Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

Palmieri, Erika M.; McGinity, Christopher; Wink, David A.; McVicar, Daniel W.

doi:10.3390/metabo10110429

Cited by 238Immune cells in cancerNitric Oxide and Endothelin EffectsRedox biology and oxidative stress

Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

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Palmieri, Erika M., McGinity, Christopher, Wink, David A., McVicar, Daniel W.·2020·Metabolites

DOI 10.3390/metabo10110429PMC PMC7693038

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Abstract

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.
“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]
The •NO/ROS balance is important during the transition from Th1 to Th2.
“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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Background
Cardioprotection by S-nitrosation of a cysteine switch on mitochondrial complex I
Chouchani, E. T., Methner, C., Nadtochiy, S. M., Logan, A., Pell, V. R., Ding, S., James, A. M., Cochemé, H. M., Reinhold, J., Lilley, K. S., et al. (2013) · Nature Medicine · doi:10.1038/nm.3212 · Cited by 619 · cited 2× · see citing works
“Considering the history of NO chemistry and the elegant dissection of metabolic mechanisms associated with macrophage cytotoxicity noted above, it is surprising that most in the immunometabolism field have been speculating that the inhibitory effects of NO on oxidative mitochondrial metabolism might be simply due to d…”
Background
Why Is L-Glutamine Metabolism Important to Cells of the Immune System in Health, Postinjury, Surgery or Infection?
Newsholme, P. (2001) · Journal of Nutrition · doi:10.1093/jn/131.9.2515s · Cited by 619 · see citing works
NO+, NO, and NO- donation by S-nitrosothiols-implications for regulation of physiological functions by S-nitrosylation and acceleration of disulfide formation
Arnelle, D. R., & Stamler, J. S. (1995) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1995.1231 · Cited by 604 · see citing works
Accelerated reaction of nitric oxide with O 2 within the hydrophobic interior of biological membranes
Liu, X., Miller, M. J. S., Joshi, M. S., Thomas, D. D., & Lancaster, J. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2175 · Cited by 602 · see citing works
Differentiation of murine macrophages to express nonspecific cytotoxicity for tumor cells results in L-arginine-dependent inhibition of mitochondrial iron-sulfur enzymes in the macrophage effector cells.
Drapier, J., & Hibbs, J. B. (1988) · The Journal of Immunology · doi:10.4049/jimmunol.140.8.2829 · Cited by 592 · cited 4× · see citing works
“First of all, as noted above, unlike IDH1, ACO2 is a long known target of NO via attack of its FeS cluster [53,68,69].”
BackgroundResultInfluential
Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome–dependent processing of IL-1β
Mishra, B. B., Rathinam, V. A. K., Martens, G. W., Martinot, A. J., Kornfeld, H., Fitzgerald, K. A., & Sassetti, C. M. (2013) · Nature Immunology · doi:10.1038/ni.2474 · Cited by 571 · see citing works
Commitment to glycolysis sustains survival of NO-producing inflammatory dendritic cells
Everts, B., Amiel, E., van der Windt, G. J. W., Freitas, T. C., Chott, R., Yarasheski, K. E., Pearce, E. L., & Pearce, E. J. (2012) · Blood · doi:10.1182/blood-2012-03-419747 · Cited by 532 · cited 4× · see citing works
“The early dissection of macrophage cytotoxic mechanisms by Hibbs and Drapier, and the finding that the metabolic switch in macrophages and DCs activated with LPS was dependent on NOS2 led to the suggestion that NO generated by NOS2 mediates the LPS-induced mitochondrial dysfunction and increase in glycolysis [142].”
BackgroundInfluential
The dual role of iNOS in cancer
Vannini, F., Kashfi, K., & Nath, N. (2015) · Redox Biology · doi:10.1016/j.redox.2015.08.009 · Cited by 529 · cited 1× · see citing works
“Therapeutically shifting the TME from tumorigenic simmering iNOS activity driven by the tumor itself, towards an immune surveillance situation where macrophages are reprogrammed to produce higher, effector level, NO fluxes could be beneficial [237,238].”
Background
Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels
Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., et al. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m115.685792 · Cited by 526 · cited 5× · see citing works
“The rapid and profound increase of itaconate in stimulated macrophages [112], Nos2−/− cells bearing higher levels of itaconate with high fractional incorporation of glucose carbon at the expense of glutamine carbon, together with the sensitivity of inhibition of PDH and ACO2 to NO, all justify a new, corrected model f…”
BackgroundInfluential
Mechanistic aspects of the reactions of nitric oxide with transition-metal complexes
Ford, P. C., & Lorkovic, I. M. (2002) · Chemical Reviews · doi:10.1021/cr0000271 · Cited by 525 · cited 1× · see citing works
“The rate constant for association of NO to heme centers is typically very high relative to other potential targets [20], such that even low nanomolar levels of NO are sufficient to activate sGC [21].”
Background
Triggering the succinate receptor GPR91 on dendritic cells enhances immunity
Rubic, T., Lametschwandtner, G., Jost, S., Hinteregger, S., Kund, J., Carballido-Perrig, N., Schwärzler, C., Junt, T., Voshol, H., Meingassner, J. G., et al. (2008) · Nature Immunology · doi:10.1038/ni.1657 · Cited by 525 · cited 1× · see citing works
“Succinate has been implicated in various aspects of inflammatory function including acting in trans via the succinate receptor expressed on internal organs as well as on immune cells [130].”
Background
Analysis and Interpretation of Microplate-Based Oxygen Consumption and pH Data
Divakaruni, A. S., Paradyse, A. R., Ferrick, D. A., Murphy, A. N., & Jastroch, M. (2014) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/b978-0-12-801415-8.00016-3 · Cited by 525 · cited 1× · see citing works
“For many years, researchers have tried to link inflammatory stimuli such as LPS to altered mitochondrial function [95,96], but recent technologies [97,98] have brought advances in the field.”
Background
PKM2 regulates the Warburg effect and promotes HMGB1 release in sepsis
Yang, L., Xie, M., Yang, M., Yu, Y., Zhu, S., Hou, W., Kang, R., Lotze, M. T., Billiar, T. R., Wang, H., et al. (2014) · Nature Communications · doi:10.1038/ncomms5436 · Cited by 503 · cited 1× · see citing works
“[151] also exposed apparent incongruences with studies indicating that HIF1α-dependent upregulation of Pdk1 and consequent suppression of acetyl-CoA synthesis, may be responsible for OXPHOS regulation in macrophages [152].”
Background
Nitric oxide and asthmatic inflammation
Barnes, P. J., & Liew, F. Y. (1995) · Immunology Today · doi:10.1016/0167-5699(95)80128-6 · Cited by 502 · see citing works
Inducible nitric oxide synthase in pulmonary alveolar macrophages from patients with tuberculosis.
Nicholson, S., Bonecini-Almeida, M. D. G., Silva, J. R. L. E., Nathan, C., Xie, Q. W., Mumford, R. A., Weidner, J. R., Calaycay, J. R., Geng, J., Boéchat, N., et al. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.183.5.2293 · Cited by 497 · see citing works
Interferon‐γ and tumor necrosis factor induce the L‐arginine‐dependent cytotoxic effector mechanism in murine macrophages*
Drapier, J., Wietzerbin, J., & Hibbs, J. B. (1988) · European Journal of Immunology · doi:10.1002/eji.1830181018 · Cited by 497 · cited 4× · see citing works
“found a correlation between the ability of combinations of stimuli to induce NO2− and NO3− synthesis from L-arginine and their ability to cause reductions in aconitase activity in the producer macrophages [67].”
BackgroundInfluential
Nitric oxide orchestrates metabolic rewiring in M1 macrophages by targeting aconitase 2 and pyruvate dehydrogenase
Palmieri, E. M., Gonzalez-Cotto, M., Baseler, W. A., Davies, L. C., Ghesquière, B., Maio, N., Rice, C. M., Rouault, T. A., Cassel, T., Higashi, R. M., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-14433-7 · Cited by 472 · cited 16× · see citing works
“Carbon tracing suggests contributions of glucose- but primarily glutamine-derived carbon during itaconate production [109].”
BackgroundInfluentialSelf-citation
Immunometabolism at the interface between macrophages and pathogens
Russell, D. G., Huang, L., & VanderVen, B. C. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0124-9 · Cited by 461 · cited 4× · see citing works
“Lastly, Hif1α -/- macrophages have been shown to maintain PDK1 expression, the stimulation-induced TCA break and to compromise PDH activity [101], and we found no significant effect of Hif1α deletion on LPS-induced glycolytic flux.”
BackgroundInfluential
Activation of the inducible form of nitric oxide synthase in the brains of patients with multiple sclerosis.
Bagasra, O., Michaels, F. H., Zheng, Y., Bobroski, L. E., Spitsin, S. V., Fu, Z., Tawadros, R., & Koprowski, H. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.26.12041 · Cited by 456 · see citing works
Human mononuclear phagocyte inducible nitric oxide synthase (iNOS): analysis of iNOS mRNA, iNOS protein, biopterin, and nitric oxide production by blood monocytes and peritoneal macrophages
Weinberg, J., Misukonis, M., Shami, P., Mason, S. N., Sauls, D., Dittman, W. A., Wood, E., Smith, G., McDonald, B., & Bachus, K. (1995) · Blood · doi:10.1182/blood.v86.3.1184.1184 · Cited by 435 · see citing works
Different Responses of Astrocytes and Neurons to Nitric Oxide: The Role of Glycolytically Generated ATP in Astrocyte Protection
Almeida, A., Almeida, J., Bolaños, J. P., & Moncada, S. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.261560998 · Cited by 423 · cited 10× · see citing works
“This changes the ETC to a more reduced state and leads to a defense response where reversal of the ATP synthase will hydrolyze cytoplasmic glycolytic ATP extruding protons (H+).”
BackgroundInfluential
Diffusion of Nitric Oxide in the Aorta Wall Monitored in Situ by Porphyrinic Microsensors
Malinski, T., Taha, Z., Grunfeld, S., Patton, S. R., Kapturczak, M., & Tomboulian, P. (1993) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1993.1735 · Cited by 417 · see citing works
Murine cytotoxic activated macrophages inhibit aconitase in tumor cells. Inhibition involves the iron-sulfur prosthetic group and is reversible.
