Model‐driven multi‐omic data analysis elucidates metabolic immunomodulators of macrophage activation

Bordbar, Aarash; Mo, Monica L.; Nakayasu, Ernesto; Schrimpe‐Rutledge, Alexandra C.; Kim, Young Mo; Metz, Thomas O.; Jones, Marcus B.; Frank, Bryan; Smith, Richard D.; Peterson, Scott N.; Hyduke, Daniel R.; Adkins, Joshua N.; Palsson, Bernhard Ø.

doi:10.1038/msb.2012.21

Cited by 144 publications

(153 citation statements)

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“…Metabolism associated genes of pathogens have been consistently linked with virulence of major pathogens, [1][2][3][4][5][6][7][8][9] such as, role of carbon metabolism related pathways like glycolysis 10 and TCA cycle 11 in virulence of Salmonella Typhimurium and requirement of metabolism associated pathways for protection of Mycobacterium tuberculosis from host immune system. 9 Salmonella is even known to modulate host to exploit the limited supply of nutrients. 8,12 Coupling of nutrition with virulence reveals metabolism associated genes that can be targeted for antimicrobial therapy.…”

Section: Potential Of Peptide Transporters In Antimicrobial Therapymentioning

confidence: 99%

Bacterial peptide transporters: Messengers of nutrition to virulence

2016

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Bacteria possess numerous peptide transporters for importing peptides as nutrients. However, these peptide transporters are now consistently reported to play a role in the virulence of various bacterial pathogens. Their ability to transport peptides has implications in antibacterial therapy as well. Therefore, it would be instrumental to have complete knowledge about the role of peptide transporters in mediating this cross connection between metabolism and pathogenesis. Studies on various peptide transporters in bacterial pathogens have improved our understanding of this field. In this review, we have given an overview of the functioning of bacterial peptide transporters and their contribution in virulence of major bacterial pathogens.

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Section: Potential Of Peptide Transporters In Antimicrobial Therapymentioning

confidence: 99%

Bacterial peptide transporters: Messengers of nutrition to virulence

2016

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“…To further investigate this possibility, as well as decipher the cellular response to Oat3 deficiency, global transcriptomic clustering was followed by pathway analysis using mouse Recon 1. This global metabolic network reconstruction is largely based on human Recon 1, which comprises known biochemical and physiologic data (Sigurdsson et al, 2010;Bordbar et al, 2012). These computational analyses revealed alterations in a number of metabolic pathways related to transcriptional regulation, solute handling, and endogenous enzymatic activities (also see Table 2).…”

Section: Oat3 Handling Of Endogenous Metabolites and Flavonoidsmentioning

confidence: 99%

Multispecific Drug Transporter Slc22a8 (Oat3) Regulates Multiple Metabolic and Signaling Pathways

Jamshidi

Eraly

et al. 2013

Drug Metab Dispos

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Multispecific drug transporters of the solute carrier and ATPbinding cassette families are highly conserved through evolution, but their true physiologic role remains unclear. Analyses of the organic anion transporter 3 (OAT3; encoded by Slc22a8/Oat3, originally Roct) knockout mouse have confirmed its critical role in the renal handling of common drugs (e.g., antibiotics, antivirals, diuretics) and toxins. Previous targeted metabolomics of the knockout of the closely related Oat1 have demonstrated a central metabolic role, but the same approach with Oat3 failed to reveal a similar set of endogenous substrates. Nevertheless, the Oat3 knockout is the only Oat described so far with a physiologically significant phenotype, suggesting the disturbance of metabolic or signaling pathways. Here we analyzed global gene expression in Oat3 knockout tissue, which implicated OAT3 in phase I and phase II metabolism (drug metabolizing enzymes or DMEs), as well as signaling pathways. Metabolic reconstruction with the recently developed "mouse Recon1" supported the involvement of Oat3 in the aforementioned pathways. Untargeted metabolomics were used to determine whether the predicted metabolic alterations could be confirmed. Many significant changes were observed; several metabolites were tested for direct interaction with mOAT3, whereas others were supported by published data. Oat3 thus appears critical for the handling of phase I (hydroxylation) and phase II (glucuronidation) metabolites. Oat3 also plays a role in bioenergetic pathways (e.g., the tricarboxylic acid cycle), as well as those involving vitamins (e.g., folate), steroids, prostaglandins, gut microbiome products, uremic toxins, cyclic nucleotides, amino acids, glycans, and possibly hyaluronic acid. The data seemingly consistent with the Remote Sensing and Signaling Hypothesis (Ahn and Nigam, 2009;Wu et al., 2011), also suggests that Oat3 is essential for the handling of dietary flavonoids and antioxidants.

