phosphorylation of CPT1a [87]. During T-cell activation, various upstream regulators modulate AMPK activity, and the signals from this kinase impact numerous downstream processes, positioning AMPK at the core of T-cell metabolic reshaping [88].
Studies have shown that Treg cell differentiation and function are intricately linked to fatty acid oxidation (FAO) [76]. Consequently, it is widely accepted that AMPK promotes the differentiation of Treg cells. In T-cells lacking LKB1, diminished AMPK activity results in heightened glycolytic metabolism and reduced fatty acid oxidation. Likewise, T-cells deficient in LKB1 tend to differentiate into Th1 and Th17 cells in the absence of inflammation [89]. Overall, the influence of the internal environment on the metabolic state and function of CD4+ T-cell subgroups demands further exploration in future studies.

5. Conclusions

In summary, current research on atherosclerosis (AS) underscores the distinct biological roles of various T-cell subgroups in AS, particularly the pro-inflammatory effects of Th1/Th17 cells and the anti-inflammatory effects of Th2/Treg cells. Research in immunometabolism shows that T-cell metabolic pathways are essential for their differentiation and function, and targeting these pathways has demonstrated therapeutic potential in treating autoimmune diseases and cancer. However, the connection between T-cell metabolic reprogramming and AS still requires further exploration. Future research will concentrate on the metabolic reprogramming of T-cells in AS, investigating new preventive and therapeutic strategies through modulation of the T-cell microenvironment and metabolic processes. This approach seeks to enhance our understanding of the metabolic foundations of immune function in AS and leverage these insights for clinical advantages.

Author Contributions

T.A.: draft manuscript preparation and figure preparation; S.C.: draft manuscript preparation; Z.W.: review and proofreading manuscripts. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (82101662 to TH. A).

Institutional Review Board Statement

This paper is a review of the existing literature and involved no patient contact. Thus, this study did not require ethical approval from institutional review boards. Informed Consent Statement: Not applicable as there was no patient contact or patient enrollment.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Lu, X.; Liu, Z.; Cui, Q.; Liu, F.; Li, J.; Niu, X.; Shen, C.; Hu, D.; Huang, K.; Chen, J.; et al. A polygenic risk score improves risk stratification of coronary artery disease: A large-scale prospective Chinese cohort study. Eur. Heart J. 2022, 43, 1702–1711. [Google Scholar] [CrossRef]
  2. Stone, P.H.; Libby, P.; Boden, W.E. Fundamental Pathobiology of Coronary Atherosclerosis and Clinical Implications for Chronic Ischemic Heart Disease Management-The Plaque Hypothesis: A Narrative Review. JAMA Cardiol. 2023, 8, 192–201. [Google Scholar] [CrossRef] [PubMed]
  3. Libby, P. The changing landscape of atherosclerosis. Nature 2021, 592, 524–533. [Google Scholar] [CrossRef]
  4. Bjorkegren, J.L.M.; Lusis, A.J. Atherosclerosis: Recent developments. Cell 2022, 185, 1630–1645. [Google Scholar] [CrossRef]
  5. Wolf, D.; Gerhardt, T.; Winkels, H.; Michel, N.A.; Pramod, A.B.; Ghosheh, Y.; Brunel, S.; Buscher, K.; Miller, J.; McArdle, S.; et al. Pathogenic Autoimmunity in Atherosclerosis Evolves From Initially Protective Apolipoprotein B100–Reactive CD4+ T-Regulatory Cells. Circulation 2020, 142, 1279–1293. [Google Scholar] [CrossRef]
  6. Saigusa, R.; Winkels, H.; Ley, K. T cell subsets and functions in atherosclerosis. Nat. Rev. Cardiol. 2020, 17, 387–401. [Google Scholar] [CrossRef] [PubMed]