Drapier, J., & Hibbs, J. B. (1986) · Journal of Clinical Investigation · doi:10.1172/jci112642 · Cited by 415 · cited 2× · see citing works
“First of all, as noted above, unlike IDH1, ACO2 is a long known target of NO via attack of its FeS cluster [53,68,69].”
Background
Nitric Oxide‐Mediated Inhibition of the Mitochondrial Respiratory Chain in Cultured Astrocytes
Bolaños, J. P., Peuchen, S., Heales, S., Land, J. M., & Clark, J. B. (1994) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1994.63030910.x · Cited by 413 · cited 1× · see citing works
“These authors, however, were skeptical of which oxidant compounds might be responsible for this inhibition: they found that NO2− + NO3− released by LPS+FNγ treatment was accompanied by enhanced hydrogen peroxide (H2O2) production consistent with superoxide production [71].”
Background
Pharmacologic or Genetic Targeting of Glutamine Synthetase Skews Macrophages toward an M1-like Phenotype and Inhibits Tumor Metastasis
Palmieri, E. M., Menga, A., Martín‐Pérez, R., Quinto, A., Riera‐Domingo, C., Tullio, G. D., Hooper, D. C., Lamers, W. H., Ghesquière, B., McVicar, D. W., et al. (2017) · Cell Reports · doi:10.1016/j.celrep.2017.07.054 · Cited by 408 · cited 1× · see citing works
“Accordingly, our older work, tracing carbon sources in M1 polarized human monocyte derived macrophages [227], showed full glucose-derived labeling of citrate and this pattern was conserved in downstream metabolites such as α-KG and malate.”
BackgroundSelf-citation
Nitric oxide suppresses NLRP3 inflammasome activation and protects against LPS-induced septic shock
Mao, K., Chen, S., Chen, M., Ma, Y., Wang, Y., Huang, B., He, Z., Zeng, Y., Hu, Y., Sun, S., et al. (2013) · Cell Research · doi:10.1038/cr.2013.6 · Cited by 397 · see citing works
Effect of exogenous and endogenous nitric oxide on mitochondrial respiration of rat hepatocytes
Stadler, J., Billiar, T. R., CURRAN, R. D., Stuehr, D. J., Ochoa, J. B., & Simmons, R. L. (1991) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1991.260.5.c910 · Cited by 396 · cited 1× · see citing works
“First of all, as noted above, unlike IDH1, ACO2 is a long known target of NO via attack of its FeS cluster [53,68,69].”
Background
The effect of nitric oxide on cell respiration: A key to understanding its role in cell survival or death
Beltrán, B., Mathur, A., Duchen, M. R., Erusalimsky, J. D., & Moncada, S. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.26.14602 · Cited by 392 · cited 10× · see citing works
“This changes the ETC to a more reduced state and leads to a defense response where reversal of the ATP synthase will hydrolyze cytoplasmic glycolytic ATP extruding protons (H+).”
BackgroundResultInfluential
Itaconic acid is a mammalian metabolite induced during macrophage activation
Strelko, C. L., Lu, W., Dufort, F. J., Seyfried, T. N., Chiles, T. C., Rabinowitz, J. D., & Roberts, M. F. (2011) · Journal of the American Chemical Society · doi:10.1021/ja2070889 · Cited by 391 · cited 1× · see citing works
“Irg1 is one of the most highly upregulated genes during macrophage M1 polarization and although it has been near the top of many lists of upregulated genes in macrophages for years, it has only recently come into the forefront [107,121].”
Background
25-Hydroxycholesterols in innate and adaptive immunity
Cyster, J. G., Dang, E. V., Reboldi, A., & Yi, T. (2014) · Nature Reviews Immunology · doi:10.1038/nri3755 · Cited by 388 · cited 1× · see citing works
“nitrogen intermediates through NOS2 [135], and increased production of effectors such as cationic peptides, lysosomal hydrolases, and metabolic inhibitors [136], including itaconate (antibacterial) [107] and 25-hydroxycholesterol (antiviral) [137], all contribute to macrophage antimicrobial responses.”
Background
Nitric oxide production and inducible nitric oxide synthase expression in inflammatory arthritides.
Sakurai, H., Kohsaka, H., Liu, M. F., Higashiyama, H., Hirata, Y., Kanno, K., Saito, I., & Miyasaka, N. (1995) · Journal of Clinical Investigation · doi:10.1172/jci118292 · Cited by 388 · see citing works
The mitochondrial citrate carrier: a new player in inflammation
Infantino, V., Convertini, P., Cucci, L., Panaro, M. A., Noia, M. A. D., Calvello, R., Palmieri, F., & Iacobazzi, V. (2011) · Biochemical Journal · doi:10.1042/bj20111275 · Cited by 386 · cited 1× · see citing works
“This was first based on evidence that human histiocytoma cell lines where the mitochondrial citrate transporter had been silenced show deficits in prostaglandin mediators [120].”
Background
Tumor Necrosis Factor and Granulocyte Macrophage-Colony Stimulating Factor Stimulate Human Macrophages to Restrict Growth of Virulent Mycobacterium avium and to Kill Avirulent M. avium: Killing Effector Mechanism Depends on the Generation of Reactive Nitrogen Intermediates
Denis, M. (1991) · Journal of Leukocyte Biology · doi:10.1002/jlb.49.4.380 · Cited by 386 · see citing works
Activation of NRF2 by Nitrosative Agents and H2O2 Involves KEAP1 Disulfide Formation
Fourquet, S., Guérois, R., Biard, D. S. F., & Tolédano, M. B. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.051714 · Cited by 378 · see citing works
The role of iron in the activation-inactivation of aconitase.
Kennedy, M. C., Emptage, M. H., Dreyer, J.-L., & Beinert, H. (1983) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)44390-0 · Cited by 377 · see citing works
Irreversible Inhibition of Mitochondrial Complex I by 1‐Methyl‐4‐Phenylpyridinium: Evidence for Free Radical Involvement
Cleeter, M. W. J., Cooper, J. M., & Schapira, A. H. V. (1992) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.1992.tb09789.x · Cited by 372 · cited 1× · see citing works
“Accordingly, inhibition of cytochrome c oxidase is required for the irreversible loss of Complex I [79].”
Background
Regulation of the immune response by nitric oxide differentially produced by T helper type 1 and T helper type 2 cells
Taylor-Robinson, A. W., Liew, F. Y., Severn, A., Xu, D., McSorley, S. J., Garside, P., Padron, J., & PHILLIPS, R. S. (1994) · European Journal of Immunology · doi:10.1002/eji.1830240430 · Cited by 370 · see citing works
Reaction between S-Nitrosothiols and Thiols: Generation of Nitroxyl (HNO) and Subsequent Chemistry
Wong, P. S.-Y., Hyun, J., Fukuto, J. M., Shirota, F. N., DeMaster, E. G., Shoeman, D. W., & Nagasawa, H. T. (1998) · Biochemistry · doi:10.1021/bi973153g · Cited by 363 · cited 3× · see citing works
“Indeed, the mechanism of irreversible inhibition of aldehyde dehydrogenase by HNO has been speculated to involve the presence of a sulfinamide [240,245].”
Background
Paradoxical fate and biological action of peroxynitrite on human platelets.
Moro, M. Á., Darley-Usmar, V. M., Goodwin, D. A., Read, N. G., Zamora-Pino, R., Feelisch, M., Radomski, M. W., & Moncada, S. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.14.6702 · Cited by 363 · cited 1× · see citing works
“Although the effect of RNS depends on the composition of the microenvironment in which this substance would be generated [84], this situation facilitates the induction of the permeability”
Background
Cell-Permeating α -Ketoglutarate Derivatives Alleviate Pseudohypoxia in Succinate Dehydrogenase-Deficient Cells
MacKenzie, E. D., Selak, M. A., Tennant, D. A., Payne, L. J., Crosby, S., Frederiksen, C. M., Watson, D. G., & Gottlieb, E. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.01927-06 · Cited by 359 · see citing works
Inhibition of Cytochromes P450 by Nitric Oxide and a Nitric Oxide-Releasing Agent
Wink, D. A., Osawa, Y., Darbyshire, J. F., Jones, C. R., Eshenaur, S. C., & Nims, R. W. (1993) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1993.1016 · Cited by 357 · see citing works
Self-citation
Sites of inhibition of mitochondrial electron transport in macrophage-injured neoplastic cells.
Granger, D. L., & Lehninger, A. L. (1982) · The Journal of Cell Biology · doi:10.1083/jcb.95.2.527 · Cited by 348 · cited 1× · see citing works
“They found that Complex I (NADH-coenzyme Q reductase) was most sensitive to inhibition, followed by Complex II (succinate-coenzyme Q reductase) [52].”
Background
The chemistry of nitroxyl (HNO) and implications in biology
Miranda, K. M. (2005) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2004.08.010 · Cited by 339 · cited 1× · see citing works
“Compared to NO and other RNS, HNO has a distinct signaling mechanism of action [242,243] and higher electrophilicity than NO [244].”
Background
Interferon Gamma Induces Reversible Metabolic Reprogramming of M1 Macrophages to Sustain Cell Viability and Pro-Inflammatory Activity
Wang, F., Zhang, S., Jeon, R., Vuckovic, I., Jiang, X., Lerman, A., Folmes, C. D., Dzeja, P. D., & Herrmann, J. (2018) · eBioMedicine · doi:10.1016/j.ebiom.2018.02.009 · Cited by 339 · cited 1× · see citing works
“IFNγ treatment alone, without LPS [170], or stimulation with monophospholipid A [171], or low LPS [112] does not result in the dramatic reductions in mitochondrial ATP production discussed above and in some circles maximal respiratory capacity (MRC) can actually increase early upon bacterial recognition [172].”
Background
Nitric Oxide Synthase Is Not a Constituent of the Antimicrobial Armature of Human Mononuclear Phagocytes
Schneemann, M., Schoedon, G., Hofer, S., Blau, N., Guerrero, L., & Schaffner, A. (1993) · The Journal of Infectious Diseases · doi:10.1093/infdis/167.6.1358 · Cited by 333 · see citing works
Comparative evaluation of itaconate and its derivatives reveals divergent inflammasome and type I interferon regulation in macrophages
Swain, A., Bambousková, M., Kim, H., Andhey, P. S., Duncan, D., Auclair, K., Chubukov, V., Simons, D. M., Roddy, T. P., Stewart, K. M., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0210-0 · Cited by 332 · cited 13× · see citing works
“However, we find that activation of NRF2 occurs regardless of intracellular availability of itaconate.”
