Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels
Open accessAbstract
Metabolic reprogramming is emerging as a hallmark of the innate immune response, and the dynamic control of metabolites such as succinate serves to facilitate the execution of inflammatory responses in macrophages and other immune cells. Immunoresponsive gene 1 (Irg1) expression is induced by inflammatory stimuli, and its enzyme product cis-aconitate decarboxylase catalyzes the production of itaconate from the tricarboxylic acid cycle. Here we identify an immunometabolic regulatory pathway that links Irg1 and itaconate production to the succinate accumulation that occurs in the context of innate immune responses. Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells. We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation. Loss of itaconate production in activated macrophages from Irg1(-/-) mice decreases the accumulation of succinate in response to LPS exposure. This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.
AI snapshot
Written from the paper’s full text.
TL;DR
This paper identifies an immunometabolic pathway in which Irg1/CAD-derived itaconate inhibits succinate dehydrogenase (SDH), causing succinate accumulation during LPS exposure. Loss of Irg1 in macrophages reduces itaconate and succinate, linking innate immune metabolism to TCA cycle and electron transport chain function.
Key findings
- In LPS-activated RAW 264.7 macrophages, itaconate and succinate levels showed similar trends over 6 h, unlike citrate, α-ketoglutarate, fumarate, and malate; basal oxygen consumption rate remained unchanged.
- Exogenous itaconate (0–25 mM, 6 h) increased intracellular itaconate dose-dependently and correlated strongly with succinate in resting and LPS-activated RAW 264.7 macrophages (r = 0.99) and in A549 cells (r = 0.99), while other TCA intermediates correlated poorly or negatively.
- Itaconate was not metabolized to succinate: [1-13C]glutamine labeling produced ~65% M1 itaconate but no succinate labeling, and prelabeling with [U-13C6]glucose/[U-13C5]glutamine left succinate labeling ~90% after unlabeled itaconate.
- Itaconate inhibited SDH/complex II: dose-dependent OCR inhibition in permeabilized RAW 264.7 macrophages and BMDMs with succinate, >75% reduction with 10 mM itaconate plus succinate/rotenone, and no effect on complex I or IV substrates; Irg1 KO BMDMs failed to produce itaconate and had significantly lower succinate than WT after LPS, while Irg1 overexpression in A549 cells increased succinate.
Methods
- Cell models and treatments: RAW 264.7 macrophages, A549 lung adenocarcinoma cells, and primary BMDMs from C57BL/6J and Irg1 KO mice; LPS at 10 ng/ml; itaconate at 5, 10, and 25 mM for 6 h; A549 cells transfected with pCMV6-Irg1 or empty vector.
- Metabolite and isotope analysis: GC-MS quantification of itaconate and TCA intermediates using external standard curves; isotopic labeling with [1-13C]glutamine, [U-13C6]glucose, and [U-13C5]glutamine; mass isotopomer distributions corrected for natural abundance.
- Respiration and statistics: Seahorse XF96 oxygen consumption measurements in intact and permeabilized cells (perfringolysin O) with succinate/rotenone, glutamate/malate, pyruvate/malate, or ascorbate/TMPD/antimycin A; Pearson correlation and two-tailed Student’s t tests.
Limitations
- Stated: The authors note variability in succinate accumulation between RAW 264.7 macrophages and BMDMs, likely due to cell, medium, and LPS variability; they also state that the physiological role of itaconate and Irg1 requires further investigation, particularly in macrophage development and differentiation.
- Stated: It is not known whether downstream inflammatory responses are mediated directly by succinate or itaconate or through other mechanisms; no mammalian mitochondrial or plasma membrane itaconate transporters have been described, and other succinate-producing pathways (GABA shunt, glutaminolysis) could compensate.
- Evident from the text: Most mechanistic experiments use cultured cells and exogenous itaconate up to 25 mM, whereas endogenous macrophage itaconate is cited as up to 8 mM; no in vivo inflammation or disease model is presented.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 41 cited sources checked · 0 supported · 0 flagged
- Findingown data
Itaconate causes dose-dependent inhibition of oxygen consumption rates in permeabilized RAW 264.7 macrophages and BMDMs.
“We observed a dose depen- dent inhibition of OCRs by itaconate in RAW 264.7 macrophages (Fig. 5a) and BMDMs (Fig. 5b)”
Quote in the paperSubstantial claim - Findingown data
Itaconate fails to impact complex IV-mediated respiration.
“Itaconate also failed to impact this complex IV-mediated respiration.”
Quote in the paperSubstantial claim - Findingown data
Basal oxygen consumption rates in LPS-activated RAW 264.7 macrophages remain unchanged compared with resting macrophages.
“Notably, basal oxygen consumption rates (OCR) remained unchanged compared with resting macrophages (Fig. 1b).”
Quote in the paperNot a substantial claim - Findingown data
Medium itaconate levels were not appreciably affected by exposure to exogenous itaconate.
“However, medium itaconate levels were not appreciably affected (Fig. 2g).”
Quote in the paperNot a substantial claim - Findingown data
Labeling of succinate after exposure to exogenous, unlabeled itaconate was unchanged in 13C-labeled resting and LPS-activated RAW 264.7 macrophages.
“Because labeling of succinate after exposure to exogenous, unlabeled itaconate was unchanged (even in the physi-ological concentration used here) (Fig. 4d)”
Quote in the paperSubstantial claim
- Findingown data
Intracellular itaconate levels correlate strongly with succinate levels in resting (r = 0.99) and LPS-activated (r = 0.99) RAW 264.7 macrophages.
“we observed that intracellular itaconate levels correlated strongly with succinate levels in resting (r ϭ 0.99) as well as LPS-activated macrophages (r ϭ 0.99)”
Quote in the paperSubstantial claim - Findingown data
In LPS-activated RAW 264.7 macrophages, itaconate and succinate levels exhibit similar trends upon activation, in contrast to citrate, α-ketoglutarate, fumarate, and malate.