  7. Sharma, M.; Schlegel, M.P.; Afonso, M.S.; Brown, E.J.; Rahman, K.; Weinstock, A.; Sansbury, B.E.; Corr, E.M.; van Solingen, C.; Koelwyn, G.J.; et al. Regulatory T Cells License Macrophage Pro-Resolving Functions During Atherosclerosis Regression. Circ. Res. 2020, 127, 335–353. [Google Scholar] [CrossRef]
  8. Wik, J.A.; Skålhegg, B.S. T Cell Metabolism in Infection. Front. Immunol. 2022, 13, 840610. [Google Scholar] [CrossRef]
  9. Madden, M.Z.; Rathmell, J.C. The Complex Integration of T-cell Metabolism and Immunotherapy. Cancer Discov. 2021, 11, 1636–1643. [Google Scholar] [CrossRef] [PubMed]
  10. Dabi, Y.T.; Andualem, H.; Degechisa, S.T.; Gizaw, S.T. Targeting Metabolic Reprogramming of T-Cells for Enhanced Anti-Tumor Response. Biologics 2022, 16, 35–45. [Google Scholar] [CrossRef]
  11. Xia, L.; Oyang, L.; Lin, J.; Tan, S.; Han, Y.; Wu, N.; Yi, P.; Tang, L.; Pan, Q.; Rao, S.; et al. The cancer metabolic reprogramming and immune response. Mol. Cancer 2021, 20, 28. [Google Scholar] [CrossRef] [PubMed]
  12. Yoshida, G.J. Metabolic reprogramming: The emerging concept and associated therapeutic strategies. J. Exp. Clin. Cancer Res. 2015, 34, 111. [Google Scholar] [CrossRef] [PubMed]
  13. Patsoukis, N.; Bardhan, K.; Weaver, J.; Herbel, C.; Seth, P.; Li, L.; Boussiotis, V.A. The role of metabolic reprogramming in T cell fate and function. Curr. Trends Immunol. 2016, 17, 1. [Google Scholar] [PubMed]
  14. Macintyre, A.N.; Gerriets, V.A.; Nichols, A.G.; Michalek, R.D.; Rudolph, M.C.; Deoliveira, D.; Anderson, S.M.; Abel, E.D.; Chen, B.J.; Hale, L.P.; et al. The glucose transporter Glut1 is selectively essential for CD4 T cell activation and effector function. Cell Metab. 2014, 20, 61–72. [Google Scholar] [CrossRef] [PubMed]
  15. Du, H.X.; Yue, S.Y.; Niu, D.; Liu, C.; Zhang, L.G.; Chen, J.; Chen, Y.; Guan, Y.; Hua, X.L.; Li, C.; et al. Gut Microflora Modulates Th17/Treg Cell Differentiation in Experimental Autoimmune Prostatitis via the Short-Chain Fatty Acid Propionate. Front. Immunol. 2022, 13, 915218. [Google Scholar] [CrossRef] [PubMed]
  16. Chen, J.; Xiang, X.; Nie, L.; Guo, X.; Zhang, F.; Wen, C.; Xia, Y.; Mao, L. The emerging role of Th1 cells in atherosclerosis and its implications for therapy. Front. Immunol. 2023, 13, 1079668. [Google Scholar] [CrossRef] [PubMed]
  17. Li, Y.; Li, X.; Geng, X.; Zhao, H. The IL-2A receptor pathway and its role in lymphocyte differentiation and function. Cytokine Growth Factor Rev. 2022, 67, 66–79. [Google Scholar] [CrossRef]
  18. Lee, S.; Bartlett, B.; Dwivedi, G. Adaptive Immune Responses in Human Atherosclerosis. Int. J. Mol. Sci. 2020, 21, 9322. [Google Scholar] [CrossRef]
  19. Dong, C. Cytokine Regulation and Function in T Cells. Annu. Rev. Immunol. 2021, 39, 51–76. [Google Scholar] [CrossRef]
  20. Colin, S.; Chinetti-Gbaguidi, G.; Staels, B. Macrophage phenotypes in atherosclerosis. Immunol. Rev. 2014, 262, 153–166. [Google Scholar] [CrossRef]
  21. Jinnouchi, H.; Guo, L.; Sakamoto, A.; Torii, S.; Sato, Y.; Cornelissen, A.; Kuntz, S.; Paek, K.H.; Fernandez, R.; Fuller, D.; et al. Diversity of macrophage phenotypes and responses in atherosclerosis. Cell. Mol. Life Sci. 2020, 77, 1919–1932. [Google Scholar] [CrossRef] [PubMed]
  22. Fernandez, D.M.; Rahman, A.H.; Fernandez, N.F.; Chudnovskiy, A.; Amir, E.D.; Amadori, L.; Khan, N.S.; Wong, C.K.; Shamailova, R.; Hill, C.A.; et al. Single-cell immune landscape of human atherosclerotic plaques. Nat. Med. 2019, 25, 1576–1588. [Google Scholar] [CrossRef] [PubMed]
  23. Durham, S.R.; Shamji, M.H. Allergen immunotherapy: Past, present and future. Nat. Rev. Immunol. 2022, 23, 317–328. [Google Scholar] [CrossRef] [PubMed]
  24. Davenport, P.; Tipping, P.G. The role of interleukin-4 and interleukin-12 in the progression of atherosclerosis in apolipo protein E-deficient mice. Am. J. Pathol. 2003, 163, 1117–1125. [Google Scholar] [CrossRef] [PubMed]
