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Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight
Open accessAbstract
Nitric Oxide (NO) is a soluble endogenous gas with various biological functions like signaling, and working as an effector molecule or metabolic regulator. In response to inflammatory signals, immune myeloid cells, like macrophages, increase production of cytokines and NO, which is important for pathogen killing. Under these proinflammatory circumstances, called “M1”, macrophages undergo a series of metabolic changes including rewiring of their tricarboxylic acid (TCA) cycle. Here, we review findings indicating that NO, through its interaction with heme and non-heme metal containing proteins, together with components of the electron transport chain, functions not only as a regulator of cell respiration, but also a modulator of intracellular cell metabolism. Moreover, diverse effects of NO and NO-derived reactive nitrogen species (RNS) involve precise interactions with different targets depending on concentration, temporal, and spatial restrictions. Although the role of NO in macrophage reprogramming has been in evidence for some time, current models have largely minimized its importance. It has, therefore, been hiding in plain sight. A review of the chemical properties of NO, past biochemical studies, and recent publications, necessitates that mechanisms of macrophage TCA reprogramming during stimulation must be re-imagined and re-interpreted as mechanistic results of NO exposure. The revised model of metabolic rewiring we describe here incorporates many early findings regarding NO biochemistry and brings NO out of hiding and to the forefront of macrophages immunometabolism.
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“The role of •NO in macrophage reprogramming has been known for a long time, but current models greatly underestimate its importance [125].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [125]
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“The •NO/ROS balance is also important during the transition from Th1 to Th2 [125,126].”
From The Role of Reactive Species on Innate Immunity (2022) · cites this paper as [125]
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“Similarly, reduced NO • production in macrophages indicates a decrease in inflammatory mediators [33].”
Hsieh, C.-Y., Yang, H., Hsu, C.-P., Chang, J., & Lin, C.-C. (2025) · Natural Product Communications · doi:10.1177/1934578x241301955 · Cited by 2
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“Similarly, mobilization of inflammatory cytokines induced by reaction cascades involving the versatile immune macrophages triggers increased synthesis of NO [55].”
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“It should be noted that NO in itself can cause mitochondrial rewiring and is currently being reframed as a cause rather than the effect of macrophage metabolic changes [88].”
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“The cellular remodeling upon classical activation encompasses transcriptional, proteomic, and metabolic changes [4,6 – 13].”
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“33 Li’s team developed BDP3, a fluorescent probe for NO detection featuring maximum emission at 668 nm (Figure 1A).”
Coutinho, L. L., Palmieri, E. M., Ridnour, L. A., Cheng, R. Y. S., Heinz, W. F., Anderson, S. K., Billiar, T. R., Chang, J. C., Lockett, S., Rangel, M. C., et al. (2026) · Redox Biology · doi:10.1016/j.redox.2026.104245 · Cited by 2
“S-nitrosation of Cys39 in the D form blocks reactivation by NADH and marks the complex for degradation, whereas the A form is relatively resistant [50].”
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InfluentialJin, S., Fu, C., Zhang, H., Ji, Y., Jiao, Q., & Liu, P. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27177910 · Cited by 1
“Macrophages quickly and ultimately shift from the oxidative phosphorylation-dependent metabolic pattern of the resting state to aerobic glycolysis, which maintains the M1 pro-inflammatory phenotype and reinforces the pro-inflammatory state of the macrophages [40–42].”
Amino acids can deplete ATP and impair nitric oxide detoxification by Escherichia coli
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Crosstalk between metabolites and myeloid cell biology
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The profound influence of nitric oxide on intercellular communication and health
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“[68] The role of the liver and lung in NO-dependent non-specific immunity is due to the functioning of these two organs as immunological filters of the circulation.”
Metabolic Regulation of Antiviral Immune Responses in Macrophages
Ahmed, D. (2021) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2021-14431 · Cited by 1
Role of Fermented Dairy Products in Enhancing the Immunity
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Joint Effects of Mexidol and Nitroglycerine on Nitric Oxide Formation in Animal Liver Tissues
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“In response to in fl ammatory signals, immune myeloid cells such as macrophages can produce cytokines and NO, which are critical for pathogens killings (Palmieri et al., 2020).”
BackgroundReungsuwat, S., Sookkhee, S., Itthidecharon, C., & Wanachantararak, P. (2023) · Trends in Sciences · doi:10.48048/tis.2023.6752
Karaduman, T. (2023) · Afyon Kocatepe University Journal of Sciences and Engineering · doi:10.35414/akufemubid.1302005
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Self-citationDevelopment and Application of a Multimodal Coherent Raman Scattering Microscope
Allen, C. H. (2024) · Carleton University's Institutional Repository (MacOdrum Library, Carleton University) · doi:10.22215/etd/2024-15880
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“…myeloid cells such as macrophages produce proinflammatory mediators, including nitric oxide (NO) and cytokines, for instance, tumor necrosis factor-α (TNF-α ), interleukin-6 (IL-6), and interleukin-1 β (IL-1 β ) upon inflammatory signals to initiate and propagate the inflammatory response [3,4].”
Corbetta, D., Grau‐Roma, L., Rees, C. E. D., Swift, B. M. C., O’Cathail, C., Barron, E. S., Verin, R., Morey‐Matamalas, A., Sorley, M., & Bennett, M. (2024) · European Journal of Wildlife Research · doi:10.1007/s10344-024-01866-4
“…furo ) do not produce nitric oxide (NO) or upregulate Toll-like Receptor 9 (TLR-9), in response to a range of agonists including MTBC (Bilham et al. 2017), and both NO and TLR-9 are involved in macrophage activation and granuloma formation in TB infections (Ito et al. 2007; Palmieri et al. 2020).”
Metadata
- Authors
- Palmieri, E. M., McGinity, C., Wink, D. A., & McVicar, D. W.
- Affiliations
- National Cancer Institute (US)
- Corresponding author
- McVicar, Daniel W.
- Venue
- Metabolites
- Publisher
- MDPI AG
- Published
- 2020-10-26
- Volume
- 10
- Issue
- 11
- Pages
- 429
- ISSN
- 2218-1989 (ISSN-L)
- PMC
- PMC7693038
- OpenAlex
- W3096340664
- Cited by
- 237
- References
- 252
- Citations by year
- 2026: 40 · 2025: 59 · 2024: 56 · 2023: 46 · 2022: 15 · 2021: 20 · 2020: 1
- FWCI
- 2.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Metabolites (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Cancer Institute (ZIA BC 010300, ZIA BC 010899)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Physiology (medical) › Nitric Oxide and Endothelin Effects
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
- Keywords
- nitric oxide, macrophage immunometabolism, M1 macrophages, reactive nitrogen species, electron transport chain, heme proteins, cellular respiration, macrophage metabolic reprogramming, inflammation
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