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Title: Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation

Abstract

Macrophages are central players in the immune response, manifesting divergent phenotypes to control inflammation and innate immunity through the release of cytokines and other regulatory factor-dependent signaling pathways. In recent years, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features critical for macrophage functions. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of macrophage activation. Metabolites well-known to be associated with immunoactivation (e.g., glucose and arginine) and immunosuppression (e.g., tryptophan and vitamin D3) were amongst the most critical effectors. Intracellular metabolic mechanisms linked to critical suppressive effectors were then assessed, identifying a suppressive role for de novo nucleotide synthesis. Finally, the underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying metabolic connections between activation and metabolic effectors.

Authors:
; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Pacific Northwest National Laboratory (PNNL), Richland, WA (US), Environmental Molecular Sciences Laboratory (EMSL)
Sponsoring Org.:
USDOE
OSTI Identifier:
1047975
Report Number(s):
PNNL-SA-87903
39976; 42294; 400412000; TRN: US201216%%598
DOE Contract Number:  
AC05-76RL01830
Resource Type:
Journal Article
Journal Name:
Molecular Systems Biology
Additional Journal Information:
Journal Volume: 8
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; AGING; ARGININE; DATA ANALYSIS; GLUCOSE; IMMUNITY; IMMUNOSUPPRESSION; INFLAMMATION; LYMPHOKINES; MACROPHAGES; METABOLISM; METABOLITES; NEOPLASMS; NUCLEOTIDES; SIMULATION; SYNTHESIS; TRYPTOPHAN; VITAMINS; Environmental Molecular Sciences Laboratory

Citation Formats

Bordbar, Aarash, Mo, Monica L., Nakayasu, Ernesto S., Rutledge, Alexandra C., Kim, Young-Mo, Metz, Thomas O., Jones, Marcus B., Frank, Bryan C., Smith, Richard D., Peterson, Scott N., Hyduke, Daniel R., Adkins, Joshua N., and Palsson, Bernhard O. Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation. United States: N. p., 2012. Web. doi:10.1038/msb.2012.21.
Bordbar, Aarash, Mo, Monica L., Nakayasu, Ernesto S., Rutledge, Alexandra C., Kim, Young-Mo, Metz, Thomas O., Jones, Marcus B., Frank, Bryan C., Smith, Richard D., Peterson, Scott N., Hyduke, Daniel R., Adkins, Joshua N., & Palsson, Bernhard O. Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation. United States. doi:10.1038/msb.2012.21.
Bordbar, Aarash, Mo, Monica L., Nakayasu, Ernesto S., Rutledge, Alexandra C., Kim, Young-Mo, Metz, Thomas O., Jones, Marcus B., Frank, Bryan C., Smith, Richard D., Peterson, Scott N., Hyduke, Daniel R., Adkins, Joshua N., and Palsson, Bernhard O. Tue . "Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation". United States. doi:10.1038/msb.2012.21.
@article{osti_1047975,
title = {Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation},
author = {Bordbar, Aarash and Mo, Monica L. and Nakayasu, Ernesto S. and Rutledge, Alexandra C. and Kim, Young-Mo and Metz, Thomas O. and Jones, Marcus B. and Frank, Bryan C. and Smith, Richard D. and Peterson, Scott N. and Hyduke, Daniel R. and Adkins, Joshua N. and Palsson, Bernhard O.},
abstractNote = {Macrophages are central players in the immune response, manifesting divergent phenotypes to control inflammation and innate immunity through the release of cytokines and other regulatory factor-dependent signaling pathways. In recent years, the focus on metabolism has been reemphasized as critical signaling and regulatory pathways of human pathophysiology, ranging from cancer to aging, often converge on metabolic responses. Here, we used genome-scale modeling and multi-omics (transcriptomics, proteomics, and metabolomics) analysis to assess metabolic features critical for macrophage functions. We constructed a genome-scale metabolic network for the RAW 264.7 cell line to determine metabolic modulators of macrophage activation. Metabolites well-known to be associated with immunoactivation (e.g., glucose and arginine) and immunosuppression (e.g., tryptophan and vitamin D3) were amongst the most critical effectors. Intracellular metabolic mechanisms linked to critical suppressive effectors were then assessed, identifying a suppressive role for de novo nucleotide synthesis. Finally, the underlying metabolic mechanisms of macrophage activation are identified by analyzing multi-omic data obtained from LPS-stimulated RAW cells in the context of our flux-based predictions. Our study demonstrates metabolism's role in regulating activation may be greater than previously anticipated and elucidates underlying metabolic connections between activation and metabolic effectors.},
doi = {10.1038/msb.2012.21},
journal = {Molecular Systems Biology},
number = ,
volume = 8,
place = {United States},
year = {2012},
month = {6}
}