  25. Dikiy, S.; Rudensky, A.Y. Principles of regulatory T cell function. Immunity 2023, 56, 240–255. [Google Scholar] [CrossRef] [PubMed]
  26. Doran, A.C. Inflammation Resolution: Implications for Atherosclerosis. Circ. Res. 2022, 130, 130–148. [Google Scholar] [CrossRef]
  27. Ait-Oufella, H.; Lavillegrand, J.R.; Tedgui, A. Regulatory T Cell-Enhancing Therapies to Treat Atherosclerosis. Cells 2021, 10, 723. [Google Scholar] [CrossRef] [PubMed]
  28. Gaddis, D.E.; Padgett, L.E.; Wu, R.; Nguyen, A.; McSkimming, C.; Dinh, H.Q.; Araujo, D.J.; Taylor, A.M.; McNamara, C.A.; Hedrick, C.C. Atherosclerosis Impairs Naive CD4 T-Cell Responses via Disruption of Glycolysis. Arterioscler. Thromb. Vasc. Biol. 2021, 41, 2387–2398. [Google Scholar] [CrossRef]
  29. Almeida, L.; Dhillon-LaBrooy, A.; Carriche, G.; Berod, L.; Sparwasser, T. CD4+ T-cell differentiation and function: Unifying glycolysis, fatty acid oxidation, polyamines NAD mitochondria. J. Allergy Clin. Immunol. 2021, 148, 16–32. [Google Scholar] [CrossRef]
  30. Peng, M.; Yin, N.; Chhangawala, S.; Xu, K.; Leslie, C.S.; Li, M.O. Aerobic glycolysis promotes T helper 1 cell differentiation through an epigenetic mechanism. Science 2016, 354, 481–484. [Google Scholar] [CrossRef]
  31. Sharma, D.; Singh, M.; Rani, R. Role of LDH in tumor glycolysis: Regulation of LDHA by small molecules for cancer therapeutics. Semin. Cancer Biol. 2022, 87, 184–195. [Google Scholar] [CrossRef] [PubMed]
  32. Xu, K.; Yin, N.; Peng, M.; Stamatiades, E.G.; Chhangawala, S.; Shyu, A.; Li, P.; Zhang, X.; Do, M.H.; Capistrano, K.J.; et al. Glycolytic ATP fuels phosphoinositide 3-kinase signaling to support effector T helper 17 cell responses. Immunity 2021, 54, 976–987.E7. [Google Scholar] [CrossRef] [PubMed]
  33. Dai, M.; Wang, L.; Yang, J.; Chen, J.; Dou, X.; Chen, R.; Ge, Y.; Lin, Y. LDHA as a regulator of T cell fate and its mechanisms in disease. Biomed. Pharmacother. 2023, 158, 114164. [Google Scholar] [CrossRef]
  34. Wallace, F.A.; Miles, E.A.; Evans, C.; Stock, T.E.; Yaqoob, P.; Calder, P.C. Dietary fatty acids influence the production of Th1-but not Th2-type cytokines. J. Leukoc. Biol. 2001, 69, 449–457. [Google Scholar] [CrossRef] [PubMed]
  35. Young, K.E.; Flaherty, S.; Woodman, K.M.; Sharma-Walia, N.; Reynolds, J.M. Fatty acid synthase regulates the pathogenicity of Th17 cells. J. Leukoc. Biol. 2017, 102, 1229–1235. [Google Scholar] [CrossRef] [PubMed]
  36. Lim, S.A.; Su, W.; Chapman, N.M.; Chi, H. Lipid metabolism in T cell signaling and function. Nat. Chem. Biol. 2022, 18, 470–481. [Google Scholar] [CrossRef] [PubMed]
  37. Petta, S.; Maggio, R.; Viscomi, C.; Andreozzi, P.; D’Ettorre, G.; Viscogliosi, G.; Barbaro, B.; Gori, M.; Vullo, V.; Balsano, C. Normocaloric Low Cholesterol Diet Modulates Th17/Treg Balance in Patients with Chronic Hepatitis C Virus Infection. PLoS ONE 2014, 9, e112346. [Google Scholar] [CrossRef]
  38. Shan, J.; Jin, H.; Xu, Y. T Cell Metabolism: A New Perspective on Th17/Treg Cell Imbalance in Systemic Lupus Erythematosus. Front. Immunol. 2020, 11, 1027. [Google Scholar] [CrossRef] [PubMed]
  39. Wagner, A.; Wang, C.; Fessler, J.; DeTomaso, D.; Avila-Pacheco, J.; Kaminski, J.; Zaghouani, S.; Christian, E.; Thakore, P.; Schellhaass, B.; et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell 2021, 184, 4168–4185.E21. [Google Scholar] [CrossRef]
  40. Haghikia, A.; Jörg, S.; Duscha, A.; Berg, J.; Manzel, A.; Waschbisch, A.; Hammer, A.; Lee, D.-H.; May, C.; Wilck, N.; et al. Dietary Fatty Acids Directly Impact Central Nervous System Autoimmunity via the Small Intestine. Immunity 2015, 43, 817–829. [Google Scholar] [CrossRef]