“Intriguingly, the levels of itaconate and succinate exhibited similar trends upon activation, in contrast to the dynamics of citrate, ␣-ketoglutarate, fumarate, and malate (Fig. 1a)”
Quote in the paperSubstantial claim - Findingown data
Levels of citrate, α-ketoglutarate, fumarate, and malate correlate poorly or negatively with intracellular itaconate levels in RAW 264.7 macrophages.
“the levels of other TCA intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate correlated poorly (or in some cases negatively) with intracellular itaconate levels (Fig. 2, a, b, d, and f).”
Quote in the paperSubstantial claim - Findingown data§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Loss of itaconate production in activated macrophages from Irg1−/− mice decreases the accumulation of succinate in response to LPS exposure.
“Loss of itaconate production in activated macrophages from Irg1 ؊/؊ mice decreases the accumulation of succinate in response to LPS exposure.”
Quote in the paperSubstantial claim - Findingown data
Oxygen consumption rates in permeabilized cells in the presence of pyruvate with malate or glutamate with malate are not affected by itaconate supplementation.
“oxygen consumption rates in permeabilized cells in the presence of either pyruvate with malate or glutamate with malate, substrates that drive respiration via complex I activity, were not affected by itaconate supplementation.”
Quote in the paperSubstantial claim - Findingown data
Exposure of resting and LPS-activated RAW 264.7 macrophages to exogenous itaconate results in increasing intracellular itaconate levels in a dose-dependent manner.
“Exposure to exogenous itaconate resulted in increasing intracellular itaconate levels in a dose-dependent manner (Fig. 2c)”
Quote in the paperSubstantial claim - Findingown data
When succinate concentration is lowered to 2.5 mM, itaconate has a greater proportional inhibitory effect.
“When the succinate concentration was lowered to 2.5 mM, itaconate had a greater proportional inhibitory effect.”
Quote in the paperSubstantial claim - Findingown data§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells.
“Itaconate levels and Irg1 expression correlate strongly with succinate during LPS exposure in macrophages and non-immune cells.”
Quote in the paperSubstantial claim - Findingown data
Itaconate is only produced at detectable levels in pCMV6 Irg1-overexpressing A549 cells (pmIrg1) compared with vector (pCMV6) controls.
“Itaconate was only produced at detectable levels in pCMV6 Irg1-overexpressing A549 cells (pmIrg1) compared with vector (pCMV6) controls (Fig. 3c).”
Quote in the paperSubstantial claim - Findingown data
Itaconate supplementation significantly reduces respiration (>75%) in the presence of succinate (SDH substrate) and rotenone (complex I inhibitor).
“itaconate supplementation significantly reduced respiration (Ͼ75%) in the presence of succinate (SDH substrate) and rotenone (complex I inhibitor).”
Quote in the paperSubstantial claim - Findingown data
pmIrg1 cells accumulate significantly higher amounts of succinate compared with pCMV6 controls.
“pmIrg1 cells accumulated significantly higher amounts of succinate compared with pCMV6 controls (Fig. 3d)”
Quote in the paperSubstantial claim - Findingown data
Itaconate acts as an SDH inhibitor.
“Substrate-specific respirometry studies in permeabilized cells confirmed that itaconate acts as an SDH inhibitor.”
- Also stated in: § Discussion · plain
“Itaconate inhibits SDH.”
- Also stated in: § Loss of Irg1 Influences Succinate Levels in · plain
“Taken together, our data highlight a mechanistic function of itaconate whereby this metabolite acts as a SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation (Fig. 7).”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingown data
Exogenous itaconate drives succinate accumulation.
“FIGURE 2. Exogenous itaconate drives succinate accumulation.”
Quote in the paperSubstantial claim - Findingreasoning
Modulation of endogenous itaconate production in LPS-activated primary macrophages from Irg1 KO mice reduces succinate levels.
“Finally, modulation of endogenous itaconate production in LPS-activated primary macrophages from Irg1 KO mice reduces succinate levels.”
Quote in the paperSubstantial claim - Findingown data
Succinate concentrations in LPS-stimulated BMDMs from Irg1 KO mice were significantly lower than in BMDMs from WT mice.
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
Quote in the paperSubstantial claim - Findingown data
Irg1 mRNA was not expressed in LPS-stimulated BMDMs derived from Irg1 KO mice.
“We confirmed that Irg1 mRNA was not expressed in LPS-stimulated KO-derived BMDMs (Fig. 6a).”
Quote in the paperSubstantial claim - Findingown data
Itaconate- and Irg1-induced succinate accumulation is not specific to immune cells.
“FIGURE 3. Itaconate-and Irg1-induced succinate accumulation is not specific to immune cells.”
Quote in the paperSubstantial claim - Findingown data
Succinate and itaconate accumulate in LPS-activated murine RAW 264.7 macrophages.
“FIGURE 1. Succinate and itaconate accumulate in LPS-activated murine RAW 264.7 macrophages.”
Quote in the paperSubstantial claim - Findingown data
LPS-stimulated BMDMs from Irg1 KO mice failed to produce significant levels of itaconate.
“Consistent with this result, LPS-stimulated BMDMs from Irg1 KO mice failed to produce significant levels of itaconate (Fig. 6b).”
Quote in the paperSubstantial claim - Findingown data
Increased succinate downstream of itaconate production or administration was consistently observed in a variety of cell types.
“However, we consistently observed increased succinate downstream of itaconate production or administration in a variety of cell types.”
Quote in the paperSubstantial claim - Findingown data
Exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation in the cells studied.
“In the cells studied, exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation.”
