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

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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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Figure 1 Biochemical mechanisms of Nitric Oxide synthesis and inhibition of mitochondrial targets. (a) Nitric oxide (NO) is synthesized from l-arginine by nitric oxide synthase (NOS) enzymes. The reaction involves the incorporation of oxygen (O2) into the unstable intermediate N omega-hydroxy-l-arginine and, subsequently, into l-citrulline, co-product of the generation of NO. N G -monomethyl-l-arginine (L-NMMA), N omega-Nitro-l-arginine (L-NAME), s-ethylisothiourea (SEITU), n-(3-(Aminomethyl)benzyl)acetamidine (1400W), and aminoguanidine (AG) are competitive inhibitor of NOS, the last two specific for inducible NOS (iNOS or NOS2), and block the pathway at the points indicated. (b) Nanomolar concentrations of NO immediately, specifically, and reversibly inhibit cytochrome c oxidase (Complex IV of mitochondrial electron transport chain, ETC) in competition with oxygen. NO reacts with the metals of the binuclear site of cytochrome c oxidase, binding tightly to the reduced iron in the distal pocket with the N closest to the Fe and the O close to, but not directly bonding, the CuB. (c) NO can target aconitase: NO is capable of oxidizing the cubane iron-sulfur (Fe-S) cluster that participates in the catalysis of the non-redox reaction of reversible isomerization of citrate to isocitrate with the intermediate cis-aconitate. This leads to iron release and consequent loss of the catalytic activity.CC BY · PubMed Central

Figure 2 Mitochondrial bioenergetics following acute and prolonged NO injury. (a) Cytochrome c oxidase exert considerable control over the rate of respiration because NO increases the Km of the enzyme for O2. Inhibition of cytochrome c oxidase by NO leads to a drop in the electron flux and consequently in proton extrusion. 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+). This will re-establish the proton leak transiently lost during initial gradient dissipation. The effect of these changes is a hyperpolarization of the inner mitochondrial membrane. (b) Prolonged exposure to NO and, therefore, persistent inhibition of respiration by NO favors the formation of superoxide anions (O2−) and peroxynitrite (ONOO–), from the reaction between superoxide and NO, resulting from changes in intracellular redox conditions and depletion of the glutathione pool. These species can activate mechanisms that lead to irreversible damage, like deleterious modifications of CI. This situation facilitates the induction of the permeability transition pore (PTP), which leads to the collapse of the membrane potential and cell death. The passage of electrons (e–) along the ETC is depicted. 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.CC BY · PubMed Central

Figure 3 A/D transition of mitochondrial Complex I. The A-form of CI is capable of catalysis, but D-form is not. Divalent cations and free fatty acids influence the dynamics of the A/D transition. Majorly, substrate availability depicted by NAD+/NADH ratio in the matrix, together with presence of NO or hypoxic conditions strongly favor the kinetic of the A/D transition. Exposure of Cys39 of ND3 subunit of CI makes the D-form susceptible for thiol modifications that define deactivation reversibility, with nitrosation being the lead for further oxidation and potentially irreversible modifications and destruction of the enzyme.CC BY · PubMed Central

Figure 4 Orchestration of macrophage metabolism by NO. Macrophage metabolism switches to a high glycolytic status upon pro-inflammatory stimulation with increase lactate production, which is independent on NO and NOS2. Accumulation of metabolites like succinate and itaconate is a hallmark of pro-inflammatory macrophages. Treatment of Bone Marrow Derived Macrophages (BMDMs) with cytokines that elicit low NO fluxes (es. IFNγ+IL-1β) or the beginning of a strong signal does not result in further metabolic characteristics. With IFNγ+TNFα or cytokine combination that produce medium NO concentrations or with time after a strong stimulation, macrophages undergo oxidative shortage most likely from an interrupted flux through PDH, underlined by decreased oxygen consumption rate (OCR)/extracellular acidification rates (ECAR), with responsive compensatory anaplerotic pathways for TCA supply, like glutaminolysis. The presence of high concentration of NO in LPS+IFNγ-stimulated macrophages results in further multiple metabolic rewirings. Entrance of carbon into TCA via PDH is halted and ACO2 is inhibited. Compensatory carboxylation and glutaminolysis are enhanced, leading to accumulation of citrate and limitation in itaconate. The lack of NADH and reduced substrates generated by the broken TCA cycle leads to inactive mitochondrial complexes and suppressed OXPHOS, with significant appreciable drops in OCR and full commitment to glycolysis. In turn, β -oxidation of fatty acids (FA) is strongly decreased, leading to esterification of intracellular FA with glycolytic-derived glycerol for the synthesis of triglycerides and neutral lipids. In absence of NO (a situation represented by Nos2−/− LPS+IFNγ -stimulated BMDMs), higher glycolysis is maintained, PDH and ACO2 are intact and mitochondrial ETC displays full function. In this scenario, production of itaconate is strongly increased. The arrows represent the general direction of the metabolic flow in the system with the specific contribution of glucose and glutamine. The red color for arrows/ metabolites represents higher flux of depicted pathway/ increase in metabolite levels upon respective condition, compared to macrophage resting state. PDH pyruvate dehydrogenase; ACO2 mitochondrial aconitase; IDH isocitrate dehydrogenase; β -ox, β -oxidation; α-KG, α-KG, alpha-ketoglutarate; Acetyl-CoA, Acetyl-coenzyme A.CC BY · PubMed Central

