Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Kono, Michihito; Maeda, Kayaho; Stocton-Gavanescu, Irina; Pan, Wenliang; Umeda, Masataka; Katsuyama, Eri; Burbano, Catalina; Orite, Seo Yeon K; Vukelic, Milena; Tsokos, Maria; Yoshida, Norimitsu; Tsokos, George C.

doi:10.1172/jci.insight.127395

Cited by 87 publications

(55 citation statements)

References 39 publications

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“…Furthermore, silencing Pkm2 limited clinical score in EAE. 154 The process whereby the inhibitory receptors of an NK cell interacts with self MHC-I molecules allows for the development of fully mature NK cells, and is termed NK licensing, or classic NK cell education. Interestingly, unlicensed NK cells depend entirely on mitochondrial respiration for cytolytic function.…”

Section: Pkm2mentioning

confidence: 99%

Targeting immunometabolism as an anti-inflammatory strategy

2020

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The growing field of immunometabolism has taught us how metabolic cellular reactions and processes not only provide a means to generate ATP and biosynthetic precursors, but are also a way of controlling immunity and inflammation. Metabolic reprogramming of immune cells is essential for both inflammatory as well as anti-inflammatory responses. Four anti-inflammatory therapies, DMF, Metformin, Methotrexate and Rapamycin all work by affecting metabolism and/or regulating or mimicking endogenous metabolites with anti-inflammatory effects. Evidence is emerging for the targeting of specific metabolic events as a strategy to limit inflammation in different contexts. Here we discuss these recent developments and speculate on the prospect of targeting immunometabolism in the effort to develop novel anti-inflammatory therapeutics. As accumulating evidence for roles of an intricate and elaborate network of metabolic processes, including lipid, amino acid and nucleotide metabolism provides key focal points for developing new therapies, we here turn our attention to glycolysis and the TCA cycle to provide examples of how metabolic intermediates and enzymes can provide potential novel therapeutic targets.

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Section: Pkm2mentioning

confidence: 99%

Targeting immunometabolism as an anti-inflammatory strategy

2020

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“…NM_000576; BioLegend), 50 ng/ml IL‐23 (nos. NP_057668 and NP_002178.2; BioLegend), 10 μg/ml anti–IL‐4 antibody (MP4‐25D2; BioXCell), and 5 μg/ml anti‐IFNγ antibody (B27; BioXCell) . For pharmacologic Gls1 inhibition experiments, BPTES (10 m M , diluted in 0.5% DMSO) or 0.5% DMSO alone was administered in culture.…”

Section: Methodsmentioning

confidence: 99%

“…The following TaqMan probes (murine; all from ThermoFisher Scientific) were used to detect target genes: Gls1 Mm01257297_m1, TATA box binding protein (Tbp) Mm00446973_m1, and β‐glucuronidase (Gusb) Mm01197698_m1. Gene expression was assessed by the comparative C t method and normalized to the reference genes Tbp and Gusb .…”

Section: Methodsmentioning

confidence: 99%

Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis

Kono

Yoshida

Maeda

et al. 2019

Arthritis & Rheumatology

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Objective Glutaminase 1 (Gls1) is the first enzyme in glutaminolysis. The selective Gls1 inhibitor bis‐2‐(5‐phenylacetamido‐1,3,4‐thiadiazol‐2‐yl)ethyl sulfide (BPTES) suppresses Th17 development and ameliorates experimental autoimmune encephalomyelitis (EAE). The present study was undertaken to investigate whether inhibition of glutaminolysis is beneficial for the treatment of systemic lupus erythematosus (SLE), and the involved mechanisms. Methods MRL/lpr mice were treated with BPTES or vehicle control, and disease activity was examined. Then naive CD4+ T cells from patients with SLE were cultured under Th17‐polarizing conditions with BPTES or vehicle. Furthermore, using newly generated Gls1 conditional‐knockout mice, in vitro Th17 differentiation was examined, and EAE was induced in the mice. Glutaminolysis and glycolysis were measured with an extracellular flux analyzer. The expression of hypoxia‐inducible factor 1α (HIF‐1α) was examined by Western blotting. Results Treatment of MRL/lpr mice with BPTES improved autoimmune pathology in a Th17‐dependent manner. T cells from patients with SLE treated with BPTES displayed decreased Th17 differentiation (P < 0.05). Using the conditional‐knockout mice, we demonstrated that both in vitro Th17 differentiation (P < 0.05) and the development of EAE were dependent on Gls1. Gls1 inhibition reduced glycolysis and the expression of HIF‐1α protein, which induces glycolysis. Conclusion We demonstrated that inhibition of glutaminolysis represents a potential new treatment strategy for patients with SLE and Th17‐related autoimmune diseases. Mechanistically, we have shown that inhibition of glutaminolysis affects the glycolysis pathway by reducing HIF‐1α protein in Th17 cells.

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“…186 Perhaps more relevant to lupus, PKM2 is required for Th1 and Th17 polarization. 39 Accordingly, preventing PKM2 dimerization also reduced glycolysis in CD4 + T cells and was protective in EAE. 39 41 Dimethyl fumarate is effective in treating multiple sclerosis, 188 and discoid lupus in small open-label clinical trials, 42,43 in which the cellular and molecular targets of the drug have not been investigated.…”

Section: G Lycolys Is and Lupusmentioning

confidence: 95%

Metabolic determinants of lupus pathogenesis

Teng

Brown

Choi

et al. 2020

Immunological Reviews

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The metabolism of healthy murine and more recently human immune cells has been investigated with an increasing amount of details. These studies have revealed the challenges presented by immune cells to respond rapidly to a wide variety of triggers by adjusting the amount, type, and utilization of the nutrients they import. A concept has emerged that cellular metabolic programs regulate the size of the immune response and the plasticity of its effector functions. This has generated a lot of enthusiasm with the prediction that cellular metabolism could be manipulated to either enhance or limit an immune response. In support of this hypothesis, studies in animal models as well as human subjects have shown that the dysregulation of the immune system in autoimmune diseases is associated with a skewing of the immunometabolic programs. These studies have been mostly conducted on autoimmune CD4 + T cells, with the metabolism of other immune cells in autoimmune settings still being understudied. Here we discuss systemic metabolism as well as cellular immunometabolism as novel tools to decipher fundamental mechanisms of autoimmunity. We review the contribution of each major metabolic pathway to autoimmune diseases, with a focus on systemic lupus erythematosus (SLE), with the relevant translational opportunities, existing or predicted from results obtained with healthy immune cells. Finally, we review how targeting metabolic programs may present novel therapeutic venues. K E Y W O R D Sglucose, glutamine, lupus, metabolic inhibitors, metabolism

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Pyruvate kinase M2 is requisite for Th1 and Th17 differentiation

Cited by 87 publications

References 39 publications

Targeting immunometabolism as an anti-inflammatory strategy

Targeting immunometabolism as an anti-inflammatory strategy

Glutaminase 1 Inhibition Reduces Glycolysis and Ameliorates Lupus‐like Disease in MRL/lpr Mice and Experimental Autoimmune Encephalomyelitis

Metabolic determinants of lupus pathogenesis

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