Quote in the paperSubstantial claim - Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
In mammals, itaconate is produced through the decarboxylation of the TCA cycle intermediate cis-aconitate, catalyzed by mammalian cis-aconitate decarboxylase (CAD, also known as IRG1 protein) encoded by immunoresponsive gene 1 (IRG1).
“In mammals, itaconate is pro-duced through the decarboxylation of the TCA cycle intermediate cis-aconitate, which is catalyzed by mammalian cis-aconitate decarboxylase (CAD, also known as immune-responsive gene 1 (IRG1) protein) encoded by immunoresponsive gene 1 (IRG1) (20).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Succinate inhibits the hydroxylation of HIF-1α by EGLN1, resulting in pseudohypoxic HIF-1α stabilization under normoxic conditions.
“Succinate inhibits the hydroxylation of HIF-1␣ by EGLN1, resulting in pseudohypoxic HIF-1␣ stabilization under normoxic conditions (10 -12).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [10] Selak, 2005, Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell source
Not checked in the free run.
- cites [11] Epstein, 2001, C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation, Cell source
Not checked in the free run.
- cites [12] Losman, 2013, What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer, Genes Dev source
Not checked in the free run.
- Interpretationown data
Itaconate functions as a metabolic trigger to modulate succinate levels.
“Collectively, these observations provide strong evidence that itaconate functions as metabolic trigger to modulate succinate levels.”
Quote in the paperSubstantial claim - Interpretationown data
Cells have the capacity to take up itaconate from medium.
“indicating that cells have the capacity to take up itaconate from medium.”
Quote in the paperSubstantial claim - Interpretationown data
Ectopic expression of CAD alone is sufficient to impact succinate levels.
“indicating that ectopic expression of CAD alone is sufficient to impact succinate levels.”
Quote in the paperSubstantial claim - Interpretationown data
Itaconate contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.
“Together, these data provide evidence that itaconate contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.”
Quote in the paperSubstantial claim - Interpretationown data
Itaconate is not metabolized to succinate in these mammalian cells.
“these data therefore confirm that itaconate is not metabolized to succinate in these mammalian cells.”
Quote in the paperSubstantial claim - Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Increased succinate levels in macrophages are important mediators of the inflammatory response, linking metabolism to innate immunity.
“Increased succinate levels in macrophages are important mediators of the inflammatory response, linking metabolism to innate immunity.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
- Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Succinate acts as a regulatory signal enhancing Il-1β expression through stabilization of HIF-1α.
“succinate acts as a regulatory signal enhancing Il-1 expression through stabilization of HIF-1␣, which, in turn, influences the function of various other metabolic pathways (9).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
- Interpretationreasoning
Itaconate-mediated succinate accumulation occurs even in the absence of an active inflammatory signaling cascade.
“they suggest that itaconate-mediated succinate accumulation occurs even in the absence of an active inflammatory signaling cascade.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- Interpretationown data§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation.
“We demonstrate that itaconate acts as an endogenous succinate dehydrogenase inhibitor to cause succinate accumulation.”
Quote in the paperSubstantial claim - Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Itaconate exhibits an antibiotic function via inhibition of isocitrate lyase, a key enzyme of the glyoxylate shunt needed by many bacteria to survive during infection.
“Itaconate exhibits an antibiotic function (20) via inhibition of isocitrate lyase, a key enzyme of the glyoxylate shunt needed by many bacteria to survive during infection (21)(22)(23).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- cites [21] Patel, 1978, Caenorhabditis elegans and Ascaris suum: inhibition of isocitrate lyase by itaconate, Exp. Parasitol. source
Not checked in the free run.
- cites [22] Williams, 1971, Mechanism of action of isocitrate lyase from Pseudomonas indigofera, Biochemistry source
Not checked in the free run.
- Premisecitation
Mammalian CAD is localized to mitochondria in murine macrophages.
“Mammalian CAD is localized to mitochondria in murine macrophages (38)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [38] Degrandi, 2009, The proinflammatory cytokine-induced IRG1 protein associates with mitochondria, J. Interferon Cytokine Res source
Not checked in the free run.
- Premisecitation
A549 cells do not express IRG1.
“because A549 cells do not express IRG1 (20)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- Interpretationreasoning§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.
“This metabolic network links the innate immune response and tricarboxylic acid metabolism to function of the electron transport chain.”
Quote in the paperSubstantial claim - Interpretationown data
Itaconate has a regulatory role for SDH activity.
“suggesting a regulatory role of itaconate for SDH activity.”
Quote in the paperSubstantial claim - Interpretationown data
Itaconate and succinate (or the enzymes metabolizing them) are regulated in a coordinated manner.
“suggesting that itaconate and succinate (or the enzymes metabolizing them) are regulated in a coordinated manner.”
Quote in the paperSubstantial claim - Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
LPS-activated murine macrophages produce up to 8 mM intracellular itaconate.
“LPS-activated murine macrophages produced up to 8 mM intracellular itaconate (20)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- Interpretationown data
The mechanism through which itaconate acts is independent of other inflammatory signaling events.
“indicating that the mechanism through which itaconate acts is independent of other inflammatory signaling events.”
Quote in the paperSubstantial claim - Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *
Synthesis of the antimicrobial metabolite itaconate is selectively up-regulated in mammalian immune cells under proinflammatory conditions.
“Recently, synthesis of the antimicrobial metabolite itaconate was identified in mammalian immune cells as being selectively up-regulated under proinflammatory conditions (19).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [19] Strelko, 2011, Itaconic acid is a mammalian metabolite induced during macrophage activation, J. Am. Chem. Soc. source
Not checked in the free run.
- Interpretationown data
Itaconate acts as a competitive SDH inhibitor in immune cells.