  41. Prado, D.S.; Damasceno, L.E.A.; Sonego, A.B.; Rosa, M.H.; Martins, T.V.; Fonseca, M.D.M.; Cunha, T.M.; Cunha, F.Q.; Alves-Filho, J.C. Pitavastatin ameliorates autoimmune neuroinflammation by regulating the Treg/Th17 cell balance through inhibition of mevalonate metabolism. Int. Immunopharmacol. 2021, 91, 107278. [Google Scholar] [CrossRef]
  42. Hunt, E.G.; Hurst, K.E.; Riesenberg, B.P.; Kennedy, A.S.; Gandy, E.J.; Andrews, A.M.; Del Mar Alicea Pauneto, C.; Ball, L.E.; Wallace, E.D.; Gao, P.; et al. Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment. Cell Metab. 2024, 36, 969–983.E10. [Google Scholar] [CrossRef] [PubMed]
  43. Aguilar-Ballester, M.; Herrero-Cervera, A.; Vinue, A.; Martinez-Hervas, S.; Gonzalez-Navarro, H. Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis. Nutrients 2020, 12, 2021. [Google Scholar] [CrossRef] [PubMed]
  44. Han, A.; Peng, T.; Xie, Y.; Zhang, W.; Sun, W.; Xie, Y.; Ma, Y.; Wang, C.; Xie, N. Mitochondrial-regulated Tregs: Potential therapeutic targets for autoimmune diseases of the central nervous system. Front. Immunol. 2023, 14, 1301074. [Google Scholar] [CrossRef] [PubMed]
  45. Anand, S.K.; Governale, T.A.; Zhang, X.; Razani, B.; Yurdagul, A., Jr.; Pattillo, C.B.; Rom, O. Amino Acid Metabolism and Atherosclerotic Cardiovascular Disease. Am. J. Pathol. 2024, 194, 510–524. [Google Scholar] [CrossRef] [PubMed]
  46. Fu, J.Y.; Huang, S.J.; Wang, B.L.; Yin, J.H.; Chen, C.Y.; Xu, J.B.; Chen, Y.L.; Xu, S.; Dong, T.; Zhou, H.N.; et al. Lysine acetyltransferase 6A maintains CD4+ T cell response via epigenetic reprogramming of glucose metabolism in autoimmunity. Cell Metab. 2024, 36, 557–574.E10. [Google Scholar] [CrossRef] [PubMed]
  47. Nitz, K.; Lacy, M.; Bianchini, M.; Wichapong, K.; Kucukgoze, I.A.; Bonfiglio, C.A.; Migheli, R.; Wu, Y.; Burger, C.; Li, Y.; et al. The Amino Acid Homoarginine Inhibits Atherogenesis by Modulating T-Cell Function. Circ. Res. 2022, 131, 701–712. [Google Scholar] [CrossRef] [PubMed]
  48. Wang, R.; Dillon, C.P.; Shi, L.Z.; Milasta, S.; Carter, R.; Finkelstein, D.; McCormick, L.L.; Fitzgerald, P.; Chi, H.; Munger, J.; et al. The Transcription Factor Myc Controls Metabolic Reprogramming upon T Lymphocyte Activation. Immunity 2011, 35, 871–882. [Google Scholar] [CrossRef] [PubMed]
  49. Nakaya, M.; Xiao, Y.; Zhou, X.; Chang, J.-H.; Chang, M.; Cheng, X.; Blonska, M.; Lin, X.; Sun, S.-C. Inflammatory T Cell Responses Rely on Amino Acid Transporter ASCT2 Facilitation of Glutamine Uptake and mTORC1 Kinase Activation. Immunity 2014, 40, 692–705. [Google Scholar] [CrossRef]
  50. Sundrud, M.S.; Koralov, S.B.; Feuerer, M.; Calado, D.P.; Kozhaya, A.E.; Rhule-Smith, A.; Lefebvre, R.E.; Unutmaz, D.; Mazitschek, R.; Waldner, H.; et al. Halofuginone Inhibits TH17 Cell Differentiation by Activating the Amino Acid Starvation Response. Science 2009, 324, 1334–1338. [Google Scholar] [CrossRef]
  51. Stark, J.M.; Tibbitt, C.A.; Coquet, J.M. The Metabolic Requirements of Th2 Cell Differentiation. Front. Immunol. 2019, 10, 2318. [Google Scholar] [CrossRef] [PubMed]
  52. Healey, D.C.C.; Cephus, J.Y.; Barone, S.M.; Chowdhury, N.U.; Dahunsi, D.O.; Madden, M.Z.; Ye, X.; Yu, X.; Olszewski, K.; Young, K.; et al. Targeting In Vivo Metabolic Vulnerabilities of Th2 and Th17 Cells Reduces Airway Inflammation. J. Immunol. 2021, 206, 1127–1139. [Google Scholar] [CrossRef] [PubMed]
  53. Aso, K.; Kono, M.; Kanda, M.; Kudo, Y.; Sakiyama, K.; Hisada, R.; Karino, K.; Ueda, Y.; Nakazawa, D.; Fujieda, Y.; et al. Itaconate ameliorates autoimmunity by modulating T cell imbalance via metabolic and epigenetic reprogramming. Nat. Commun. 2023, 14, 984. [Google Scholar] [CrossRef] [PubMed]
  54. Angelin, A.; Gil-de-Gomez, L.; Dahiya, S.; Jiao, J.; Guo, L.; Levine, M.H.; Wang, Z.; Quinn, W.J., 3rd; Kopinski, P.K.; Wang, L.; et al. Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments. Cell Metab. 2017, 25, 1282–1293.e1287. [Google Scholar] [CrossRef] [PubMed]
