Network Integration of Parallel Metabolic and Transcriptional Data Reveals Metabolic Modules that Regulate Macrophage Polarization
Open accessAbstract
Macrophage polarization involves a coordinated metabolic and transcriptional rewiring that is only partially understood. By using an integrated high-throughput transcriptional-metabolic profiling and analysis pipeline, we characterized systemic changes during murine macrophage M1 and M2 polarization. M2 polarization was found to activate glutamine catabolism and UDP-GlcNAc-associated modules. Correspondingly, glutamine deprivation or inhibition of N-glycosylation decreased M2 polarization and production of chemokine CCL22. In M1 macrophages, we identified a metabolic break at Idh, the enzyme that converts isocitrate to alpha-ketoglutarate, providing mechanistic explanation for TCA cycle fragmentation. (13)C-tracer studies suggested the presence of an active variant of the aspartate-arginosuccinate shunt that compensated for this break. Consistently, inhibition of aspartate-aminotransferase, a key enzyme of the shunt, inhibited nitric oxide and interleukin-6 production in M1 macrophages, while promoting mitochondrial respiration. This systems approach provides a highly integrated picture of the physiological modules supporting macrophage polarization, identifying potential pharmacologic control points for both macrophage phenotypes.
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Succinate is a pro-inflammatory metabolite that accumulates in LPS/IFN-γ-treated macrophages.
“Recent data indicate that succinate is a pro-inflammatory metabolite that accumulates in LPS/IFN-γ-treated macrophages1,2.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [1]
Jha et al 2015 described induction of an inflammatory argininosuccinate shunt linking the Krebs cycle to the Urea cycle.
“Using an integrated high-throughput transcriptional metabolic profiling and analysis pipeline (CoMBI-T), Jha and colleagues (2015) described the induction of an inflammatory argininosuccinate shunt, a metabolic pathway that links the Krebs cycle to the Urea cycle1.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [1]
Induction of the argininosuccinate shunt occurs via an increase in Ass1 expression.
“Induction of this pathway occurred via an increase in the expression of argininosuccinate synthase (Ass1), which catalyses the formation of argininosuccinate from aspartate, citrulline and ATP98.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [1]
The argininosuccinate shunt accounts for elevated fumarate levels observed in macrophages.
“As Asl cleaves argininosuccinate into arginine and fumarate, the authors proposed that this metabolic pathway accounted for the elevated fumarate levels observed in macrophages1.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [1]
Fumarate accumulates in LPS-activated macrophages.
“Outside of trained immunity, fumarate has previously been reported to accumulate in LPS-activated macrophages1,13.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [1]
The first TCA cycle break occurs at isocitrate dehydrogenase, leading to accumulation of citrate, the precursor for itaconate.
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [25]
The second TCA cycle break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [25]
Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, particularly those that regulate succinate levels, which can influence HIF signaling or other pathways.
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13,25,40,41).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [25]
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- Authors
- Jha, A. K., Huang, S. C.-C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K. M., Ashall, J., Everts, B., Pearce, E. J., Driggers, E. M., & Artyomov, M. N.
- Affiliations
- Agios Pharmaceuticals (United States) (US)
- Washington University in St. Louis (US)
- ITMO University (RU)
- Corresponding author
- Driggers, Edward M.
- Artyomov, Maxim N.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2015-03
- Volume
- 42
- Issue
- 3
- Pages
- 419-430
- ISSN
- 1074-7613 (ISSN-L)
- OpenAlex
- W2076272449
- Cited by
- 2,066
- References
- 39
- Citations by year
- 2026: 207 · 2025: 218 · 2024: 217 · 2023: 209 · 2022: 244 · 2021: 259 · 2020: 212 · 2019: 152 · 2018: 124 · 2017: 112 · 2016: 69 · 2015: 29 · 2014: 1 · 2012: 1
- FWCI
- 54.77
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion, other-oa)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial Metabolic Engineering and Bioproduction
- Keywords
- macrophage polarization, M1 macrophages, M2 macrophages, metabolic reprogramming, glutamine catabolism, N-glycosylation, UDP-GlcNAc, CCL22, isocitrate dehydrogenase, aspartate aminotransferase, nitric oxide, interleukin-6, mitochondrial respiration, metabolic modules, gene expression profiling
- MeSH terms
- Animals, Argininosuccinic Acid, Aspartic Acid, Citric Acid Cycle, Gene Expression Regulation, Glutamine, Glycosylation, Immunity, Innate, Isocitrate Dehydrogenase, Macrophages, Mitochondria, Nitric Oxide, Transcription, Genetic, Uridine Diphosphate N-Acetylglucosamine, Signal Transduction, Interleukin-6, Aspartate Aminotransferase, Mitochondrial, Mice, Gene Regulatory Networks, Metabolic Networks and Pathways, Chemokine CCL22
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