“our data suggest that itaconate acts as a competitive SDH inhibitor in immune cells”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning
Irg1-mediated itaconate production may influence downstream inflammatory responses in macrophages, such as expression of Il-1β or associated inflammatory genes.
“Our results suggest that Irg1mediated itaconate production may influence downstream inflammatory responses in macrophages (e.g.expression of Il-1 or associated inflammatory genes).”
Quote in the paperSubstantial claim - Interpretationown data
Itaconate acts as a key regulatory metabolite to modulate TCA metabolism and succinate levels.
“Here we have demonstrated an important function of itaconate; it acts as a key regulatory metabolite to modulate TCA metabolism and succinate levels.”
Quote in the paperSubstantial claim - Interpretationown data
CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages.
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
Quote in the paperSubstantial claim- Rests on an assumption: The Irg1 KO mouse model specifically abolishes itaconate production without other metabolic adaptations that affect succinate levels.
- Premisecitation
Succinate accumulation contributes to the induction of Il-1β expression via HIF-1α stabilization.
“Succinate accumulation plays important roles during inflammation so that it contributes to the induction of Il-1 expression via HIF-1␣ stabilization (9).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
- Interpretationreasoning
Itaconate alters mitochondrial metabolism to influence succinate accumulation in macrophages.
“Thus, itaconate alters mitochondrial metabolism to influence succinate accumulation in macrophages (Fig. 7).”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
- Interpretationreasoning
Itaconate produced by mammalian CAD at the first break-point regulates SDH activity at the second break point.
“We have now identified a functional link between these nodes of the TCA cycle, where itaconate produced by mammalian CAD at the first break-point regulates SDH activity at the second break point.”
Quote in the paperSubstantial claim - Interpretationown data
Irg1-mediated itaconate production plays a role in succinate accumulation within immune cells.
“These results provide evidence that Irg1-mediated itaconate production plays a role in succinate accumulation within immune cells.”
Quote in the paperSubstantial claim - Premisecitation
Under inflammatory conditions such as LPS stimulation, mammalian CAD catalyzes the decarboxylation of cis-aconitate to produce itaconate.
“Under inflammatory conditions, such as LPS stimulation, mammalian CAD catalyzes the decarboxylation of the TCA cycle intermediate cis-aconitate to produce itaconate.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
- Interpretationcitation
Inhibition of SDH by endogenously produced itaconate may buffer against potential oxidative damage that can occur under ischemia/reperfusion conditions.
“Notably, SDH inhibition protected against brain injury after ischemia/reperfusion (40,41), suggesting that inhibition of SDH by endogenously produced itaconate may buffer against potential oxidative damage that can occur under such conditions.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
Not checked in the free run.
- cites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
Not checked in the free run.
- Interpretationown data
Mammalian CAD-produced itaconate serves as a metabolic inhibitor to cause succinate accumulation.
“Our findings provide critical new insights into the regulatory machinery governing TCA cycle function, with mammalian CAD-produced itaconate serving as a metabolic inhibitor to cause succinate accumulation.”
Quote in the paperSubstantial claim- Rests on an assumption: The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
- May combine two claims. 10
- Classified as probably not a substantial claim. 13
May combine two claims.
Findingown dataIn A549 lung adenocarcinoma cells, succinate levels increase linearly with itaconate levels and correlate strongly (r = 0.99), whereas citrate, α-ketoglutarate, fumarate, and malate do not accumulate.
“Succinate levels increased linearly with itaconate levels and correlated strongly (r ϭ 0.99), whereas other TCA cycle intermediates, including citrate, ␣-ketoglutarate, fumarate, and malate, did not accumulate (Fig. 3a).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn LPS-activated RAW 264.7 macrophages, high fractions of M1 itaconate isotopologues (~65%) are observed because of itaconate production via reductive glutamine metabolism, but no labeling is detected on succinate.
“Although we observed high fractions of M1 itaconate isotopologues (ϳ65%) because of itaconate production via reductive glutamine metabolism, no labeling was detected on succinate (Fig. 4b).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataExposure to exogenous itaconate induces succinate accumulation in resting RAW 264.7 macrophages and resting BMDMs.
“exposure to exogenous itaconate induces succinate accumulation in resting RAW 264.7 macrophages (Fig. 2e) as well as resting BMDMs (Fig. 2h)”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataVariability in succinate accumulation upon LPS stimulation was observed when comparing RAW 264.7 macrophages and BMDMs.
“Within our analyses, we did observe variability in succinate accumulation upon LPS stimulation when comparing RAW 264.7 macrophages and BMDMs.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *The first TCA cycle break occurs at isocitrate dehydrogenase, leading to accumulation of citrate, the precursor for itaconate.
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [24] O'Neill, 2015, A broken Krebs cycle in macrophages, Immunity source
Not checked in the free run.
- cites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *Itaconate inhibits SDH ex vivo.
“Although itaconate has been shown previously to inhibit SDH ex vivo (26 -28)”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [26] Booth, 1952, The inhibitory effects of itaconic acid in vitro and in vivo, J. Biol. Chem. source
Not checked in the free run.
- cites [27] Ackermann, 1949, Enzyme inhibition in relation to chemotherapy, Proc. Soc. Exp. Biol. Med. source
Not checked in the free run.
- cites [28] Dervartanian, 1964, Studies on succinate dehydrogenase: I: spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes, Biochim. Biophys. Acta.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *Glycolytic metabolism is a prerequisite for succinate accumulation.
“although glycolytic metabolism is a prerequisite (14).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
Not checked in the free run.
May combine two claims.
Premisecitation§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels *The second TCA cycle break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [24] O'Neill, 2015, A broken Krebs cycle in macrophages, Immunity source
Not checked in the free run.
- cites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
Not checked in the free run.
Classified as probably not a substantial claim.