BackgroundInfluential
Nitric Oxide Potently and Reversibly Deenergizes Mitochondria at Low Oxygen Tension
Schweizer, M., & Richter, C. (1994) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1994.2441 · Cited by 331 · see citing works
Regulation of nitric oxide synthase activity in human immunodeficiency virus type 1 (HIV-1)-infected monocytes: implications for HIV-associated neurological disease.
Bukrinsky, M., Nottet, H. S. L. M., Schmidtmayerova, H., Dubrovsky, L., Flanagan, C. R., Mullins, M. E., Lipton, S. A., & Gendelman, H. E. (1995) · The Journal of Experimental Medicine · doi:10.1084/jem.181.2.735 · Cited by 331 · see citing works
Nitric oxide and peroxynitrite exert distinct effects on mitochondrial respiration which are differentially blocked by glutathione or glucose
Lizasoaín, I., Moro, M. Á., Knowles, R. G., Darley-Usmar, V. M., & Moncada, S. (1996) · Biochemical Journal · doi:10.1042/bj3140877 · Cited by 318 · see citing works
Prolonged inhibition of muscle carnitine palmitoyltransferase-1 promotes intramyocellular lipid accumulation and insulin resistance in rats
Dobbins, R. L., Szczepaniak, L. S., Bentley, B., Esser, V., Myhill, J., & McGarry, J. D. (2001) · Diabetes · doi:10.2337/diabetes.50.1.123 · Cited by 315 · see citing works
Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense
Garaude, J., Acín-Pérez, R., Martínez-Cano, S., Enamorado, M., Ugolini, M., Nistal-Villán, E., Hervás-Stubbs, S., Pelegrín, P., Sander, L. E., Enríquez, J. A., et al. (2016) · Nature Immunology · doi:10.1038/ni.3509 · Cited by 313 · cited 1× · see citing works
“IFNγ treatment alone, without LPS [170], or stimulation with monophospholipid A [171], or low LPS [112] does not result in the dramatic reductions in mitochondrial ATP production discussed above and in some circles maximal respiratory capacity (MRC) can actually increase early upon bacterial recognition [172].”
Background
Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes
Lachmandas, E., Boutens, L., Ratter, J. M., Hijmans, A., Hooiveld, G. J. E. J., Joosten, L. A. B., Rodenburg, R. J., Fransen, J. A. M., Houtkooper, R. H., van Crevel, R., et al. (2016) · Nature Microbiology · doi:10.1038/nmicrobiol.2016.246 · Cited by 310 · cited 1× · see citing works
“Many studies have reported complex metabolic footprints in macrophages activated under different stimuli and tissue environments [168,169].”
Background
The Nucleotide Sensor ZBP1 and Kinase RIPK3 Induce the Enzyme IRG1 to Promote an Antiviral Metabolic State in Neurons
Daniels, B. P., Kofman, S. B., Smith, J. R., Norris, G. T., Snyder, A. G., Kolb, J. P., Gao, X., Locasale, J. W., Martinez, J., Gale, M., et al. (2019) · Immunity · doi:10.1016/j.immuni.2018.11.017 · Cited by 305 · see citing works
Triacylglycerol synthesis enhances macrophage inflammatory function
Castoldi, Â., Monteiro, L. D. B., Bakker, N. V. T., Sanin, D. E., Rana, N., Corrado, M., Cameron, A. M., Hässler, F., Matsushita, M., Caputa, G., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-17881-3 · Cited by 299 · cited 1× · see citing works
“Although DGAT1-dependent TG synthesis has recently been reported to enhance macrophage inflammatory function together with PGE2 signaling [197], this finding still lacks mechanistic understanding regarding its intrinsic connections to metabolic needs and cell function.”
Background
Production of nitric oxide in the synovial membrane of rheumatoid and osteoarthritis patients.
McInnes, I. B., Leung, B. P. L., Field, M., Wei, X., Huang, F., Sturrock, R. D., Kinninmonth, A. W. G., Weidner, J. R., Mumford, R. A., & Liew, F. Y. (1996) · The Journal of Experimental Medicine · doi:10.1084/jem.184.4.1519 · Cited by 288 · see citing works
Biological nitric oxide signalling: chemistry and terminology
Heinrich, T. A., da Silva, R. S., Miranda, K. M., Switzer, C., Wink, D. A., & Fukuto, J. M. (2013) · British Journal of Pharmacology · doi:10.1111/bph.12217 · Cited by 287 · cited 2× · see citing works
“Nitrosation requires NO+ donors since in solution, NO+ has an appreciable lifetime only under high acidic conditions [35].”
BackgroundSelf-citation
A biochemical rationale for the discrete behavior of nitroxyl and nitric oxide in the cardiovascular system
Miranda, K. M., Paolocci, N., Katori, T., Thomas, D. D., Ford, E., Bartberger, M. D., Espey, M. G., Kass, D. A., Feelisch, M., Fukuto, J. M., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1430507100 · Cited by 283 · cited 1× · see citing works
“Compared to NO and other RNS, HNO has a distinct signaling mechanism of action [242,243] and higher electrophilicity than NO [244].”
BackgroundSelf-citation
Nitric oxide prevents a pathogen-permissive granulocytic inflammation during tuberculosis
Mishra, B. B., Lovewell, R. R., Olive, A. J., Zhang, G., Wang, W., Eugenín, E. A., Smith, C. M., Phuah, J. Y., Long, J. E., Dubuke, M. L., et al. (2017) · Nature Microbiology · doi:10.1038/nmicrobiol.2017.72 · Cited by 280 · see citing works
Irg1 expression in myeloid cells prevents immunopathology during M. tuberculosis infection
Nair, S., Huynh, J. P., Lampropoulou, V., Loginicheva, E., Esaulova, E., Gounder, A. P., Boon, A. C. M., Schwarzkopf, E. A., Bradstreet, T. R., Edelson, B. T., et al. (2018) · Journal of Experimental Medicine · doi:10.1084/jem.20180118 · Cited by 280 · see citing works
The killing of Leishmania major by human macrophages is mediated by nitric oxide induced after ligation of the Fc epsilon RII/CD23 surface antigen.
Vouldoukis, I., Riveros‐Moreno, V., Dugas, B., Ouaaz, F., Bécherel, P., Debré, P., Moncada, S., & Mossalayi, M. D. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.17.7804 · Cited by 267 · see citing works
The Inhibition of Arginase by Nω-Hydroxy- l -Arginine Controls the Growth of Leishmania Inside Macrophages
Iniesta, V., Gómez-Nieto, L. C., & Corraliza, I. (2001) · The Journal of Experimental Medicine · doi:10.1084/jem.193.6.777 · Cited by 267 · cited 1× · see citing works
“Moreover, the NOS intermediate NOHA, supporting effective NO production by suppressing arginase activity freeing cellular arginine for NO production [139], has been shown to be critical in controlling parasites such as Leishmania [140].”
Background
Itaconic acid mediates crosstalk between macrophage metabolism and peritoneal tumors
Weiss, J. M., Davies, L. C., Karwan, M., Ileva, L., Ozaki, M. K., Cheng, R. Y. S., Ridnour, L. A., Annunziata, C. M., Wink, D. A., & McVicar, D. W. (2018) · Journal of Clinical Investigation · doi:10.1172/jci99169 · Cited by 267 · cited 1× · see citing works
“Itaconate production by the resident macrophages of the peritoneal cavity has also been shown to regulate their ROS production and facilitate their ability to promote tumor growth in this anatomical site [127].”
BackgroundSelf-citation
Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation
Bailey, J. D., Diotallevi, M., NICOL, T., McNeill, E., Shaw, A., Chuaiphichai, S., Hale, A., Starr, A., Nandi, M., Stylianou, E., et al. (2019) · Cell Reports · doi:10.1016/j.celrep.2019.06.018 · Cited by 266 · cited 20× · see citing works
“Cyt c, cytochrome c; FADH2, flavin-adenine dinucleotide reduced; NADH, nicotinamide adenine dinucleotide reduced; Q, ubiquinone; I, II, III, and IV refer to the complexes of ETC. ANT, adenosine nucleotide translocator.”
BackgroundMethodInfluential
Nitric oxide-mediated mitochondrial damage: A potential neuroprotective role for glutathione
Bolaños, J. P., Heales, S. J. R., Peuchen, S., Barker, J. E., Land, J. M., & Clark, J. B. (1996) · Free Radical Biology and Medicine · doi:10.1016/s0891-5849(96)00240-7 · Cited by 263 · see citing works
Nitrite Inhibition of Clostridium botulinum : Electron Spin Resonance Detection of Iron-Nitric Oxide Complexes
Reddy, D. S. A., Lancaster, J. R., & Cornforth, D. P. (1983) · Science · doi:10.1126/science.6308761 · Cited by 258 · cited 1× · see citing works
“Through Electron Spin Resonance, iron-nitric oxide complexes were detected in proteins in these cells [59].”
Background
Apoptosis-induced mitochondrial dysfunction causes cytoplasmic lipid droplet formation
Boren, J., & Brindle, K. M. (2012) · Cell Death and Differentiation · doi:10.1038/cdd.2012.34 · Cited by 255 · see citing works
Nitric Oxide Regulates Mitochondrial Fatty Acid Metabolism Through Reversible Protein S -Nitrosylation
Doulias, P.-T., Tenopoulou, M., Greene, J. L., Raju, K., & Ischiropoulos, H. (2013) · Science Signaling · doi:10.1126/scisignal.2003252 · Cited by 250 · cited 1× · see citing works
“Others have referred to evidence that many metabolic enzymes could be s-nitrosated by NO [143] and assumed that cysteine nitrosation could affect the activity of these enzymes in immune cells as well [144].”
Background
Mechanisms of triglyceride accumulation in activated macrophages
Feingold, K. R., Shigenaga, J. K., Kazemi, M. R., McDonald, C. M., Patzek, S. M., Cross, A. S., Moser, A. H., & Grünfeld, C. (2012) · Journal of Leukocyte Biology · doi:10.1189/jlb.1111537 · Cited by 249 · cited 3× · see citing works
“Therefore, the NO-dependent increased formation of lipid vesicles during macrophage activation may facilitate the production and storage of compounds important for subsequent effector function [156,194].”