  55. Yang, J.; Chen, Y.; Li, X.; Qin, H.; Bao, J.; Wang, C.; Dong, X.; Xu, D. Complex Interplay Between Metabolism and CD4+ T-Cell Activation, Differentiation, and Function: A Novel Perspective for Atherosclerosis Immunotherapy. Cardiovasc. Drugs Ther. 2023, 1–14, Published Online. [Google Scholar] [CrossRef]
  56. Li, W.; Qu, G.; Choi, S.C.; Cornaby, C.; Titov, A.; Kanda, N.; Teng, X.; Wang, H.; Morel, L. Targeting T Cell Activation and Lupus Autoimmune Phenotypes by Inhibiting Glucose Transporters. Front. Immunol. 2019, 10, 833. [Google Scholar] [CrossRef] [PubMed]
  57. Miska, J.; Lee-Chang, C.; Rashidi, A.; Muroski, M.E.; Chang, A.L.; Lopez-Rosas, A.; Zhang, P.; Panek, W.K.; Cordero, A.; Han, Y.; et al. HIF-1α Is a Metabolic Switch Between Glycolytic-Driven Migration and Oxidative Phosphorylation-Driven Immunosuppression of Tregs in Glioblastoma. Cell Rep. 2022, 39, 110934. [Google Scholar] [CrossRef] [PubMed]
  58. Kabat, A.M.; Hackl, A.; Sanin, D.E.; Zeis, P.; Grzes, K.M.; Baixauli, F.; Kyle, R.; Caputa, G.; Edwards-Hicks, J.; Villa, M.; et al. Resident TH2 cells orchestrate adipose tissue remodeling at a site adjacent to infection. Sci. Immunol. 2022, 7, eadd3263. [Google Scholar] [CrossRef] [PubMed]
  59. Zeiser, R. Immune modulatory effects of statins. Immunology 2018, 154, 69–75. [Google Scholar] [CrossRef]
  60. Pacella, I.; Piconese, S. Immunometabolic Checkpoints of Treg Dynamics: Adaptation to Microenvironmental Opportunities and Challenges. Front. Immunol. 2019, 10, 1889. [Google Scholar] [CrossRef]
  61. Zhou, J.; Lu, N.; Lv, X.; Wang, X.; Li, J.; Ke, L. Role of Huangqin Decoction in Intestinal Homeostasis and Colon Carcinogenesis Based on “SREBP1 Cholesterol Metabolism Treg Cell Differentiation”. Evid.-Based Complement. Altern. Med. 2023, 2023, 6715978. [Google Scholar] [CrossRef] [PubMed]
  62. Raud, B.; Roy, D.G.; Divakaruni, A.S.; Tarasenko, T.N.; Franke, R.; Ma, E.H.; Samborska, B.; Hsieh, W.Y.; Wong, A.H.; Stüve, P.; et al. Etomoxir Actions on Regulatory and Memory T Cells Are Independent of Cpt1a-Mediated Fatty Acid Oxidation. Cell Metab. 2018, 28, 504–515.E7. [Google Scholar] [CrossRef]
  63. Gostner, J.M.; Becker, K.; Kofler, H.; Strasser, B.; Fuchs, D. Tryptophan Metabolism in Allergic Disorders. Int. Arch. Allergy Immunol. 2016, 169, 203–215. [Google Scholar] [CrossRef] [PubMed]
  64. Mezrich, J.D.; Fechner, J.H.; Zhang, X.; Johnson, B.P.; Burlingham, W.J.; Bradfield, C.A. An Interaction between Kynurenine and the Aryl Hydrocarbon Receptor Can Generate Regulatory T Cells. J. Immunol. 2010, 185, 3190–3198. [Google Scholar] [CrossRef] [PubMed]
  65. Liu, G.Y.; Sabatini, D.M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 2020, 21, 183–203. [Google Scholar] [CrossRef]
  66. Battaglioni, S.; Benjamin, D.; Wälchli, M.; Maier, T.; Hall, M.N. mTOR substrate phosphorylation in growth control. Cell 2022, 185, 1814–1836. [Google Scholar] [CrossRef]
  67. Szwed, A.; Kim, E.; Jacinto, E. Regulation and metabolic functions of mTORC1 and mTORC2. Physiol. Rev. 2021, 101, 1371–1426. [Google Scholar] [CrossRef]
  68. Ma, E.H.; Bantug, G.; Griss, T.; Condotta, S.; Johnson, R.M.; Samborska, B.; Mainolfi, N.; Suri, V.; Guak, H.; Balmer, M.L.; et al. Serine Is an Essential Metabolite for Effector T Cell Expansion. Cell Metab. 2017, 25, 345–357. [Google Scholar] [CrossRef]
  69. Ma, S.; Sandhoff, R.; Luo, X.; Shang, F.; Shi, Q.; Li, Z.; Wu, J.; Ming, Y.; Schwarz, F.; Madi, A.; et al. Serine enrichment in tumors promotes regulatory T cell accumulation through sphinganine-mediated regulation of c-Fos. Sci. Immunol. 2024, 9, eadg8817. [Google Scholar] [CrossRef]
  70. Kurniawan, H.; Franchina, D.G.; Guerra, L.; Bonetti, L.; Baguet, L.S.; Grusdat, M.; Schlicker, L.; Hunewald, O.; Dostert, C.; Merz, M.P.; et al. Glutathione Restricts Serine Metabolism to Preserve Regulatory T Cell Function. Cell Metab. 2020, 31, 920–936.e927. [Google Scholar] [CrossRef]