InterpretationreasoningItaconate is a regulatory molecule that reprograms immune cell metabolism.
“The emerging role of itaconate as a regulatory molecule to reprogram immune cell metabolism provides an intriguing link between innate immunity, metabolism, and disease pathogenesis.”
Quote in the paperSubstantial claim- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationItaconate is produced by mammalian CAD activity on cis-aconitate.
“Itaconate was only recently identified as an endogenous mammalian biochemical (19), and subsequent studies demonstrated that this molecule was produced by mammalian CAD activity on cis-aconitate (20).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Michelucci, 2013, Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production, Proc. Natl. Acad. Sci. U.S.A source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationNumerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, particularly those that regulate succinate levels, which can influence HIF signaling or other pathways.
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13,25,40,41).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
Not checked in the free run.
- cites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
Not checked in the free run.
- cites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
Not checked in the free run.
- cites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIntracellular signaling pathways play key roles in macrophage polarization and likely sustain inflammation to some degree in the absence of Irg1.
“Intracellular signaling pathways also play key roles in macrophage polarization and likely sustain inflammation to some degree in the absence of Irg1 (44).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [44] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J. Clin. Invest. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationGlutamine serves as a major carbon source for succinate production in LPS-activated macrophages via α-ketoglutarate or through the GABA shunt.
“Glutamine serves as a major carbon source for succinate production in LPSactivated macrophages via ␣-ketoglutarate or, alternatively, through the GABA shunt (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
InterpretationcitationThe variance in succinate accumulation is in the range reported by others and is likely a function of cell, medium formulation, and LPS variability.
“This variance is in the range of succinate accumulation levels reported by others and is likely a function of cell, medium formulation, and LPS variability (9).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
InterpretationreasoningItaconate may have pleiotropic effects on cells depending on the expression, Ki, and compartment-specific impacts on succinate concentrations.
“As such, itaconate may have pleiotropic effects on cells depending on the expression, K i , and compartment-specific impacts on succinate concentrations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationVarious other pathways, such as the GABA shunt and glutaminolysis, contribute to succinate synthesis in macrophages and could allow compensation.
“As noted above, various other pathways (e.g.GABA shunt, glutaminolysis) contribute to succinate synthesis in macrophages and could allow compensation (9, 13, 14).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Not checked in the free run.
- cites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
Not checked in the free run.
- cites [14] Palsson-McDermott, 2015, Pyruvate kinase M2 regulates Hif-1α activity and IL-1β induction and is a critical determinant of the Warburg effect in LPS-activated macrophages, Cell Metab source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).
InterpretationreasoningIRG1-mediated itaconate production may act as a signaling molecule in other inflammatory situations or cellular states.
“Given the regulatory role of itaconate in succinate accumulation described here, IRG1-mediated itaconate production may act as a signaling molecule in other inflammatory situations or cellular states.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataItaconate acts as an SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation.
“Taken together, our data highlight a mechanistic function of itaconate whereby this metabolite acts as a SDH inhibitor to influence TCA cycle metabolism by driving succinate accumulation (Fig. 7).”
- Also stated in: § Discussion · plain
“This metabolite contributes to succinate accumulation in macrophages by acting as an endogenous SDH inhibitor.”
Quote in the paperSubstantial claim- Also stated in: § Discussion · plain
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSuccinate inhibits HIF-1α signaling through inhibition of PHD2 but can also impact the activity of numerous α-ketoglutarate-dependent dioxygenases.
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2 but can also impact the activity of numerous ␣-ketoglutarate-dependent dioxygenases (42,43).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [42] Xiao, 2012, Inhibition of α-KG-dependent histone and DNA demethylases by fumarate and succinate that are accumulated in mutations of FH and SDH tumor suppressors, Genes Dev source
Not checked in the free run.
- cites [43] Metallo, 2013, Understanding metabolic regulation and its influence on cell physiology, Mol. Cell. source
Not checked in the free run.
The paper relies on this without support.
The specific driver(s) of succinate accumulation in inflammatory macrophages have not yet been identified.
“However, the specific driver(s) of this phenomenon has/have not yet been identified.”
The paper relies on this without support.
A potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.
“a potential role of endogenously produced itaconate in succinate accumulation under inflammatory conditions has not yet been addressed and is unknown.”
The paper relies on this without support.
The Irg1 KO mouse model specifically abolishes itaconate production without other metabolic adaptations that affect succinate levels.
“Notably, succinate concentrations in stimulated BMDMs from Irg1 KO mice were significantly lower than those quantified in BMDMs from WT mice, suggesting that CAD-derived itaconate influences succinate accumulation in LPS-induced macrophages (Fig. 6c).”
The paper relies on this without support.
The effects of exogenous itaconate on succinate accumulation reflect the physiological role of endogenous itaconate.
“In the cells studied, exogenous and endogenous, CAD-produced itaconate strongly correlated with succinate accumulation.”
The paper relies on this without support.
The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
“However, we consistently observed increased succinate downstream of itaconate production or administration in a variety of cell types.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
LDHA-deficient T cells show decreased acetyl-CoA levels and decreased H3K9Ac on the Ifng promoter.
“Mechanistically LDHA-deficient T cells showed decreased acetyl-CoA levels and decreased histone H3 acetylation at the lysine 9 residue (H3K9Ac), a histone mark associated with active transcription, on the Ifng promoter.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
Mice with T cell-specific LDHA deficiency produce less IFN-γ and are protected from immunopathology.
“Mice with an T cell-specific LDHA deficiency produced less IFN-γ and were protected from immunopathology.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
LDHA is induced in activated T cells and enhances histone acetylation of Ifng via maintenance of acetyl-CoA levels to promote its expression.