Background
Leukocyte lipid bodies — Biogenesis and functions in inflammation
Bozza, P. T., Magalhães, K. G., & Weller, P. F. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids · doi:10.1016/j.bbalip.2009.01.005 · Cited by 245 · cited 1× · see citing works
“Therefore, the NO-dependent increased formation of lipid vesicles during macrophage activation may facilitate the production and storage of compounds important for subsequent effector function [156,194].”
Background
Trained Immunity: An Ancient Way of Remembering
Netea, M. G., & van der Meer, J. W. M. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.02.003 · Cited by 245 · cited 1× · see citing works
“Many studies have reported complex metabolic footprints in macrophages activated under different stimuli and tissue environments [168,169].”
Background
Nitric oxide in parasitic infections
Brunet, L. R. (2001) · International Immunopharmacology · doi:10.1016/s1567-5769(01)00090-x · Cited by 240 · cited 1× · see citing works
“In contrast to vascular integrity, the roles of NO in immunity involve it being a toxic agent towards infectious organisms [13,22,23], an inducer or suppressor of leukocyte apoptosis [24] or an immunoregulator [25–31].”
Background
Reaction of Superoxide and Nitric Oxide with Peroxynitrite
Jourd’heuil, D., Jourd’heuil, F. L., Kutchukian, P. S., Musah, R. A., Wink, D. A., & Grisham, M. B. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m102341200 · Cited by 239 · see citing works
Self-citation
Nitrite in Human Saliva. Its Possible Relationship to Nitrosamine Formation23
Tannenbaum, S. R., Sinskey, A. J., Weisman, M., & Bishop, W. (1974) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/53.1.79 · Cited by 237 · see citing works
Nitric oxide inhibition of respiration involves both competitive (heme) and noncompetitive (copper) binding to cytochrome c oxidase
Mason, M. G., Nicholls, P., Wilson, M. T., & Cooper, C. E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0506562103 · Cited by 233 · see citing works
A broken Krebs cycle in macrophages
O’Neill, L. A. J. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.017 · Cited by 232 · cited 5× · see citing works
“These findings led to the suggestion that in polarized macrophages, pseudo-hypoxia, caused by reduction in α-KG /succinate ratios and suppression of dioxygenase activity [113,114], leads to HIF1α stabilization and expression of Pyruvate Dehydrogenase Kinase 1 (Pdk1) that phosphorylates Pyruvate Dehydrogenase (PDH), re…”
BackgroundInfluential
The Immunomodulatory Potential of the Metabolite Itaconate
Hooftman, A., & O'Neill, L. A. J. (2019) · Trends in Immunology · doi:10.1016/j.it.2019.05.007 · Cited by 232 · cited 1× · see citing works
“The biology and biochemistry of itaconate has been recently reviewed in detail by others [128,129].”
Background
Human and murine macrophages exhibit differential metabolic responses to lipopolysaccharide - A divergent role for glycolysis
Vijayan, V., Pradhan, P., Braud, L., Fuchs, H. R., Gueler, F., Motterlini, R., Foresti, R., & Immenschuh, S. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101147 · Cited by 231 · cited 1× · see citing works
“For example, the mitochondrial bioenergetic changes observed in murine M1 polarized BMDMs are largely absent in similarly stimulated human PBMC-derived macrophages [100,226].”
Background
MYC inhibition induces metabolic changes leading to accumulation of lipid droplets in tumor cells
Zirath, H., Frenzel, A., Oliynyk, G., Segerström, L., Westermark, U., Larsson, K., Persson, M. M., Hultenby, K. R., Lehtiö, J., Einvik, C., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1222404110 · Cited by 229 · see citing works
Nitric Oxide, Cytochrome C Oxidase, and the Cellular Response to Hypoxia
Taylor, C. T., & Moncada, S. (2010) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.108.181628 · Cited by 220 · cited 1× · see citing works
“Although the mechanism of A/D transition may only operate in pathological conditions, when enzyme turnover is limited by hypoxia or by a high NO/O2 ratios [92,162], we suggested that it is the lack of substrates, (i.”
Background
Immune‐Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2–Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia–Reperfusion Injury
Yi, Z., Deng, M., Scott, M. J., Fu, G., Loughran, P., Lei, Z., Li, S., Sun, P., Yang, C., Li, W., et al. (2020) · Hepatology · doi:10.1002/hep.31147 · Cited by 216 · see citing works
Molecular Mechanisms of Nitric Oxide in Cancer Progression, Signal Transduction, and Metabolism
Somasundaram, V., Basudhar, D., Bharadwaj, G., No, J. H., Ridnour, L. A., Cheng, R. Y. S., Fujita, M., Thomas, D. D., Anderson, S. K., McVicar, D. W., et al. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2018.7527 · Cited by 215 · cited 4× · see citing works
“Superoxide is generated within complexes I and III as byproduct of mitochondrial electron transfer which, if not consumed by mitochondrial manganese-dependent SOD (MnSOD) [77,78], can react with NO to form ONOO− which is rapidly converted to NO2 and N2O3 [34].”
BackgroundInfluentialSelf-citation
On the expression of nitric oxide synthase by human macrophages. Why no NO?
Albina, J. E. (1995) · Journal of Leukocyte Biology · doi:10.1002/jlb.58.6.643 · Cited by 213 · see citing works
Hypoxia stimulates release of endothelium-derived relaxant factor
Pohl, U., & Busse, R. (1989) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.1989.256.6.h1595 · Cited by 207 · cited 1× · see citing works
“As reduced supplies of O2 will make endogenous NO even more effective at inhibiting cytochrome c oxidase [48], this might indeed be a mechanism in the microcirculation by which NO, sensing hypoxia, diverts O2 into adjacent issues and at the same time induces vasodilation in an attempt to improve tissue perfusion [45].”
Background
Inhibition of cytochrome c oxidase in turnover by nitric oxide: mechanism and implications for control of respiration
Torres, J., Darley-Usmar, V. M., & Wilson, M. T. (1995) · Biochemical Journal · doi:10.1042/bj3120169 · Cited by 206 · cited 1× · see citing works
“In later studies, NO was found to bind and dissociate very rapidly from the enzyme [40,41].”
Background
Immunocytochemical Characterization of the Expression of Inducible and Constitutive Isoforms of Nitric Oxide Synthase in Demyelinating Multiple Sclerosis Lesions
Groot, C. J. A. D., Ruuls, S. R., THEEUWES, J. W. M., Dijkstra, C. D., & van der Valk, P. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199701000-00002 · Cited by 205 · see citing works
Catalytic properties of the mitochondrial NADH–ubiquinone oxidoreductase (Complex I) and the pseudo-reversible active/inactive enzyme transition
Vinogradov, A. D. (1998) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/s0005-2728(98)00026-7 · Cited by 202 · cited 3× · see citing works
“Deactive or dormant (D) enzyme is reactivated by a pulse of NADH, when the enzyme undergoes one or several slow turnovers or chemical conversions as NADH is oxidized and ubiquinone is reduced [87].”
Background
Subcompartments of the macrophage recycling endosome direct the differential secretion of IL-6 and TNFα
Manderson, A. P., Kay, J. G., Hammond, L. A., Brown, D. L., & Stow, J. L. (2007) · The Journal of Cell Biology · doi:10.1083/jcb.200612131 · Cited by 198 · cited 1× · see citing works
“Unlike the NOS2− and NO-independent lipogenesis of species like phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI) which is important to support the need of cytokine secretion within the ER and Golgi network [195,196], the role of TG synthesis via DGAT1 is less clear.”
Background
Resistance to Leishmania major infection correlates with the induction of nitric oxide synthase in murine macrophages
Liew, F. Y., Li, Y., Moss, D., Parkinson, C., Rogers, M. V., & Moncada, S. (1991) · European Journal of Immunology · doi:10.1002/eji.1830211216 · Cited by 197 · see citing works
Activation of human macrophages for the killing of intracellular Trypanosoma cruzi by TNF-α and IFN-γ through a nitric oxide-dependent mechanism
Muñoz‐Fernández, M. Á., Fernández, M. A., & Fresno, M. (1992) · Immunology Letters · doi:10.1016/0165-2478(92)90090-b · Cited by 197 · see citing works
Oxidative stress and S‐nitrosylation of proteins in cells
Beltrán, B., Orsi, A., Clementi, E., & Moncada, S. (2000) · British Journal of Pharmacology · doi:10.1038/sj.bjp.0703147 · Cited by 196 · cited 1× · see citing works
“transition pore (PTP), which leads to the collapse of the membrane potential, mitochondrial swelling, outer mitochondrial membrane rupture, release of mitochondrial pro-apoptotic factors, and cell death [85] (Figure 2b).”
Background
Inducible nitric oxide synthase in the liver: regulation and function.
Taylor, B. S., Alarcon, L. H., & Billiar, T. R. (1998) · PubMed · Cited by 195 · see citing works
Aconitase post-translational modification as a key in linkage between Krebs cycle, iron homeostasis, redox signaling, and metabolism of reactive oxygen species
Lushchak, O. V., Piroddi, M., Galli, F., & Lushchak, V. I. (2013) · Redox Report · doi:10.1179/1351000213y.0000000073 · Cited by 195 · see citing works
Neuronal Nitric Oxide Synthase Self-inactivates by Forming a Ferrous-Nitrosyl Complex during Aerobic Catalysis
Abu‐Soud, H. M., Wang, J., Rousseau, D. L., Fukuto, J. M., Ignarro, L. J., & Stuehr, D. J. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.39.22997 · Cited by 193 · see citing works
Cytokine Secretion in Macrophages: SNAREs, Rabs, and Membrane Trafficking
Murray, R. Z., & Stow, J. L. (2014) · Frontiers in Immunology · doi:10.3389/fimmu.2014.00538 · Cited by 190 · cited 1× · see citing works
“Unlike the NOS2− and NO-independent lipogenesis of species like phosphatidylcholine (PC), phosphatidylethanolamine (PE), and phosphatidylinositol (PI) which is important to support the need of cytokine secretion within the ER and Golgi network [195,196], the role of TG synthesis via DGAT1 is less clear.”