  71. Mak, T.W.; Grusdat, M.; Duncan, G.S.; Dostert, C.; Nonnenmacher, Y.; Cox, M.; Binsfeld, C.; Hao, Z.; Brustle, A.; Itsumi, M.; et al. Glutathione Primes T Cell Metabolism for Inflammation. Immunity 2017, 46, 675–689. [Google Scholar] [CrossRef]
  72. Lian, G.; Gnanaprakasam, J.R.; Wang, T.; Wu, R.; Chen, X.; Liu, L.; Shen, Y.; Yang, M.; Yang, J.; Chen, Y.; et al. Glutathione de novo synthesis but not recycling process coordinates with glutamine catabolism to control redox homeostasis and directs murine T cell differentiation. eLife 2018, 7, e36158. [Google Scholar] [CrossRef] [PubMed]
  73. Maciejewski-Duval, A.; Comarmond, C.; Leroyer, A.; Zaidan, M.; Le Joncour, A.; Desbois, A.C.; Fouret, J.P.; Koskas, F.; Cluzel, P.; Garrido, M.; et al. mTOR pathway activation in large vessel vasculitis. J. Autoimmun. 2018, 94, 99–109. [Google Scholar] [CrossRef] [PubMed]
  74. Saravia, J.; Raynor, J.L.; Chapman, N.M.; Lim, S.A.; Chi, H. Signaling networks in immunometabolism. Cell Res. 2020, 30, 328–342. [Google Scholar] [CrossRef]
  75. Pollizzi, K.N.; Powell, J.D. Regulation of T cells by mTOR: The known knowns and the known unknowns. Trends Immunol. 2015, 36, 13–20. [Google Scholar] [CrossRef]
  76. Luo, Y.; Guo, J.; Zhang, P.; Cheuk, Y.C.; Jiang, Y.; Wang, J.; Xu, S.; Rong, R. Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis. Front. Immunol. 2021, 12, 684197. [Google Scholar] [CrossRef] [PubMed]
  77. Herzig, S.; Shaw, R.J. AMPK: Guardian of metabolism and mitochondrial homeostasis. Nat. Rev. Mol. Cell Biol. 2018, 19, 121–135. [Google Scholar] [CrossRef]
  78. Carling, D. AMPK signalling in health and disease. Curr. Opin. Cell Biol. 2017, 45, 31–37. [Google Scholar] [CrossRef]
  79. Harly, C.; Joyce, S.P.; Domblides, C.; Bachelet, T.; Pitard, V.; Mannat, C.; Pappalardo, A.; Couzi, L.; Netzer, S.; Massara, L.; et al. Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2. Sci. Immunol. 2021, 6, eaba9010. [Google Scholar] [CrossRef]
  80. Lepez, A.; Pirnay, T.; Denanglaire, S.; Perez-Morga, D.; Vermeersch, M.; Leo, O.; Andris, F. Long-term T cell fitness and proliferation is driven by AMPK-dependent regulation of reactive oxygen species. Sci. Rep. 2020, 10, 21673. [Google Scholar] [CrossRef]
  81. Steinberg, G.R.; Hardie, D.G. New insights into activation and function of the AMPK. Nat. Rev. Mol. Cell Biol. 2022, 24, 255–272. [Google Scholar] [CrossRef] [PubMed]
  82. Jaroonwitchawan, T.; Visitchanakun, P.; Dang, P.C.; Ritprajak, P.; Palaga, T.; Leelahavanichkul, A. Dysregulation of lipid metabolism in macrophages is responsible for severe endotoxin tolerance in FcgRIIB-deficient lupus mice. Front. Immunol. 2020, 11, 959. [Google Scholar] [CrossRef] [PubMed]
  83. Chen, Z.; Zhuo, R.; Zhao, Y.; Yang, L.; Zhou, Y.; Cheng, X.; Peng, L.; Jin, X.; Wang, Y. Oleoylethanolamide stabilizes atherosclerotic plaque through regulating macrophage polarization via AMPK-PPARα pathway. Biochem. Biophys. Res. Commun. 2020, 524, 308–316. [Google Scholar] [CrossRef] [PubMed]
  84. Mayer, K.A.; Smole, U.; Zhu, C.; Derdak, S.; Minervina, A.A.; Salnikova, M.; Witzeneder, N.; Christamentl, A.; Boucheron, N.; Waidhofer-Söllner, P.; et al. The energy sensor AMPK orchestrates metabolic and translational adaptation in expanding T helper cells. FASEB J. 2021, 35, e21217. [Google Scholar] [CrossRef]
  85. Tan, C.; Gu, J.; Li, T.; Chen, H.; Liu, K.; Liu, M.; Zhang, H.; Xiao, X. Inhibition of aerobic glycolysis alleviates sepsis-induced acute kidney injury by promoting lactate/Sirtuin 3/AMPK-regulated autophagy. Int. J. Mol. Med. 2021, 47, 19. [Google Scholar] [CrossRef] [PubMed]