“The authors demonstrate that LDA, an enzyme that catalyzes the reversible conversion of pyruvate and NADH to lactate and NAD+, is induced in activated T cells and enhances histone acetylation of interferon gamma (Ifng) via the maintenance of acetyl-CoA levels to promote its expression 55.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
Artificial acetyl-CoA reduction through ACLY inhibition decreases IFN-γ expression, and acetate supplementation corrects H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.
“Furthermore, artificial acetyl-CoA reduction, through inhibition of ACLY, decreased IFN-γ expression and acetate supplementation, which augmented acetyl-CoA production, corrected H3K9Ac marks and IFN-γ expression in LDHA-deficient T cells.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
Itaconate primarily acts as a protective, anti-inflammatory metabolite.
“The generation of itaconate from the Krebs Cycle intermediate cis-aconitate contrasts with most other metabolite signals emanating from mitochondria, in that it primarily acts as a protective, anti-inflammatory metabolite55,59,60.”
From Coupling Krebs cycle metabolites to signalling in immunity and cancer (2018) · cites this paper as [55]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Inconsistent itaconate concentrations for respiration assays
MinorThe methods list four itaconate concentrations for the permeabilized-cell respiration assay, but the Figure 5 caption lists five, including 2.5 mM.
“increasing itaconate concentrations (0, 5, 10, and 25 mM)”
“increasing itaconate concentrations (0, 2.5, 5, 10, and 25 mM)”
Opposite claims about succinate's effect on HIF-1α signaling
MinorThe discussion says succinate inhibits HIF-1α signaling, whereas the earlier account says succinate stabilizes HIF-1α and enhances its downstream effect.
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2”
“succinate acts as a regulatory signal enhancing Il-1 expression through stabilization of HIF-1␣”
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,706 · see citing works
Pathogen Recognition and Innate Immunity
Akira, S., Uematsu, S., & Takeuchi, O. (2006) · Cell · doi:10.1016/j.cell.2006.02.015 · Cited by 11,974 · see citing works
Macrophage plasticity and polarization: in vivo veritas
Sica, A., & Mantovani, A. (2012) · Journal of Clinical Investigation · doi:10.1172/jci59643 · Cited by 6,335 · see citing works
Succinate is an inflammatory signal that induces IL-1β through HIF-1α
Tannahill, G. M., Curtis, A. M., Adamik, J., Palsson-McDermott, E. M., McGettrick, A. F., Goel, G., Frezza, C., Bernard, N. J., Kelly, B., Foley, N. H., et al. (2013) · Nature · doi:10.1038/nature11986 · Cited by 4,176 · see citing works
Epstein, A. C. R., Gleadle, J. M., McNeill, L. A., Hewitson, K. S., O'Rourke, J., Mole, D. R., Mukherji, M., Metzen, E., Wilson, M. I., Dhanda, A., et al. (2001) · Cell · doi:10.1016/s0092-8674(01)00507-4 · Cited by 3,333 · see citing works
Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
Chouchani, E. T., Pell, V. R., Gaude, E., Aksentijević, D., Sundier, S. Y., Robb, E. L., Logan, A., Nadtochiy, S. M., Ord, E. N. J., Smith, A. C., et al. (2014) · Nature · doi:10.1038/nature13909 · Cited by 2,907 · cited 3× · see citing works
“Numerous metabolic pathways have been implicated in the metabolic reprogramming of immune cells, in particular those that regulate succinate levels, which, in turn, can influence HIF signaling or other pathways (13, 25, 40, 41).”
BackgroundGiard, D. J., Aaronson, S. A., Todaro, G. J., Arnstein, P., Kersey, J. H., Dosik, H., & Parks, W. P. (1973) · JNCI Journal of the National Cancer Institute · doi:10.1093/jnci/51.5.1417 · Cited by 2,293 · see citing works
Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., & Gottlieb, E. (2005) · Cancer Cell · doi:10.1016/j.ccr.2004.11.022 · Cited by 2,108 · see citing works
Jha, A. K., Huang, S. C.-C., Sergushichev, A., Lampropoulou, V., Ivanova, Y., Loginicheva, E., Chmielewski, K., Stewart, K. M., Ashall, J., Everts, B., et al. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.005 · Cited by 2,066 · see citing works
Metabolic reprogramming in macrophages and dendritic cells in innate immunity
Kelly, B., & O'Neill, L. A. (2015) · Cell Research · doi:10.1038/cr.2015.68 · Cited by 1,876 · see citing works
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Self-citationMetabolic Pathways in Immune Cell Activation and Quiescence
Pearce, E. L., & Pearce, E. J. (2013) · Immunity · doi:10.1016/j.immuni.2013.04.005 · Cited by 1,692 · see citing works
The Isolation and Characterization of Murine Macrophages
Zhang, X., Gonçalves, R., & Mosser, D. M. (2008) · Current Protocols in Immunology · doi:10.1002/0471142735.im1401s83 · Cited by 1,536 · see citing works
Palsson-McDermott, E. M., Curtis, A. M., Goel, G., Lauterbach, M. A. R., Sheedy, F. J., Gleeson, L. E., van den Bosch, M. W. M., Quinn, S. R., Domingo-Fernandez, R., Johnston, D. G. W., et al. (2015) · Cell Metabolism · doi:10.1016/j.cmet.2014.12.005 · Cited by 1,397 · see citing works
Toll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
Krawczyk, C. M., Holowka, T., Sun, J., Blagih, J., Amiel, E., DeBerardinis, R. J., Cross, J. R., Jung, E., Thompson, C. B., Jones, R. G., et al. (2010) · Blood · doi:10.1182/blood-2009-10-249540 · Cited by 1,246 · see citing works
Immune-responsive gene 1 protein links metabolism to immunity by catalyzing itaconic acid production
Michelucci, A., Cordes, T., Ghelfi, J., Pailot, A., Reiling, N., Goldmann, O., Binz, T., Wegner, A., Tallam, A., Rausell, A., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1218599110 · Cited by 1,191 · see citing works
Self-citationXiao, M., Yang, H., Xu, W., Ma, S., Lin, H., Zhu, H., Liu, L., Liu, Y., Yang, C., Xu, Y., et al. (2012) · Genes & Development · doi:10.1101/gad.191056.112 · Cited by 1,188 · cited 2× · see citing works
“Indeed, succinate can inhibit various other -ketoglutarate-dependent dioxygenases to impact diverse cellular processes (42, 43).”