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“…Our work indicates that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for inflammatory response, while sparing Mycdependent proliferation. macrophages and also provides precursors for lipid and amino acid biosynthesis, all of which may support intracellular membrane reorganization and the production and secretion of proinflammatory cytokines (17)(18)(19)(20). Meanwhile, the increase of PPP-derived NADPH supports the production of reduced glutathione and therefore limits oxidative stress in M1 macrophages (12,21,22).…”

Section: Significancementioning

confidence: 99%

Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1 α -dependent

Liu

Martinez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

188

166

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As a phenotypically plastic cellular population, macrophages change their physiology in response to environmental signals. Emerging evidence suggests that macrophages are capable of tightly coordinating their metabolic programs to adjust their immunological and bioenergetic functional properties, as needed. Upon mitogenic stimulation, quiescent macrophages enter the cell cycle, increasing their bioenergetic and biosynthetic activity to meet the demands of cell growth. Proinflammatory stimulation, however, suppresses cell proliferation, while maintaining a heightened metabolic activity imposed by the production of bactericidal factors. Here, we report that the mitogenic stimulus, colony-stimulating factor 1 (CSF-1), engages a myelocytomatosis viral oncogen (Myc)-dependent transcriptional program that is responsible for cell cycle entry and the up-regulation of glucose and glutamine catabolism in bone marrow-derived macrophages (BMDMs). However, the proinflammatory stimulus, lipopolysaccharide (LPS), suppresses Myc expression and cell proliferation and engages a hypoxia-inducible factor alpha (HIF1α)-dependent transcriptional program that is responsible for heightened glycolysis. The acute deletion of Myc or HIF1α selectively impaired the CSF-1-or LPS-driven metabolic activities in BMDM, respectively. Finally, inhibition of glycolysis by 2-deoxyglucose (2-DG) or genetic deletion of HIF1α suppressed LPS-induced inflammation in vivo. Our studies indicate that a switch from a Myc-dependent to a HIF1α-dependent transcriptional program may regulate the robust bioenergetic support for an inflammatory response, while sparing Myc-dependent proliferation.T he cells of the immune system are constantly exposed to environmental challenges and are capable of tailoring their metabolic programs to meet distinct physiological needs. Macrophages, like other immune cells, rapidly change their physiology in response to various environmental cues. Macrophages undergo proliferation in response to mitogenic stimuli, such as colony-stimulating factor 1 (CSF-1) [also known as macrophage CSF (M-CSF)], and this cellular turnover is essential for macrophage homeostasis and may occur in mature macrophages, bypassing the need for self-renewing progenitors (1, 2). Proliferating macrophages consume considerable amounts of energy and require de novo synthesis of macromolecules to support their growth and proliferation (3-6). Therefore, macrophages must coordinately regulate metabolic programs to meet their bioenergetic and biosynthetic demand during proliferation. Despite the emerging view that extracellular signaling events dictate cell growth, proliferation, and death, in part by modulating metabolic activities in cancer cells and T lymphocytes, the precise mechanisms and crucial players of reprogramming metabolism during macrophage proliferation are incompletely understood.Upon encountering an invading microorganism, the bioenergetic potential in macrophages quickly shifts away from fulfilling the needs of cell proliferation to mount a robust...

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Model‐driven multi‐omic data analysis elucidates metabolic immunomodulators of macrophage activation

Abstract: Genome-scale metabolic network reconstruction and analysis of the murine leukemic macrophage cell line RAW 264.7 reveal a complementary relationship between how known metabolic immunomodulators are biochemically processed and their role in macrophage activation.

Cited by 144 publications

References 78 publications

Bacterial peptide transporters: Messengers of nutrition to virulence

Bacterial peptide transporters: Messengers of nutrition to virulence

Multispecific Drug Transporter Slc22a8 (Oat3) Regulates Multiple Metabolic and Signaling Pathways

Proinflammatory signal suppresses proliferation and shifts macrophage metabolism from Myc-dependent to HIF1 α -dependent

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