  86. Li, Y.; Xu, S.; Mihaylova, M.M.; Zheng, B.; Hou, X.; Jiang, B.; Park, O.; Luo, Z.; Lefai, E.; Shyy, J.Y.; et al. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet-induced insulin-resistant mice. Cell Metab. 2011, 13, 376–388. [Google Scholar] [CrossRef] [PubMed]
  87. Liu, Z.; Liu, W.; Wang, W.; Ma, Y.; Wang, Y.; Drum, D.L.; Cai, J.; Blevins, H.; Lee, E.; Shah, S.; et al. CPT1A-mediated fatty acid oxidation confers cancer cell resistance to immune-mediated cytolytic killing. Proc. Natl. Acad. Sci. USA 2023, 120, e2302878120. [Google Scholar] [CrossRef] [PubMed]
  88. Ma, E.H.; Poffenberger, M.C.; Wong, A.H.; Jones, R.G. The role of AMPK in T cell metabolism and function. Curr. Opin. Immunol. 2017, 46, 45–52. [Google Scholar] [CrossRef]
  89. Baixauli, F.; Piletic, K.; Puleston, D.J.; Villa, M.; Field, C.S.; Flachsmann, L.J.; Quintana, A.; Rana, N.; Edwards-Hicks, J.; Matsushita, M.; et al. An LKB1–mitochondria axis controls TH17 effector function. Nature 2022, 610, 555–561. [Google Scholar] [CrossRef]
  90. Kokubo, K.; Onodera, A.; Kiuchi, M.; Tsuji, K.; Hirahara, K.; Nakayama, T. Conventional and pathogenic Th2 cells in inflammation, tissue repair, and fibrosis. Front. Immunol. 2022, 13, 945063. [Google Scholar] [CrossRef]
  91. Xu, H.; Agalioti, T.; Zhao, J.; Steglich, B.; Wahib, R.; Vesely, M.C.A.; Bielecki, P.; Bailis, W.; Jackson, R.; Perez, D. The induction and function of the anti-inflammatory fate of TH17 cells. Nature communications 2020, 11, 3334. [Google Scholar] [CrossRef]
  92. Gong, F.; Liu, Z.; Liu, J.; Zhou, P.; Liu, Y.; Lu, X. The paradoxical role of IL-17 in atherosclerosis. Cell. Immunol. 2015, 297, 33–39. [Google Scholar] [CrossRef] [PubMed]
  93. Scicchitano, P.; Marzullo, A.; Santoro, A.; Zito, A.; Cortese, F.; Galeandro, C.; Ciccone, A.S.; Angiletta, D.; Manca, F.; Pulli, R. The prognostic role of ST2L and sST2 in patients who underwent carotid plaque endarterectomy: A five-year follow-up study. J. Clin. Med. 2022, 11, 3142. [Google Scholar] [CrossRef] [PubMed]
  94. Miller, A.M.; Xu, D.; Asquith, D.L.; Denby, L.; Li, Y.; Sattar, N.; Baker, A.H.; McInnes, I.B.; Liew, F.Y. IL-33 reduces the development of atherosclerosis. J. Exp. Med. 2008, 205, 339–346. [Google Scholar] [CrossRef] [PubMed]
  95. Wasserman, A.; Ben-Shoshan, J.; Entin-Meer, M.; Maysel-Auslender, S.; Guzner-Gur, H.; Keren, G. Interleukin-33 augments Treg cell levels: A flaw mechanism in atherosclerosis. Sat 2012, 7, 23. [Google Scholar]
  96. An, T.; Guo, M.; Fan, C.; Huang, S.; Liu, H.; Liu, K.; Wang, Z. sFgl2-Treg positive feedback pathway protectsagainst atherosclerosis. Int. J. Mol. Sci. 2023, 24, 2338. [Google Scholar] [CrossRef] [PubMed]
  97. Li, T.; Han, J.; Jia, L.; Hu, X.; Chen, L.; Wang, Y. PKM2 coordinates glycolysis with mitochondrial fusion and oxidative phosphorylation. Protein Cell 2019, 10, 583–594. [Google Scholar] [CrossRef] [PubMed]
  98. Cai, X.; Ng, C.P.; Jones, O.; Fung, T.S.; Ryu, K.W.; Li, D.; Thompson, C.B. Lactate activates the mitochondrial electron transport chain independently of its metabolism. Mol. Cell 2023, 83, 3904–3920.E7. [Google Scholar] [CrossRef] [PubMed]
  99. Zhong, X.; He, X.; Wang, Y.; Hu, Z.; Huang, H.; Zhao, S.; Wei, P.; Li, D. Warburg effect in colorectal cancer: The emerging roles in tumor microenvironment and therapeutic implications. J. Hematol. Oncol. 2022, 15, 160. [Google Scholar] [CrossRef] [PubMed]
  100. Chang, C.H.; Curtis, J.D.; Maggi, L.B., Jr.; Faubert, B.; Villarino, A.V.; O’Sullivan, D.; Huang, S.C.; van der Windt, G.J.; Blagih, J.; Qiu, J.; et al. Posttranscriptional control of T cell effector function by aerobic glycolysis. Cell 2013, 153, 1239–1251. [Google Scholar] [CrossRef]
  101. Bian, X.; Jiang, H.; Meng, Y.; Li, Y.-p.; Fang, J.; Lu, Z. Regulation of gene expression by glycolytic and gluconeogenic enzymes. Trends Cell Biol. 2022, 32, 786–799. [Google Scholar] [CrossRef]