BackgroundRodríguez-Prados, J.-C., Través, P. G., Cuenca, J., Rico, D., Aragonés, J., Martín-Sanz, P., Cascante, M., & Boscá, L. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.0901698 · Cited by 1,022 · see citing works
Functional macrophage cell lines transformed by abelson leukemia virus
Raschke, W. C., Baird, S. M., Ralph, P., & Nakoinz, I. (1978) · Cell · doi:10.1016/0092-8674(78)90101-0 · Cited by 906 · see citing works
A Unifying Mechanism for Mitochondrial Superoxide Production during Ischemia-Reperfusion Injury
Chouchani, E. T., Pell, V. R., James, A. M., Work, L. M., Saeb-Parsy, K., Frezza, C., Krieg, T., & Murphy, M. P. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2015.12.009 · Cited by 752 · see citing works
Succinate: a metabolic signal in inflammation
Mills, E., & O’Neill, L. A. J. (2014) · Trends in Cell Biology · doi:10.1016/j.tcb.2013.11.008 · Cited by 741 · see citing works
Serine is a natural ligand and allosteric activator of pyruvate kinase M2
Chaneton, B., Hillmann, P., Zheng, L., Martin, A. C. L., Maddocks, O. D. K., Chokkathukalam, A., Coyle, J. E., Jankevics, A., Holding, F. P., Vousden, K. H., et al. (2012) · Nature · doi:10.1038/nature11540 · Cited by 661 · see citing works
What a difference a hydroxyl makes: mutant IDH, (<i>R</i>)-2-hydroxyglutarate, and cancer
Losman, J.-A., & Kaelin, W. G. (2013) · Genes & Development · doi:10.1101/gad.217406.113 · Cited by 570 · see citing works
Interleukin-1β and Tumor Necrosis Factor- Stimulate DNA Binding of Hypoxia-Inducible Factor-1
Hellwig‐Bürgel, T., Rutkowski, K., Metzen, E., Fandrey, J., & JELKMANN, W. E. B. (1999) · Blood · doi:10.1182/blood.v94.5.1561.417a06_1561_1567 · Cited by 475 · see citing works
Blouin, C. C., Pagé, E. L., Soucy, G. M., & Richard, D. E. (2003) · Blood · doi:10.1182/blood-2003-07-2427 · Cited by 459 · see citing works
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 · see citing works
Understanding metabolic regulation and its influence on cell physiology
Metallo, C. M., & Vander Heiden, M. G. (2013) · Molecular Cell · doi:10.1016/j.molcel.2013.01.018 · Cited by 367 · see citing works
Rocking cell metabolism: revised functions of the key glycolytic regulator PKM2 in cancer
Chaneton, B., & Gottlieb, E. (2012) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2012.04.003 · Cited by 294 · see citing works
Enzyme Inhibition in Relation to Chemotherapy.
Ackermann, W. W., & Potter, V. R. (1949) · Experimental Biology and Medicine · doi:10.3181/00379727-72-17313 · Cited by 262 · cited 2× · see citing works
“Indeed, in vitro enzyme activity assays using isolated SDH and respiratory studies have indicated that itaconate can reduce the activity of SDH (27, 28, 37).”
A broken Krebs cycle in macrophages
O’Neill, L. A. J. (2015) · Immunity · doi:10.1016/j.immuni.2015.02.017 · Cited by 232 · see citing works
Cho, H., Proll, S. C., Szretter, K. J., Katze, M. G., Gale, M., & Diamond, M. S. (2013) · Nature Medicine · doi:10.1038/nm.3108 · Cited by 228 · see citing works
Itaconate, an isocitrate lyase-directed inhibitor in Pseudomonas indigofera
McFadden, B. A., & Purohit, S. (1977) · Journal of Bacteriology · doi:10.1128/jb.131.1.136-144.1977 · Cited by 220 · see citing works
Itaconic Acid: The Surprising Role of an Industrial Compound as a Mammalian Antimicrobial Metabolite
Cordes, T., Michelucci, A., & Hiller, K. (2015) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071714-034243 · Cited by 183 · see citing works
Self-citationEoh, H., & Rhee, K. Y. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1400390111 · Cited by 170 · see citing works
Activation of Hypoxia-Inducible Factor-1 in Bacillary Angiomatosis
Kempf, V. A. J., Lebiedziejewski, M., Alitalo, K. K., Wälzlein, J.-H., Ehehalt, U., Fiebig, J., Huber, S. M., Schüett, B. S., Sander, C. A., Müller, S., et al. (2005) · Circulation · doi:10.1161/01.cir.0000155608.07691.b7 · Cited by 162 · see citing works
The proinflammatory cytokine-induced IRG1 protein associates with mitochondria
Degrandi, D., Hoffmann, R., Beuter-Gunia, C., & Pfeffer, K. (2009) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2008.0013 · Cited by 155 · see citing works
Divakaruni, A. S., Rogers, G. W., & Murphy, A. N. (2014) · Current Protocols in Toxicology · doi:10.1002/0471140856.tx2502s60 · Cited by 141 · see citing works
Self-citationNémeth, B., Doczi, J., Csete, D., Kacso, G., Ravasz, D., Adams, D., Kiss, G., Nagy, A. M., Horvath, G., Tretter, L., et al. (2016) · The FASEB Journal · doi:10.1096/fj.15-279398 · Cited by 136 · see citing works
Studies on succinate dehydrogenase
Dervartanian, D. V., & Veeger, C. (1964) · Biochimica et Biophysica Acta (BBA) - Specialized Section on Enzymological Subjects · doi:10.1016/0926-6569(64)90182-8 · Cited by 130 · see citing works
How metabolites modulate metabolic flux
Wegner, A., Meiser, J., Weindl, D., & Hiller, K. (2014) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2014.11.008 · Cited by 104 · see citing works
Self-citationBailey, E., Stirpe, F., & Taylor, C. B. (1968) · Biochemical Journal · doi:10.1042/bj1080427 · Cited by 104 · see citing works
Mechanism of action of isocitrate lyase from Pseudomonas indigofera
McFadden, B. A., Williams, J. O., & Roche, T. E. (1971) · Biochemistry · doi:10.1021/bi00784a017 · Cited by 99 · see citing works
THE METABOLISM OF ITACONIC ACID BY LIVER MITOCHONDRIA
Adler, J., Wang, S., & Lardy, H. A. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)63691-4 · Cited by 88 · see citing works
Smith, J., Sadeyen, J.-R., Paton, I. R., Hocking, P. M., Salmon, N., Fife, M. S., Nair, V., Burt, D. W., & Kaiser, P. (2011) · Journal of Virology · doi:10.1128/jvi.05499-11 · Cited by 86 · see citing works
Sepsis, oxidative stress, and hypoxia: Are there clues to better treatment?