Background
Role of nitric oxide in lysis of tumor cells by cytokine-activated endothelial cells.
Li, L. M., Kilbourn, R. G., Adams, J. M., & Fidler, I. J. (1991) · PubMed · Cited by 189 · see citing works
NITRIC OXIDE—A NEW ENDOGENOUS IMMUNOMODULATOR
Langrehr, J. M., HOFFMAN, R. A., Lancaster, J. R., & Simmons, R. L. (1993) · Transplantation · doi:10.1097/00007890-199306000-00001 · Cited by 187 · see citing works
IFN-γ-activated macrophages: Detection by electron paramagnetic resonance of complexes between L-Arginine-derived nitric oxide and non-heme iron proteins
Pellat‐Deceunynck, C., Henry, Y. A., & Drapier, J. (1990) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(90)91919-j · Cited by 185 · cited 1× · see citing works
“This work led to the conclusion that inhibition of mitochondrial non-heme iron-dependent enzymes in macrophages is mediated by autologous NO binding to enzymes containing iron-prosthetic groups [67,70].”
Background
Sustained Generation of Nitric Oxide and Control of Mycobacterial Infection Requires Argininosuccinate Synthase 1
Qualls, J. E., Subramanian, C., Rafi, W., Smith, A. M., Balouzian, L., DeFreitas, A. A., Shirey, K. A., Reutterer, B., Kernbauer, E., Stockinger, S., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.07.012 · Cited by 184 · see citing works
Cutting Edge: Nitric Oxide Inhibits the NLRP3 Inflammasome
Hernandez-Cuellar, E., Tsuchiya, K., Hara, H., Fang, R., Sakai, S., Kawamura, I., Akira, S., & Mitsuyama, M. (2012) · The Journal of Immunology · doi:10.4049/jimmunol.1202479 · Cited by 184 · see citing works
Injury of neoplastic cells by murine macrophages leads to inhibition of mitochondrial respiration.
Granger, D. L., Taintor, R. R., Cook, J. L., & Hibbs, J. B. (1980) · Journal of Clinical Investigation · doi:10.1172/jci109679 · Cited by 180 · cited 1× · see citing works
“Reports from 1980 began to show that incubation of a variety of neoplastic cell types with cytotoxic macrophage-conditional medium (CM) leads to inhibition of target cell mitochondrial respiration by as much as 80–90% [51].”
Background
Increased exhaled nitric oxide in active pulmonary tuberculosis due to inducible NO synthase upregulation in alveolar macrophages
Wang, C., Liu, C. Y., Lin, H.-C., Yu, C.-T., Chung, K. F., & Kuo, H.-P. (1998) · European Respiratory Journal · doi:10.1183/09031936.98.11040809 · Cited by 176 · see citing works
Triggering of human monocyte activation through CD69, a member of the natural killer cell gene complex family of signal transducing receptors.
Maria, R. D., Cifone, M. G., Trotta, R., Rippo, M. R., Festuccia, C., Santoni, A., & Testi, R. (1994) · The Journal of Experimental Medicine · doi:10.1084/jem.180.5.1999 · Cited by 176 · see citing works
Two-stage metabolic remodelling in macrophages in response to lipopolysaccharide and interferon-γ stimulation
Seim, G. L., Britt, E. C., John, S. V., Yeo, F. J., Johnson, A. R., Eisenstein, R. S., Pagliarini, D. J., & Fan, J. (2019) · Nature Metabolism · doi:10.1038/s42255-019-0083-2 · Cited by 174 · cited 21× · see citing works
“concluded that that mechanism only partially reduces the flux through PDH [153].”
BackgroundInfluential
Mechanisms of Inhibition of Aldehyde Dehydrogenase by Nitroxyl, the Active Metabolite of the Alcohol Deterrent Agent Cyanamide
DeMaster, E. G., Redfern, B., & Nagasawa, H. T. (1998) · Biochemical Pharmacology · doi:10.1016/s0006-2952(98)00080-x · Cited by 173 · cited 1× · see citing works
“Indeed, the mechanism of irreversible inhibition of aldehyde dehydrogenase by HNO has been speculated to involve the presence of a sulfinamide [240,245].”
Background
Sorting cells alters their redox state and cellular metabolome
Llufrio, E. M., Wang, L., Naser, F. J., & Patti, G. J. (2018) · Redox Biology · doi:10.1016/j.redox.2018.03.004 · Cited by 172 · cited 1× · see citing works
“Given known metabolic plasticity in vivo and reports that redox states and metabolomes are altered during ex vivo manipulations [228], our in vivo study [109] of a modified Schwartzman-like reaction has important implications for the understanding of the regulation of immunity and disease pathogenesis.”
Background
The Fpg protein, a DNA repair enzyme, is inhibited by the biomediator nitric oxide in vitro and in vivo
Wink, D. A., & Laval, J. (1994) · Carcinogenesis · doi:10.1093/carcin/15.10.2125 · Cited by 167 · see citing works
Self-citation
Analysis of Nitric Oxide Synthase and Nitrotyrosine Expression in Human Pulmonary Tuberculosis
Choi, H.-S., Rai, P. R., Chu, H. W., Cool, C. D., & Chan, E. D. (2002) · American Journal of Respiratory and Critical Care Medicine · doi:10.1164/rccm.2201023 · Cited by 161 · see citing works
Inducible nitric oxide synthase-derived nitric oxide in gene regulation, cell death and cell survival
Kröncke, K., Fehsel, K., Suschek, C. V., & Kolb-Bachofen, V. (2001) · International Immunopharmacology · doi:10.1016/s1567-5769(01)00087-x · Cited by 161 · cited 1× · see citing works
“In contrast to vascular integrity, the roles of NO in immunity involve it being a toxic agent towards infectious organisms [13,22,23], an inducer or suppressor of leukocyte apoptosis [24] or an immunoregulator [25–31].”
Background
Nitric Oxide-induced Transcriptional Up-regulation of Protective Genes by Nrf2 via the Antioxidant Response Element Counteracts Apoptosis of Neuroblastoma Cells
Dhakshinamoorthy, S., & Porter, A. G. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m312492200 · Cited by 159 · see citing works
Nitric oxide activates Nrf2 through S-nitrosylation of Keap1 in PC12 cells
Um, H.-C., Jang, J.-H., Kim, D.-H., Lee, C., & Surh, Y.-J. (2011) · Nitric Oxide · doi:10.1016/j.niox.2011.06.001 · Cited by 153 · cited 1× · see citing works
“Ongoing expression analysis and targeted metabolomics in BMDM from Acod1−/−, Nos2−/−, and double knockouts mice and the use of NO donors will likely definitively find that the NRF2 pathway is driven directly by NO as has been suggested for other cell types [193].”
Background
Nitric oxide stimulates Nrf2 nuclear translocation in vascular endothelium
Buckley, B. J., Marshall, Z. M., & Whorton, A. R. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01308-1 · Cited by 152 · see citing works
Signaling and stress: The redox landscape in NOS2 biology
Thomas, D. D., Heinecke, J. L., Ridnour, L. A., Cheng, R. Y., Kesarwala, A. H., Switzer, C. H., McVicar, D. W., Roberts, D. D., Glynn, S., Fukuto, J. M., et al. (2015) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2015.06.002 · Cited by 150 · cited 5× · see citing works
“The rate constant for association of NO to heme centers is typically very high relative to other potential targets [20], such that even low nanomolar levels of NO are sufficient to activate sGC [21].”
BackgroundInfluentialSelf-citation
Regulation of iNOS function and cellular redox state by macrophage Gch1 reveals specific requirements for tetrahydrobiopterin in NRF2 activation
McNeill, E., Crabtree, M. J., Sahgal, N., Patel, J., Chuaiphichai, S., Iqbal, A. J., Hale, A., Greaves, D. R., & Channon, K. M. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.10.575 · Cited by 150 · cited 4× · see citing works
“Moreover, Bailey et al. observed increased transcription of Il1b, and although HIF1α can transcriptionally regulate Il1b, both labs concluded that HIF1α was not responsible for their findings.”
BackgroundInfluential
Identification of the Mitochondrial ND3 Subunit as a Structural Component Involved in the Active/Deactive Enzyme Transition of Respiratory Complex I
Galkin, A., Meyer, B., Wittig, I., Karas, M., Schägger, H., Vinogradov, A., & Brandt, U. (2008) · Journal of Biological Chemistry · doi:10.1074/jbc.m803190200 · Cited by 147 · see citing works
On the Mechanism of Inhibition of Cytochrome c Oxidase by Nitric Oxide
Giuffrè, A., Sarti, P., D’Itri, E., Buse, G., Soulimane, T., & Brunori, M. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.52.33404 · Cited by 144 · see citing works
Regulation of mitochondrial processes by protein S-nitrosylation
Piantadosi, C. A. (2011) · Biochimica et Biophysica Acta (BBA) - General Subjects · doi:10.1016/j.bbagen.2011.03.008 · Cited by 144 · cited 1× · see citing works
“Older reports on the E3 of PDH support its targeting by nitroxyl (HNO) or peroxynitrite [154,155].”
Background
Epigenetic Silencing of the Human NOS2 Gene: Rethinking the Role of Nitric Oxide in Human Macrophage Inflammatory Responses
Gross, T. J., Kremens, K., Powers, L. S., Brink, B., Knutson, T. M., Domann, F. E., Philibert, R. A., Milhem, M. M., & Monick, M. M. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1301758 · Cited by 139 · see citing works
Oxidized Mitochondrial Protein Degradation and Repair in Aging and Oxidative Stress
Ugarte, N., Petropoulos, I., & Friguet, B. (2009) · Antioxidants and Redox Signaling · doi:10.1089/ars.2009.2998 · Cited by 136 · see citing works
Human Alveolar and Peritoneal Macrophages Mediate Fungistasis Independently of L-Arginine Oxidation to Nitrite or Nitrate
Cameron, M. L., Granger, D. L., Weinberg, J. B., Kozumbo, W. J., & Koren, H. S. (1990) · American Review of Respiratory Disease · doi:10.1164/ajrccm/142.6_pt_1.1313 · Cited by 135 · cited 1× · see citing works
“An alternative hypothesis was that human monocytes/macrophages cannot synthesize tetrahydrobiopterin, an essential co-factor for iNOS activity and, thus, needed to acquire it from other cells, such as lymphocytes [218,219].”