  102. Patra, K.C.; Hay, N. The pentose phosphate pathway and cancer. Trends Biochem. Sci. 2014, 39, 347–354. [Google Scholar] [CrossRef]
  103. Hayes, J.D.; Dinkova-Kostova, A.T.; Tew, K.D. Oxidative Stress in Cancer. Cancer Cell 2020, 38, 167–197. [Google Scholar] [CrossRef]
  104. Fischer, M.; Ruhnau, J.; Schulze, J.; Obst, D.; Floel, A.; Vogelgesang, A. Spermine and spermidine modulate T-cell function in older adults with and without cognitive decline ex vivo. Aging 2020, 12, 13716–13739. [Google Scholar] [CrossRef]
  105. Nakamura, A.; Takahashi, D.; Nakamura, Y.; Yamada, T.; Matsumoto, M.; Hase, K. Polyamines polarized Th2/Th9 cell-fate decision by regulating GATA3 expression. Arch. Biochem. Biophys. 2020, 693, 108587. [Google Scholar] [CrossRef] [PubMed]
  106. Carriche, G.M.; Almeida, L.; Stüve, P.; Velasquez, L.; Dhillon-LaBrooy, A.; Roy, U.; Lindenberg, M.; Strowig, T.; Plaza-Sirvent, C.; Schmitz, I.; et al. Regulating T-cell differentiation through the polyamine spermidine. J. Allergy Clin. Immunol. 2021, 147, 335–348.E11. [Google Scholar] [CrossRef] [PubMed]
Biomedicines 12 01844 g001
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 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.
Biomedicines 12 01844 g001
Biomedicines 12 01844 g002
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.
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.
Biomedicines 12 01844 g002
Table 1. Key findings in the references.
Table 1. Key findings in the references.
Key FindingsReferences
1. The Role of Pro-inflammatory and Anti-inflammatory T-Cells in Atherosclerosis (AS) Progression
   ① Pro-inflammatory Th1 and Th17 cells drive the progression of AS.[16,17,18,19,20,21,22]
   ② Anti-inflammatory Th2 and Treg cells can slow down or even reverse AS progression.[23,24,25,26,27]
2. Metabolic Reprogramming in Pro-inflammatory and Anti-inflammatory T-Cell Differentiation
   Pro-inflammatory T-Cell
   ① LDHA and PDK1 are crucial for glucose metabolic reprogramming.[28,29,30,31,32,33]
   ② ACC is essential for fatty acid metabolic reprogramming.[34,35,36,37,38,39,40,41,42,43,44]
   ③ Amino acid transporters are key in amino acid metabolic reprogramming.[45,46,47,48,49,50]
   Anti-inflammatory T-Cell
   ① GLUT 1/3 are critical for glucose metabolic reprogramming.[51,52,53,54,55,56,57]
   ② PPAR-γ, FASN, and CPT1 are essential for fatty acid metabolic reprogramming.[58,59,60,61,62]
   ③ Arginine and kynurenine are significant in fatty acid metabolic reprogramming.[63,64]
3. Key Molecular Mechanisms in T-Cell Metabolic Reprogramming
   ① mTOR[65,66,67,68,69,70,71,72,73,74,75,76]
   ② AMPK[77,78,79,80,81,82,83,84,85,86,87,88,89]
Abbreviations: LDHA, Lactate Dehydrogenase A; PDK1, Pyruvate Dehydrogenase Kinase 1; ACC, Acetyl-CoA Carboxylase; GLUT 1/3, glucose transporter 1/3; PPAR-γ, peroxisome proliferator-activated receptor γ; FASN, fatty acid synthase; CPT1, Carnitine Palmitoyl transferase I. mTOR, mammalian target of rapamycin; AMPK, AMP-activated protein kinase.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Chang, S.; Wang, Z.; An, T. T-Cell Metabolic Reprogramming in Atherosclerosis. Biomedicines 2024, 12, 1844. https://doi.org/10.3390/biomedicines12081844

AMA Style

Chang S, Wang Z, An T. T-Cell Metabolic Reprogramming in Atherosclerosis. Biomedicines. 2024; 12(8):1844. https://doi.org/10.3390/biomedicines12081844

Chicago/Turabian Style

Chang, Shuye, Zhaohui Wang, and Tianhui An. 2024. "T-Cell Metabolic Reprogramming in Atherosclerosis" Biomedicines 12, no. 8: 1844. https://doi.org/10.3390/biomedicines12081844

APA Style

Chang, S., Wang, Z., & An, T. (2024). T-Cell Metabolic Reprogramming in Atherosclerosis. Biomedicines, 12(8), 1844. https://doi.org/10.3390/biomedicines12081844

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop