Fine tuning of immunometabolism for the treatment of rheumatic diseases

Rhoads, Jillian P.; Major, Amy S.; Rathmell, Jeffrey C.

doi:10.1038/nrrheum.2017.54

Cited by 64 publications

(62 citation statements)

References 116 publications

(140 reference statements)

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“…To this end, we studied the impact of PDK4-deficiency on the development of EAE, an autoimmune disease induced by pathogenic Th17 cells. Consistent with previous studies that glycolysis promotes inflammation [57], [69]- [71], mice with global knockout of PDK4 developed less severe disease as determined by the clinical disease scores ( Figure 3H) with decrease in Th17 cells and increase in the infiltration of Foxp3 + Tregs in the CNS of the mice undergoing EAE (Figure 3I). We therefore conclude that PDK4-deficient Th17p cells resemble Th17n in their central carbon metabolic state, but not in other metabolic pathways.…”

Section: Pdk4-deficient Th17p Cells Adopt a Non-pathogenic-like Centrsupporting

confidence: 91%

In Silico Modeling of Metabolic State in Single Th17 Cells Reveals Novel Regulators of Inflammation and Autoimmunity

Wagner¹,

Wang

DeTomaso³

et al. 2020

Preprint

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Cellular metabolism, a key regulator of immune responses, is difficult to study with current technologies in individual cells Here, we present Compass, an algorithm to characterize the metabolic state of cells based on single-cell RNA-Seq and flux balance analysis. We applied Compass to associate metabolic states with functional variability (pathogenic potential) amongst Th17 cells and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known differences between Th17 and Treg cells, as well as novel targets in amino-acid pathways, which we tested through targeted metabolic assays. Compass further predicted a particular glycolytic reaction (phosphoglycerate mutase -PGAM) that promotes an anti-inflammatory Th17 phenotype, contrary to the common understanding of glycolysis as pro-inflammatory. We demonstrate that PGAM inhibition leads non-pathogenic Th17 cells to adopt a pro-inflammatory transcriptome and induce autoimmunity in vivo. Compass is broadly applicable for characterizing metabolic states of cells and relating metabolic heterogeneity to other cellular phenotypes. / 27 RESULTS Compass -an algorithm for comprehensive characterization of single-cell metabolismWe reasoned that even though the mRNA expression of individual enzymes does not necessarily provide an accurate proxy for their metabolic activity, a global analysis the entire metabolic network (as enabled by RNA-Seq) in the context of a large sample set (as offered by single cell genomics) coupled with strict criteria for hypotheses testing, would provide an effective framework for predicting cellular metabolic status of the cell. This led us to develop the Compass algorithm, which integrates scRNA-Seq profiles with prior knowledge of the metabolic network to infer a metabolic state of the cell (Figure 1A).The metabolic network is encoded in a Genome-Scale Metabolic Model (GSMM) that includes reaction stoichiometry, biochemical constraints such as reaction irreversibility and nutrient availability, and gene-enzyme-reaction associations. Here, we use Recon2, which comprises of 7,440 reactions and 2,626 unique metabolites [41]. To explore the metabolic capabilities of each cell, Compass solves a series of constraint-based optimization problems (formalized as linear programs) that produce a set of numeric scores, one per reaction (Methods). Intuitively, the score of each reaction in each cell reflects how well adjusted is the cell's overall transcriptome to maintaining high flux through that reaction. Henceforth, we refer to the scores as quantifying the "potential activity" of a metabolic reaction (or "activity" in short when it is clear from the context that Compass predictions are discussed).Compass belongs to the family of Flux Balance Analysis (FBA) algorithms that model metabolic fluxes, namely the rate by which chemical reactions convert substrates to products and apply constrained optimization methods to find flux distributions that satisfy desired properties (a flux distribution is an assignment of flux value to ever...

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Section: Pdk4-deficient Th17p Cells Adopt a Non-pathogenic-like Centrsupporting

confidence: 91%

In Silico Modeling of Metabolic State in Single Th17 Cells Reveals Novel Regulators of Inflammation and Autoimmunity

Wagner¹,

Wang

DeTomaso³

et al. 2020

Preprint

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“…As mentioned earlier, T cells from RA patients function in a hyper-reduced phenotype due to a hyperactive PPP, probably in response to the deficiency of necessary intermediates and the hypoxic environment [5,9,58]. As mentioned earlier, T cells from RA patients function in a hyper-reduced phenotype due to a hyperactive PPP, probably in response to the deficiency of necessary intermediates and the hypoxic environment [5,9,58].…”

Section: Oxidative Phosphorylation and Fatty Acid Oxidationmentioning

confidence: 65%

“…A number of studies have demonstrated alterations in the OXPHOS and FAO metabolic pathways in autoimmune diseases. As mentioned earlier, T cells from RA patients function in a hyper-reduced phenotype due to a hyperactive PPP, probably in response to the deficiency of necessary intermediates and the hypoxic environment [5,9,58]. This is probably a result of oxidative stress from macrophages and other reactive oxygen species (ROS) releasing cells in the symptomatic tissue [59].…”

Section: Oxidative Phosphorylation and Fatty Acid Oxidationmentioning

confidence: 94%

“…The next decade has seen an explosive growth of research in immunometabolism that has defined nutrient utilization and cellular processes to sustain the unique energy biosynthetic needs of immune cells to achieve rapid growth and to perform effector functions upon challenge with pathogens [3]. While most of the research has characterized the metabolism of healthy immune cells, it has been rapidly recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities [4,5]. Exploiting the intricately dysregulated metabolic networks in cancer is being considered to develop therapeutic approaches that would either starve tumor cells or boost the immune system [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases. mental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity. Clinical and Experimental Immunology 2019, 197: 161-169. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experi

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“…3 Initially focused on the metabolism of immune cells, studies performed in mouse models or with patients with autoimmune diseases have later associated their impaired immune system with metabolic abnormalities, which were predicted to present novel therapeutic targets. 4,5 Early on, parallels have been established between rapidly proliferating activated lymphocytes and tumor cells both relying on glycolysis in the so-called Warburg effect. 6 Cellular metabolism research in oncology is still largely leading the field, with the goal of dissecting intricately dysregulated metabolic networks in both tumors and infiltrating immune cells.…”

Section: Introductionmentioning

confidence: 99%

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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Fine tuning of immunometabolism for the treatment of rheumatic diseases

Cited by 64 publications

References 116 publications

In Silico Modeling of Metabolic State in Single Th17 Cells Reveals Novel Regulators of Inflammation and Autoimmunity

In Silico Modeling of Metabolic State in Single Th17 Cells Reveals Novel Regulators of Inflammation and Autoimmunity

Immune cell metabolism in autoimmunity

Metabolic determinants of lupus pathogenesis

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