Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells

Iwata, S.; Zhang, Mingzeng; He, Hao; Trimova, Gulzhan; Hajime, Maiko; Miyazaki, Yusuke; Ohkubo, Naoaki; Kanda, Yurie Satoh; Todoroki, Yasuyuki; Miyata, Hiroko; Ueno, Makoto; Nagayasu, Atsushi; Nakayamada, Shingo; Sakata, Kimio

doi:10.3389/fimmu.2020.593103

Cited by 15 publications

(10 citation statements)

References 54 publications

(59 reference statements)

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“…IFN-ɣ might also be implicated in central nervous system alterations observed in SLE [ 49 ]. Recently, it has been demonstrated that IFN-ɣ production by T-bet + CD4 + cells is regulated by metabolic regulators, such as fatty acid synthesis inhibitors [ 50 ]. In keeping with our data, Kaplan and colleagues showed that, in splenocytes derived from CB 1 −/− /CB 2 −/− mice, treated in vitro with 2-AG, the IFN-ɣ secretion was reduced [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol Reduces the Production of Interferon-Gamma in T Lymphocytes from Patients with Systemic Lupus Erythematosus

et al. 2022

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Background: the endocannabinoid 2-arachidonoylglycerol (2-AG) plays a pivotal role in immune cells regulation. The plasma levels of 2-AG are increased in patients with systemic lupus erythematosus (SLE) and correlate with disease activity. Moreover, in plasmacytoid dendritic cells from SLE patients, 2-AG is able to control the production of type 1 interferon (IFN) through CB2 activation. The aim of this study was to evaluate the potential role of 2-AG on T lymphocytes from SLE patients. Methods: peripheral blood mononuclear cells (PBMCs) from SLE participants and age- and sex-matched healthy donors (HD) were isolated by Ficoll–Hypaque density-gradient centrifugation. The PBMCs were treated with increasing concentrations of 2-AG, and AM251 and AM630 were used to antagonize CB1 and CB2, respectively. Flow cytometry was used to assess the expression of CD3, CD4, CD8, CD25, IFN-ɣ, IL-4, and IL-17A. Results: 2-AG (1 μM) decreased IFN-ɣ expression (p = 0.0005) in the Th1 lymphocytes of SLE patients. 2-AG did not modulate the cytokine expression of any other T lymphocyte population from either SLE or HD. Treatment with both 2-AG and AM630 increased the IFN-ɣ expression in Th1 lymphocytes of SLE patients (p = 0.03). Discussion: 2-AG is able to modulate type 2 IFN production from CD4+ T lymphocytes from SLE patients through CB2 activation.

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Section: Discussionmentioning

confidence: 99%

2-Arachidonoylglycerol Reduces the Production of Interferon-Gamma in T Lymphocytes from Patients with Systemic Lupus Erythematosus

et al. 2022

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“…Paradoxically, mitochondria in SLE produce less ATP compared to healthy controls (HC) even though they are hyperpolarized ( 26 ). Additionally, evidence suggests that there are significant differences in glutamine ( 27 ) and lipid metabolism ( 28 ) in SLE T cells. A subset of CD4 + T cells producing IL-17 (Th17 cells) is expanded in SLE patients.…”

Section: Pathogenic Rewiring Of T Cells In Slementioning

confidence: 99%

A global view of T cell metabolism in systemic lupus erythematosus

Goetz,

Cagmat,

Brusko

et al. 2024

Front. Immunol.

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Impaired metabolism is recognized as an important contributor to pathogenicity of T cells in Systemic Lupus Erythematosus (SLE). Over the last two decades, we have acquired significant knowledge about the signaling and transcriptomic programs related to metabolic rewiring in healthy and SLE T cells. However, our understanding of metabolic network activity derives largely from studying metabolic pathways in isolation. Here, we argue that enzymatic activities are necessarily coupled through mass and energy balance constraints with in-built network-wide dependencies and compensation mechanisms. Therefore, metabolic rewiring of T cells in SLE must be understood in the context of the entire network, including changes in metabolic demands such as shifts in biomass composition and cytokine secretion rates as well as changes in uptake/excretion rates of multiple nutrients and waste products. As a way forward, we suggest cell physiology experiments and integration of orthogonal metabolic measurements through computational modeling towards a comprehensive understanding of T cell metabolism in lupus.

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“…Through cytokine and regulatory T cell (T-reg) mediated pathways, 2-DG exhibits anti-inflammatory properties. By increasing the production of cytokine production (IL-2) and preventing CTLA-4, a T-reg suppressor, 2DG therapy enhanced T-reg function [ 124 , 125 ]. According to a study, 2-DG inhibited the PI3K/Akt pathway to reduce TNF production during the early stages of inflammation [ 126 ].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections

et al. 2023

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Metabolic and inflammatory pathways are highly interdependent, and both systems are dysregulated in Type 2 diabetes (T2D). T2D is associated with pre-activated inflammatory signaling networks, aberrant cytokine production and increased acute phase reactants which leads to a pro-inflammatory ‘feed forward loop’. Nutrient ‘excess’ conditions in T2D with hyperglycemia, elevated lipids and branched-chain amino acids significantly alter the functions of immune cells including neutrophils. Neutrophils are metabolically active cells and utilizes energy from glycolysis, stored glycogen and β-oxidation while depending on the pentose phosphate pathway for NADPH for performing effector functions such as chemotaxis, phagocytosis and forming extracellular traps. Metabolic changes in T2D result in constitutive activation and impeded acquisition of effector or regulatory activities of neutrophils and render T2D subjects for recurrent infections. Increased flux through the polyol and hexosamine pathways, elevated production of advanced glycation end products (AGEs), and activation of protein kinase C isoforms lead to (a) an enhancement in superoxide generation; (b) the stimulation of inflammatory pathways and subsequently to (c) abnormal host responses. Neutrophil dysfunction diminishes the effectiveness of wound healing, successful tissue regeneration and immune surveillance against offending pathogens. Hence, Metabolic reprogramming in neutrophils determines frequency, severity and duration of infections in T2D. The present review discusses the influence of the altered immuno-metabolic axis on neutrophil dysfunction along with challenges and therapeutic opportunities for clinical management of T2D-associated infections.

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Enhanced Fatty Acid Synthesis Leads to Subset Imbalance and IFN-γ Overproduction in T Helper 1 Cells

Cited by 15 publications

References 54 publications

2-Arachidonoylglycerol Reduces the Production of Interferon-Gamma in T Lymphocytes from Patients with Systemic Lupus Erythematosus

2-Arachidonoylglycerol Reduces the Production of Interferon-Gamma in T Lymphocytes from Patients with Systemic Lupus Erythematosus

A global view of T cell metabolism in systemic lupus erythematosus

Neutrophil (dys)function due to altered immuno-metabolic axis in type 2 diabetes: implications in combating infections

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