Background
Characterisation of the active/de-active transition of mitochondrial complex I
Babot, M., Birch, A., Labarbuta, P., & Galkin, A. S. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.02.018 · Cited by 133 · cited 2× · see citing works
“In brief, the enzyme spontaneously converts into the D-form after exposure to high physiological temperatures (>30 °C) or in the absence of substrate [86,87].”
Background
Lack of Oxygen Deactivates Mitochondrial Complex I
Galkin, A. S., Abramov, A. Y., Frakich, N., Duchen, M. R., & Moncada, S. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.054346 · Cited by 131 · see citing works
Nitric oxide and T helper cell immunity
van der Veen, R. C. (2001) · International Immunopharmacology · doi:10.1016/s1567-5769(01)00093-5 · Cited by 131 · see citing works
The reemergence of nitric oxide and cancer
Wink, D. A., Ridnour, L. A., Hussain, S. P., & Harris, C. C. (2008) · Nitric Oxide · doi:10.1016/j.niox.2008.05.003 · Cited by 130 · see citing works
Self-citation
Biosynthesis and metabolism of pterins in peripheral blood mononuclear cells and leukemia lines of man and mouse
Schoedon, G., Troppmair, J., FONTANA, A., Huber, C., Curtius, H., & Niederwieser, A. (1987) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1987.tb13515.x · Cited by 130 · cited 1× · see citing works
“An alternative hypothesis was that human monocytes/macrophages cannot synthesize tetrahydrobiopterin, an essential co-factor for iNOS activity and, thus, needed to acquire it from other cells, such as lymphocytes [218,219].”
Background
Direct Evidence of Nitric Oxide Presence within Mitochondria
López-Figueroa, M. O., Caamaño, C. A., Morano, M. I., Rønn, L. C. B., Akil, H., & Watson, S. J. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2748 · Cited by 124 · see citing works
S-Nitrosation of Mitochondrial Complex I Depends on Its Structural Conformation
Galkin, A., & Moncada, S. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m707543200 · Cited by 122 · cited 2× · see citing works
“Re-activation of the D form by NADH was inhibited by nitrosothiols and peroxynitrite whilst the A form was insensitive to such treatment [92].”
Background
Superoxide fluxes limit nitric oxide-induced signaling
Thomas, D. D., Ridnour, L. A., Espey, M. G., Donzelli, S., Ambs, S., Hussain, S. P., Harris, C. C., DeGraff, W., Roberts, D. D., Mitchell, J. B., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602242200 · Cited by 121 · cited 1× · see citing works
“Superoxide is generated within complexes I and III as byproduct of mitochondrial electron transfer which, if not consumed by mitochondrial manganese-dependent SOD (MnSOD) [77,78], can react with NO to form ONOO− which is rapidly converted to NO2 and N2O3 [34].”
BackgroundSelf-citation
Nitric oxide stimulates heme oxygenase-1 gene transcription via the Nrf2/ARE complex to promote vascular smooth muscle cell survival
LIU, X., Peyton, K. J., Ensenat, D., WANG, H., HANNINK, M., Alam, J., & Durante, W. (2007) · Cardiovascular Research · doi:10.1016/j.cardiores.2007.03.004 · Cited by 120 · see citing works
Evaluation of nitrite production by human monocyte-derived macrophages
Padgett, E. L., & Pruett, S. B. (1992) · Biochemical and Biophysical Research Communications · doi:10.1016/0006-291x(92)90813-z · Cited by 118 · see citing works
Superoxide production by mitochondria in the presence of nitric oxide forms peroxynitrite
Packer, M. A., Porteous, C. M., & Murphy, M. P. (1996) · IUBMB Life · doi:10.1080/15216549600201103 · Cited by 118 · see citing works
Mechanistic Target of Rapamycin Inhibition Extends Cellular Lifespan in Dendritic Cells by Preserving Mitochondrial Function
Amiel, E., Everts, B., Fritz, D. I., Beauchamp, S., Ge, B., Pearce, E. L., & Pearce, E. J. (2014) · The Journal of Immunology · doi:10.4049/jimmunol.1302498 · Cited by 116 · cited 1× · see citing works
“This second wave of glycolytic induction is mediated in DCs by mTOR/ HIF1α /NOS2 [142,146].”
Background
Autocrine IL-10 functions as a rheostat for M1 macrophage glycolytic commitment by tuning nitric oxide production
Baseler, W. A., Davies, L. C., Quigley, L., Ridnour, L. A., Weiss, J. M., Hussain, S. P., Wink, D. A., & McVicar, D. W. (2016) · Redox Biology · doi:10.1016/j.redox.2016.09.005 · Cited by 113 · cited 2× · see citing works
“[151] also exposed apparent incongruences with studies indicating that HIF1α-dependent upregulation of Pdk1 and consequent suppression of acetyl-CoA synthesis, may be responsible for OXPHOS regulation in macrophages [152].”
BackgroundSelf-citation
In Vivo Study Of Tissue Oxygen Metabolism Using Optical And Nuclear Magnetic Resonance Spectroscopies
Tamura, M., Hazeki, O., Nioka, S., & Chance, B. (1989) · Annual Review of Physiology · doi:10.1146/annurev.ph.51.030189.004121 · Cited by 111 · cited 1× · see citing works
“Intracellularly, the concentration of O2 has been reported to be as low as 10 μM [42].”
Background
Coexpression of NOS2 and COX2 accelerates tumor growth and reduces survival in estrogen receptor-negative breast cancer
Basudhar, D., Glynn, S. A., Greer, M., Somasundaram, V., No, J. H., Scheiblin, D. A., Garrido, P., Heinz, W. F., Ryan, A. E., Weiss, J. M., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1709119114 · Cited by 110 · cited 1× · see citing works
“Although human endothelial cells, hepatocytes, and other non-myeloid human cell types [198] have been shown to readily express NOS2 [199] and produce substantial fluxes of NO, many authors have reported limited induction of iNOS in human monocytes/macrophages causing continued controversy regarding the role of NO in h…”
BackgroundSelf-citation
Nitric oxide activation of Keap1/Nrf2 signaling in human colon carcinoma cells
Li, C.-Q., Kim, M. Y., Godoy, L. C., Thiantanawat, A., Trudel, L. J., & Wogan, G. N. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907539106 · Cited by 108 · see citing works
NG-hydroxy- l -arginine and nitric oxide inhibit Caco-2 tumor cell proliferation by distinct mechanisms
Buga, G. M., Liu, W., Bauer, P. M., Fukuto, J. M., & Ignarro, L. J. (1998) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.1998.275.4.r1256 · Cited by 108 · see citing works
The role of nitric oxide in metabolic regulation of Dendritic cell immune function
Thwe, P. M., & Amiel, E. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.10.032 · Cited by 107 · cited 2× · see citing works
“This phenomenon has led many researchers to assume that HIF1α is critically required for DC glycolytic reprogramming, when in fact this is only the case for the sustained commitment to glycolysis observed in NO-producing DCs [145].”
Background
Mitochondrial hyperpolarization during chronic complex I inhibition is sustained by low activity of complex II, III, IV and V
Forkink, M., Manjeri, G. R., Liemburg-Apers, D. C., Nibbeling, E. A. R., Blanchard, M. G., Wojtala, A., Smeitink, J. A. M., Wieckowski, M. R., Willems, P. H. G. M., & Koopman, W. J. H. (2014) · Biochimica et Biophysica Acta (BBA) - Bioenergetics · doi:10.1016/j.bbabio.2014.04.008 · Cited by 106 · cited 1× · see citing works
“They align perfectly with a model where the hyperpolarization of mitochondrial membranes, the condition where the mitochondrial inner membrane becomes more negative on the matrix side [148,149], is induced by NO initially blocking Complex IV and favoring hydrolysis of glycolytically-derived ATP [80,150] (Figure 2a).”
Background
Targeting Tumor Perfusion and Oxygenation to Improve the Outcome of Anticancer Therapy1
Jordan, B. F., & Sonveaux, P. (2012) · Frontiers in Pharmacology · doi:10.3389/fphar.2012.00094 · Cited by 104 · see citing works
Hypoxia-driven immunosuppression: A new reason to use thermal therapy in the treatment of cancer?
Lee, C.-T., Mace, T. A., & Repasky, E. A. (2010) · International Journal of Hyperthermia · doi:10.3109/02656731003601745 · Cited by 102 · cited 1× · see citing works
“Of consequence, the increased available pO2 associated with elevated NO levels can affect the immune response [234].”
Background
HIF1α-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection
Li, C., Wang, Y., Li, Y., Yu, Q., Jin, X., Wang, X., Jia, A., Hu, Y., Han, L., Wang, J., et al. (2018) · Scientific Reports · doi:10.1038/s41598-018-22039-9 · Cited by 101 · cited 1× · see citing works
“The result is so called M1, proinflammatory macrophages, which demonstrate reduced mitochondrial activity together with substantial upregulation of glycolytic metabolism for the fast generation of ATP needed to sustain phagocytosis and microbial killing [102,104,105].”
Background
Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway
Kolb, J., Paul‐Eugène, N., Damais, C., Yamaoka, K. A., Drapier, J., & Dugas, B. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)36955-7 · Cited by 100 · see citing works
Mössbauer studies of aconitase. Substrate and inhibitor binding, reaction intermediates, and hyperfine interactions of reduced 3Fe and 4Fe clusters.
Kent, T. A., Emptage, M. H., Merkle, H., Kennedy, M. C., Beinert, H., & Münck, E. (1985) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)88861-5 · Cited by 100 · see citing works
The TLR4 Agonist Monophosphoryl Lipid A Drives Broad Resistance to Infection via Dynamic Reprogramming of Macrophage Metabolism
Fensterheim, B. A., Young, J. D., Luan, L., Kleinbard, R. R., Stothers, C. L., Patil, N. K., Pereira, A. G. M., Guo, Y., Trenary, I. A., Hernandez, A., et al. (2018) · The Journal of Immunology · doi:10.4049/jimmunol.1800085 · Cited by 99 · cited 1× · see citing works
“IFNγ treatment alone, without LPS [170], or stimulation with monophospholipid A [171], or low LPS [112] does not result in the dramatic reductions in mitochondrial ATP production discussed above and in some circles maximal respiratory capacity (MRC) can actually increase early upon bacterial recognition [172].”
Background
Intraphagosomal Measurement of the Magnitude and Duration of the Oxidative Burst
VanderVen, B. C., Yates, R. M., & Russell, D. G. (2009) · Traffic · doi:10.1111/j.1600-0854.2009.00877.x · Cited by 98 · see citing works
Role of nitric oxide in Sjögren's syndrome
Konttinen, Y. T., Platts, L. A. M., Tuominen, S., Eklund, K. K., Santavirta, N., Törnwall, J., Sorsa, T. A., Hukkanen, M., & Polak, J. M. (1997) · Arthritis & Rheumatism · doi:10.1002/art.1780400515 · Cited by 98 · see citing works
Nitric Oxide Generated by Tumor-Associated Macrophages Is Responsible for Cancer Resistance to Cisplatin and Correlated With Syntaxin 4 and Acid Sphingomyelinase Inhibition
Perrotta, C., Cervia, D., Renzo, I. D., Moscheni, C., Bassi, M. T., Campana, L., Martelli, C., Catalani, E., Giovarelli, M., Zecchini, S., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.01186 · Cited by 98 · cited 1× · see citing works
“Therapeutically shifting the TME from tumorigenic simmering iNOS activity driven by the tumor itself, towards an immune surveillance situation where macrophages are reprogrammed to produce higher, effector level, NO fluxes could be beneficial [237,238].”
Background

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Macrophages in immunoregulation and therapeutics
Chen, S., Saeed, A. F. U. H., Liu, Q., Jiang, Q., Xu, H., Xiao, G. G., Rao, L., & Duo, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01452-1 · Cited by 2,348 · see citing works
Macrophage plasticity: signaling pathways, tissue repair, and regeneration
Yan, L., Wang, J., Cai, X., Liou, Y., Shen, H., Hao, J., Huang, C., Luo, G., & He, W. (2024) · MedComm · doi:10.1002/mco2.658 · Cited by 396 · see citing works
Macrophage Reprogramming and Cancer Therapeutics: Role of iNOS-Derived NO
Kashfi, K., Kannikal, J. J., & Nath, N. (2021) · Cells · doi:10.3390/cells10113194 · Cited by 236 · see citing works
“If the cell situation could be altered such that the TME’s low iNOS activity is reprogrammed to produce higher iNOS/NO concentrations, it may then be of therapeutic value [74,75].”
Background
Role of metabolic reprogramming in pro-inflammatory cytokine secretion from LPS or silica-activated macrophages
Marrocco, A., & Ortiz, L. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.936167 · Cited by 166 · see citing works
The Role of Reactive Species on Innate Immunity
Andrés, C., Pérez de la Lastra, J., Juan, C., Plou, F., & Pérez-Lebeña, E. (2022) · Vaccines · doi:10.3390/vaccines10101735 · Cited by 142 · see citing works
“The •NO/ROS balance is also important during the transition from Th1 to Th2 [125,126].”
Background
Duplex metal co-doped carbon quantum dots-based drug delivery system with intelligent adjustable size as adjuvant for synergistic cancer therapy
Han, C., Zhang, X., Wang, F., Yu, Q., Chen, F., Shen, D., Yang, Z., Wang, T., Jiang, M., Deng, T., et al. (2021) · Carbon · doi:10.1016/j.carbon.2021.07.063 · Cited by 135 · see citing works
An Overview of NO Signaling Pathways in Aging
Pourbagher-Shahri, A. M., Farkhondeh, T., Talebi, M., Kopustinskiene, D. M., Samarghandian, S., & Bernatoniene, J. (2021) · Molecules · doi:10.3390/molecules26154533 · Cited by 101 · see citing works
Tenebrio molitor as a source of interesting natural compounds, their recovery processes, biological effects, and safety aspects
Errico, S., Spagnoletta, A., Verardi, A., Moliterni, S., Dimatteo, S., & Sangiorgio, P. (2021) · Comprehensive Reviews in Food Science and Food Safety · doi:10.1111/1541-4337.12863 · Cited by 100 · see citing works
Redox regulation of macrophages
Tran, N., & Mills, E. L. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103123 · Cited by 97 · see citing works
“S cluster (see reviews [65,93] for further discussion).”
Background
Arginine metabolism in myeloid cells in health and disease
Karadima, E., Chavakis, T., & Alexaki, V. I. (2025) · Seminars in Immunopathology · doi:10.1007/s00281-025-01038-9 · Cited by 83 · see citing works
“Aside from its function in elimination of bacteria, NO exerts numerous functions within macrophages and their surrounding micro-environment [37].”
Modulation of macrophage metabolism as an emerging immunotherapy strategy for cancer
Dussold, C., Zilinger, K., Turunen, J. R., Heimberger, A. B., & Miska, J. M. (2024) · Journal of Clinical Investigation · doi:10.1172/jci175445 · Cited by 78 · see citing works
“These changes, which are mediated by LPS, promote inflammatory polarization, which leads to increased cytokine and NO production by macrophages (128).”
Modulating Nitric Oxide: Implications for Cytotoxicity and Cytoprotection
Belenichev, I. F., Popazova, O., Bukhtiyarova, N. V., Savchenko, D., Oksenych, V., & Kamyshnyi, O. (2024) · Antioxidants · doi:10.3390/antiox13050504 · Cited by 80 · see citing works
Effect of micro- and nanoplastic particles on human macrophages
Adler, M. Y., Issoual, I., Rückert, M., Deloch, L., Meier, C., Tschernig, T., Alexiou, C., Pfister, F., Ramsperger, A. F. R. M., Laforsch, C., et al. (2024) · Journal of Hazardous Materials · doi:10.1016/j.jhazmat.2024.134253 · Cited by 69 · see citing works
Structure characteristics and immunomodulatory activities of a polysaccharide RGRP-1b from radix ginseng Rubra
Zhang, X., Liu, Z., Zhong, C., Pu, Y., Yang, Z., & Bao, Y. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.08.176 · Cited by 64 · see citing works
Immune-Enhancing Effects of a Novel Glucan from Purple Sweet Potato Ipomoea batatas (L.) Lam on RAW264.7 Macrophage Cells via TLR2- and TLR4-Mediated Pathways
Ji, C., Zhang, Z., Chen, J., Song, D., Liu, B., Li, J., Liu, R., Niu, J., Wang, D., Ling, N., et al. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.1c03850 · Cited by 61 · see citing works
Syzygium aromaticum enhances innate immunity by triggering macrophage M1 polarization and alleviates Helicobacter pylori-induced inflammation
Peng, C., Feng, Z., Ou, L., Zou, Y., Sang, S., Liu, H., Zhu, W., Gan, G., Zhang, G., & Yao, M. (2023) · Journal of Functional Foods · doi:10.1016/j.jff.2023.105626 · Cited by 57 · see citing works
Pyruvate dehydrogenase operates as an intramolecular nitroxyl generator during macrophage metabolic reprogramming
Palmieri, E. M., Holewinski, R. J., McGinity, C. L., Pierri, C. L., Maio, N., Weiss, J. M., Tragni, V., Miranda, K. M., Rouault, T. A., Andrésson, Þ., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-40738-4 · Cited by 57 · see citing works
“In addition, NO suppresses mitochondrial aconitase (ACO2) activity, leading to the accumulation of citrate, which upon export to the cytoplasm supports in ﬂ ammatory lipid production 6 – 8 .”
Self-citation
Immunoregulatory effects of Tetrastigma hemsleyanum polysaccharide via TLR4-mediated NF-κB and MAPK signaling pathways in Raw264.7 macrophages
Wu, J., Mo, J., Xiang, W. D., Shi, X., Guo, L., Li, Y., Bao, Y., & Li, Z. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.114471 · Cited by 54 · see citing works
Evaluation of the Molecular Mechanisms of Sepsis Using Proteomics
He, M., Chen, S., & Ding, R. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.733537 · Cited by 49 · see citing works
Histone deacetylase 3 regulates microglial function through histone deacetylation
Meleady, L., Towriss, M., Kim, J. S., Bacarac, V., Dang, V., Rowland, M. E., & Ciernia, A. V. (2023) · Epigenetics · doi:10.1080/15592294.2023.2241008 · Cited by 47 · see citing works
“The primary function of NO release by immune cells is to defend against pathogens [42].”
Background
Nitric oxide favours tumour-promoting inflammation through mitochondria-dependent and -independent actions on macrophages
Drehmer, D., Luiz, J. P. M., Speck‐Hernandez, C. A., Alves-Filho, J. C., Hussell, T., Townsend, P. A., & Moncada, S. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102350 · Cited by 43 · see citing works
“8 decreased availability of the essential cofactor tetrahydrobiopterin, hence have limited ability to generate NO [54].”
Background
Nitric Oxide Modulates Metabolic Processes in the Tumor Immune Microenvironment
McGinity, C. L., Palmieri, E. M., Somasundaram, V., Bhattacharyya, D. D., Ridnour, L. A., Cheng, R. Y. S., Ryan, A. E., Glynn, S. A., Thomas, D. D., Miranda, K. M., et al. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22137068 · Cited by 41 · see citing works
“, heme and non-heme iron proteins) [35,69] and (2) reactive radicals (i.”
BackgroundSelf-citation
Involvement of Nitric Oxide in Protecting against Radical Species and Autoregulation of M1-Polarized Macrophages through Metabolic Remodeling
Fujii, J., & Osaki, T. (2023) · Molecules · doi:10.3390/molecules28020814 · Cited by 42 · see citing works
The Cys Sense: Thiol Redox Switches Mediate Life Cycles of Cellular Proteins
Radzinski, M., Oppenheim, T., Metanis, N., & Reichmann, D. (2021) · Biomolecules · doi:10.3390/biom11030469 · Cited by 40 · see citing works
“One of the major sources of cellular nitric oxide molecules is the enzymatic activity of a family of nitric oxide synthetase (NOS) enzymes involved in cell signaling and immune defense [65,66].”
Background
NOS2 and COX-2 Co-Expression Promotes Cancer Progression: A Potential Target for Developing Agents to Prevent or Treat Highly Aggressive Breast Cancer
Coutinho, L. L., Femino, E. L., González, A. L., Moffat, R. L., Heinz, W. F., Cheng, R. Y. S., Lockett, S., Rangel, M. C., Ridnour, L. A., & Wink, D. A. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25116103 · Cited by 37 · see citing works
“Similarly to oxygen, NO is a gas with diffusible properties that exhibits higher sol-ubility in hydrophobic compartments than in aqueous environments [24].”
BackgroundSelf-citation
A fructan-type garlic polysaccharide upregulates immune responses in macrophage cells and in immunosuppressive mice
Wu, J., Yu, G., Zhang, X., Staiger, M. P., Gupta, T. B., Yao, H. L., & Wu, X. (2024) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2024.122530 · Cited by 35 · see citing works
iNOS in Macrophage Polarization: Pharmacological and Regulatory Insights
Kang, J.-H., Kim, J., Gim, J., & Lee, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262412056 · Cited by 35 · see citing works
“…the iNOS heme-or BH 4 -binding environment [3]. iNOS is primarily induced in immune cells such as macrophages and T lymphocytes upon exposure to pro-inflammatory signals including lipopolysaccharide (LPS), interleukin-1 β (IL-1 β ), tumor necrosis factor-α (TNF-α ), and interferon-γ (IFN-γ ) [4].”
The Metabolic Orchestration of Immune Evasion in Glioblastoma: From Molecular Perspectives to Therapeutic Vulnerabilities
Medikonda, R. T., Abikenari, M. A., Schonfeld, E., & Lim, M. K. (2025) · Cancers · doi:10.3390/cancers17111881 · Cited by 33 · see citing works
“Glutamine deficiency also polarizes TAMs and MDSCs toward more immunosuppressive phenotypes and promotes Treg expansion [56,58].”
BODIPY-Based NO Probe for Macrophage-Targeted Immunotherapy Response Monitoring
Li, X., Chen, H., Wang, Y., Chen, H., & Gao, Y. (2023) · Analytical Chemistry · doi:10.1021/acs.analchem.3c00409 · Cited by 32 · see citing works
The Immunomodulatory Effects of Active Ingredients From Nigella sativa in RAW264.7 Cells Through NF-κB/MAPK Signaling Pathways
Wei, J., Wang, B., Chen, Y., Wang, Q., Ahmed, A. F., Zhang, Y., & Kang, W. (2022) · Frontiers in Nutrition · doi:10.3389/fnut.2022.899797 · Cited by 31 · see citing works
Grossamide attenuates inflammation by balancing macrophage polarization through metabolic reprogramming of macrophages in mice
Zhao, W., Xu, D., Hong, W., Zhang, L., Wu, Q., Gao, M., & Wang, J. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.109190 · Cited by 30 · see citing works
Anti-Inflammatory Effect of Ebractenoid F, a Major Active Compound of Euphorbia ebracteolata Hayata, through Inhibition of Nuclear Factor-κB Activation
Chun, J., Mah, S. Y., & Kim, Y. S. (2023) · Plants · doi:10.3390/plants12152845 · Cited by 29 · see citing works
“However, NO is regarded as a proinflammatory mediator that induces inflammation because of excessive production in abnormal physiological situations [20].”
Background
The versatile biochemistry of iron in macrophage effector functions
Behmoaras, J. V. (2020) · FEBS Journal · doi:10.1111/febs.15682 · Cited by 30 · see citing works
Recent Advances in the Development of Non‐Invasive Imaging Probes for Cancer Immunotherapy
Kazim, M., & Yoo, E. (2023) · Angewandte Chemie International Edition · doi:10.1002/anie.202310694 · Cited by 28 · see citing works
Nitric oxide-based multi-synergistic nanomedicine: an emerging therapeutic for anticancer
Tang, Y., Li, Q., Zhou, Z., Bai, H., Xiao, N., Xie, J., & Li, C. (2024) · Journal of Nanobiotechnology · doi:10.1186/s12951-024-02929-z · Cited by 27 · see citing works
“Moreover, NO has a complex effect on the activity of natural killer (NK) cells and macrophages [25, 133, 134].”
Background
Oral streptococci S. anginosus and S. mitis induce distinct morphological, inflammatory, and metabolic signatures in macrophages
Kumar, S. S., Gunda, V., Reinartz, D. M., Pond, K. W., Thorne, C. A., Raj, P. V. S., Johnson, M. D. L., & Wilson, J. E. (2024) · Infection and Immunity · doi:10.1128/iai.00536-23 · Cited by 26 · see citing works
From Gasotransmitter to Immunomodulator: The Emerging Role of Hydrogen Sulfide in Macrophage Biology
Cornwell, A., & Badiei, A. (2023) · Antioxidants · doi:10.3390/antiox12040935 · Cited by 26 · see citing works
“NO interacts with metal-containing proteins and the electron transport chain, altering cellular respiration and regulating energy production [10].”
Background
Nitric Oxide: The Missing Factor in COVID-19 Severity?
Nikolaidis, A., Kramer, R., & Ostojić, S. M. (2021) · Medical Sciences · doi:10.3390/medsci10010003 · Cited by 25 · see citing works
“Nitric oxide is also essential in macrophage activation in response to infection and to the body’s whole immune response [58],—macrophage cells release NO in response to inflammatory signals—and the NO increase in macrophages results in a multitude of changes in macrophage immunometabolism with multiple implications i…”
Background
Impact of nitric oxide in liver cancer microenvironment
Barbeito, S. D., González, R., Cadenas, M., García, L. F., Víctor, V. M., Padillo, F. J., & Muntané, J. (2022) · Nitric Oxide · doi:10.1016/j.niox.2022.07.006 · Cited by 25 · see citing works
Phytochemical Constituents and Biological Activity of Wild and Cultivated Rosmarinus officinalis Hydroalcoholic Extracts
Francolino, R., Martino, M., Caputo, L., Amato, G., Chianese, G., Gargiulo, E., Formisano, C., Romano, B., Ercolano, G., Ianaro, A., et al. (2023) · Antioxidants · doi:10.3390/antiox12081633 · Cited by 25 · see citing works
“To better characterize the anti-inflammatory effect of WRO and CRO, their ability to modulate the NO pathway, one of the major players involved in macrophage activation [36], was also investigated.”
Background
Nitric Oxide‐Activated Bioorthogonal Codelivery Nanoassembly for In Situ Synthesis of Photothermal Agent for Precise and Safe Anticancer Treatment
Li, B., Tian, J., Wu, C., Li, Z., Qiao, L., Xie, Z., Song, B., Shan, Y., Chen, S., Tang, Y., et al. (2024) · Advanced Materials · doi:10.1002/adma.202405502 · Cited by 25 · see citing works
Peptidoglycan-induced modulation of metabolic and inflammatory responses
Wolf, A. J. (2023) · Immunometabolism · doi:10.1097/in9.0000000000000024 · Cited by 22 · see citing works
“The impact of PGE2 on mitochondrial function may be a result of increased iNOS expression induced by PGE2 leading to high levels of NO production, which has been shown to inhibit mitochondrial complex IV function [56].”
Background
Acute Effects on the Human Peripheral Blood Transcriptome of Decompression Sickness Secondary to Scuba Diving
Magri, K., Eftedal, I., Magri, V. P., Mátity, L., Azzopardi, C. P., Muscat, S., & Pace, N. P. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.660402 · Cited by 21 · see citing works
“Metabolic differences between murine and human M1 macrophages have been described (Vijayan et al., 2019; Palmieri et al., 2020).”
Background
Platelet Membrane‐Derived Nanodiscs for Neutralization of Endogenous Autoantibodies and Exogenous Virulence Factors
Sun, L., Yu, Y., Peng, Y., Wang, D., Wang, S., Noh, I., Fang, R. H., Gao, W., & Zhang, L. (2023) · Small · doi:10.1002/smll.202308327 · Cited by 21 · see citing works
Unravelling the Influence of Chlorogenic Acid on the Antioxidant Phytochemistry of Avocado (Persea americana Mill.) Fruit Peel
Izu, G. O., Njoya, E. M., Tabakam, G. T., Nambooze, J., Otukile, K. P., Tsoeu, S. E., Fasiku, V. O., Adegoke, A. M., Erukainure, O. L., Mashele, S. S., et al. (2024) · Antioxidants · doi:10.3390/antiox13040456 · Cited by 20 · see citing works
Distinct metabolic responses to heme in inflammatory human and mouse macrophages – Role of nitric oxide
Pradhan, P., Vijayan, V., Liu, B., Martínez–Delgado, B., Matamala, N., Nikolin, C., Greite, R., DeLuca, D. S., Janciauskiene, S. M., Motterlini, R., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103191 · Cited by 20 · see citing works
“Accordingly, a number of metabolic changes in mouse macrophages, including impairment of mitochondrial respiration and mitochondrial function due to inflammatory activation, have been attributed to NO [37,38].”
Dynamic changes of macrophage activation in mice infected with Trichinella spiralis
Sun, Q., Huang, J., Gu, Y., Liu, S., & Zhu, X. (2022) · International Immunopharmacology · doi:10.1016/j.intimp.2022.108716 · Cited by 19 · see citing works
A matter of time: temporal structure and functional relevance of macrophage metabolic rewiring
Seim, G. L., & Fan, J. (2022) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2022.02.005 · Cited by 20 · see citing works
“Drug-Free” chitosan nanoparticles as therapeutic for cancer treatment
Iskandar, A., Kim, S., & Wong, T. W. (2024) · Journal of macromolecular science. Part C, Reviews in macromolecular chemistry and physics/Journal of macromolecular science. Reviews in macromolecular chemistry and physics · doi:10.1080/15583724.2024.2323943 · Cited by 19 · see citing works
The role of nitric oxide synthase/ nitric oxide in infection-related cancers: Beyond antimicrobial activity
Hu, X., Li, Y., Cao, Y., Shi, F., & Li, S. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189156 · Cited by 20 · see citing works
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Authors: Palmieri, E. M., McGinity, C., Wink, D. A., & McVicar, D. W.
Affiliations: National Cancer Institute (US)
Corresponding author: McVicar, Daniel W.
ORCID: Palmieri, Erika M.
Wink, David A.
McVicar, Daniel W.
Venue: Metabolites
Publisher: MDPI AG
Published: 2020-10-26
Volume: 10
Issue: 11
Pages: 429
ISSN: 2218-1989 (ISSN-L)
DOI: 10.3390/metabo10110429
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: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
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 › 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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Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

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