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“A consequence of NO inhibition of cytochrome c oxidase would be increased availability of O2 in the surrounding tissues [46,47].”
Background
Complexes of .NO with nucleophiles as agents for the controlled biological release of nitric oxide. Vasorelaxant effects
Maragos, C. M., Morley, D., Wink, D. A., Dunams, T. M., Saavedra, J. E., Hoffman, A., Bove, A. A., Isaac, L., Hrabie, J. A., & Keefer, L. K. (1991) · Journal of Medicinal Chemistry · doi:10.1021/jm00115a013 · Cited by 722
Self-citation
Induction of nitrite/nitrate synthesis in murine macrophages by BCG infection, lymphokines, or interferon-gamma.
Stuehr, D. J., & Marletta, M. A. (1987) · The Journal of Immunology · doi:10.4049/jimmunol.139.2.518 · Cited by 713 · cited 10×
“A year before these studies on tumor cells, Stuehr and Marletta had demonstrated that macrophages exposed to recombinant interferon-γ (rIFNγ) and LPS synthesize nitrite (NO2−) and nitrate (NO3−) [7,65].”
BackgroundInfluential
Inhibition of Mitochondrial Electron Transport by Peroxynitrite
Radi, R., Rodriguez, M., Castro, L., & Telleri, R. (1994) · Archives of Biochemistry and Biophysics · doi:10.1006/abbi.1994.1013 · Cited by 693 · cited 14×
“Interestingly, Cysteine39 in the ND3 subunit becomes exposed in the D-form and is susceptible to covalent modification by nitrosothiols (RSNO), ROS, and RNS [89–91], perhaps making it a specific site of physiological SNO regulation.”
BackgroundInfluential
The multifaceted roles of nitric oxide in cancer
Wink, D. (1998) · Carcinogenesis · doi:10.1093/carcin/19.5.711 · Cited by 682 · cited 1×
“Together, the integration of these effects may define a powerful therapeutic target [235,236].”
BackgroundSelf-citation
A roadmap for interpreting 13C metabolite labeling patterns from cells
Buescher, J. M., Antoniewicz, M. R., Boros, L. G., Burgess, S. C., Brunengraber, H., Clish, C. B., DeBerardinis, R. J., Féron, O., Frezza, C., Ghesquière, B., et al. (2015) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2015.02.003 · Cited by 644 · cited 1×
“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
Itaconate: the poster child of metabolic reprogramming in macrophage function
O'Neill, L. A. J., & Artyomov, M. N. (2019) · Nature reviews. Immunology · doi:10.1038/s41577-019-0128-5 · Cited by 643 · cited 1×
“The biology and biochemistry of itaconate has been recently reviewed in detail by others [128,129].”
Background
The Sedoheptulose Kinase CARKL Directs Macrophage Polarization through Control of Glucose Metabolism
Haschemi, A., Kosma, P., Gille, L., Evans, C. R., Burant, C. F., Starkl, P., Knapp, B., Haas, R., Schmid, J. A., Jandl, C., et al. (2012) · Cell Metabolism · doi:10.1016/j.cmet.2012.04.023 · Cited by 635 · cited 1×
“[101] demonstrated this at the level of gene expression and many groups [102,103] have now shown that metabolic changes can be present as early as 30 min after activation.”
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×
“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
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
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
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×
“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
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 545 · cited 1×
“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
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 543 · cited 1×
“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
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×
“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
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×
“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×
“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×
“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
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 509 · cited 1×
“[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
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
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×
“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 483 · cited 16×
“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 470 · cited 4×
“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
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
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×
“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
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 417 · cited 1×
“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
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×
“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×
“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
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 408
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×
“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 395 · cited 10×
“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×
“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
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 389
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×
“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
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×
“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 383
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
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×
“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
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×
“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×
“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
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
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 346 · cited 1×
“They found that Complex I (NADH-coenzyme Q reductase) was most sensitive to inhibition, followed by Complex II (succinate-coenzyme Q reductase) [52].”
Background
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 341 · cited 13×
“However, we find that activation of NRF2 occurs regardless of intracellular availability of itaconate.”
BackgroundInfluential
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×
“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×
“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
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
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
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 321 · cited 1×
“Many studies have reported complex metabolic footprints in macrophages activated under different stimuli and tissue environments [168,169].”
Background
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
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
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×
“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
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
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 305 · cited 1×
“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
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 288 · cited 2×
“Nitrosation requires NO+ donors since in solution, NO+ has an appreciable lifetime only under high acidic conditions [35].”
BackgroundSelf-citation
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
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 285
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×
“Compared to NO and other RNS, HNO has a distinct signaling mechanism of action [242,243] and higher electrophilicity than NO [244].”
BackgroundSelf-citation
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
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
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×
“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×
“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×
“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
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 259
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 259 · cited 1×
“Many studies have reported complex metabolic footprints in macrophages activated under different stimuli and tissue environments [168,169].”
Background
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×
“Through Electron Spin Resonance, iron-nitric oxide complexes were detected in proteins in these cells [59].”
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 257 · cited 3×
“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
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×
“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
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 248 · cited 1×
“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
Nitric oxide in parasitic infections
Brunet, L. R. (2001) · International Immunopharmacology · doi:10.1016/s1567-5769(01)00090-x · Cited by 240 · cited 1×
“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
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
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 236 · cited 1×
“The biology and biochemistry of itaconate has been recently reviewed in detail by others [128,129].”
Background
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
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 233 · cited 1×
“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
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×
“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
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
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×
“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 218
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 217 · cited 4×
“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
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×
“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×
“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
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 204 · cited 3×
“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
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 200 · cited 1×
“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
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×
“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
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
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×
“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
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
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
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
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
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×
“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
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
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×
“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
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 179 · cited 21×
“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 176 · cited 1×
“Indeed, the mechanism of irreversible inhibition of aldehyde dehydrogenase by HNO has been speculated to involve the presence of a sulfinamide [240,245].”
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
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
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×
“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
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 165
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×
“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
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×
“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
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×
“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×
“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
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 147 · cited 1×
“Older reports on the E3 of PDH support its targeting by nitroxyl (HNO) or peroxynitrite [154,155].”
Background
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
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
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
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×
“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 135 · cited 2×
“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 132
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
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
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×
“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
S-Nitrosation of Mitochondrial Complex I Depends on Its Structural Conformation
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“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
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 121
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×
“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
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 120 · cited 1×
“This second wave of glycolytic induction is mediated in DCs by mTOR/ HIF1α /NOS2 [142,146].”
Background
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
Superoxide production by mitochondria in the presence of nitric oxide forms peroxynitrite
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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 115 · cited 2×
“[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
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 113 · cited 2×
“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
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 113 · cited 1×
“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
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×
“Intracellularly, the concentration of O2 has been reported to be as low as 10 μM [42].”
Background
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 109
HIF1α-dependent glycolysis promotes macrophage functional activities in protecting against bacterial and fungal infection
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“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
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 108 · cited 1×
“Of consequence, the increased available pO2 associated with elevated NO levels can affect the immune response [234].”
Background
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
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×
“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
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 105 · cited 1×
“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
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
Interleukin-4 stimulates cGMP production by IFN-gamma-activated human monocytes. Involvement of the nitric oxide synthase pathway
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Mössbauer studies of aconitase. Substrate and inhibitor binding, reaction intermediates, and hyperfine interactions of reduced 3Fe and 4Fe clusters.
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Intraphagosomal Measurement of the Magnitude and Duration of the Oxidative Burst
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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
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×
“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

Sorted by citations

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 2,477
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 406
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 244
“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 173
The Role of Reactive Species on Innate Immunity
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“The •NO/ROS balance is also important during the transition from Th1 to Th2 [125,126].”
Background

See all 238

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 (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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Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight

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