Bar‐Or, D., Carrick, M. M., Mains, C. W., Rael, L. T., Slone, D. S., & Brody, E. N. (2015) · Redox Report · doi:10.1179/1351000215y.0000000005 · Cited by 85 · see citing works
Cheon, Y.-P., Xu, X., Bagchi, M. K., & Bagchi, I. C. (2003) · Endocrinology · doi:10.1210/en.2003-0585 · Cited by 76 · see citing works
The inhibition of succinate dehydrogenase by oxaloacetate
Wojtczak, L., Wojtczak, A., & Ernster, L. (1969) · Biochimica et Biophysica Acta (BBA) - Enzymology · doi:10.1016/0005-2744(69)90310-6 · Cited by 70 · see citing works
Hall, C. J., Boyle, R. H., Sun, X., Wicker, S. M., Misa, J. P., Krissansen, G. W., Print, C. G., Crosier, K. E., & Crosier, P. S. (2014) · Nature Communications · doi:10.1038/ncomms4880 · Cited by 68 · see citing works
The utilization of itaconate by Pseudomonas sp
Cooper, R., & Kornberg, H. L. (1964) · Biochemical Journal · doi:10.1042/bj0910082 · Cited by 53 · see citing works
Caenorhabditis elegans and Ascaris suum: inhibition of isocitrate lyase by itaconate
Patel, T. R., & McFadden, B. A. (1978) · Experimental Parasitology · doi:10.1016/0014-4894(78)90107-8 · Cited by 46 · see citing works
The inhibitory effects of itaconic acid in vitro and in vivo
Booth, A. N., Taylor, J., Wilson, R. H., & DeEds, F. (1952) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)55778-1 · Cited by 42 · see citing works
Preuße, M., Tantawy, M. A., Klawonn, F., Schughart, K., & Peßler, F. (2013) · BMC Microbiology · doi:10.1186/1471-2180-13-293 · Cited by 37 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Mitochondrial TCA cycle metabolites control physiology and disease
Martínez-Reyes, I., & Chandel, N. S. (2020) · Nature Communications · doi:10.1038/s41467-019-13668-3 · Cited by 2,813 · see citing works
Defining trained immunity and its role in health and disease
Netea, M. G., Domínguez-Andrés, J., Barreiro, L. B., Chavakis, T., Divangahi, M., Fuchs, E., Joosten, L. A. B., van der Meer, J. W. M., Mhlanga, M. M., Mulder, W. J. M., et al. (2020) · Nature Reviews Immunology · doi:10.1038/s41577-020-0285-6 · Cited by 2,690 · see citing works
Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1
Mills, E. L., Ryan, D. G., Prag, H. A., Dikovskaya, D., Menon, D., Zaslona, Z., Jedrychowski, M. P., Costa, A. S. H., Higgins, M., Hams, E., et al. (2018) · Nature · doi:10.1038/nature25986 · Cited by 1,885 · see citing works
Macrophage Immunometabolism: Where Are We (Going)?
den Bossche, J. V., O'Neill, L. A. J., & Menon, D. (2017) · Trends in Immunology · doi:10.1016/j.it.2017.03.001 · Cited by 1,162 · see citing works
Metabolic reprogramming and epigenetic modifications on the path to cancer
Sun, L., Zhang, H., & Gao, P. (2021) · Protein & Cell · doi:10.1007/s13238-021-00846-7 · Cited by 796 · see citing works
Navigating metabolic pathways to enhance antitumour immunity and immunotherapy
Li, X., Wenes, M., Romero, P. J., Huang, S. C., Fendt, S., & Ho, P. (2019) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-019-0203-7 · Cited by 745 · see citing works
Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis
Bambouskova, M., Gorvel, L., Lampropoulou, V., Sergushichev, A., Loginicheva, E., Johnson, K., Korenfeld, D., Mathyer, M. E., Kim, H., Huang, L.-H., et al. (2018) · Nature · doi:10.1038/s41586-018-0052-z · Cited by 713 · see citing works
Glycolysis – a key player in the inflammatory response
Soto‐Heredero, G., Heras, M. M. G. D. L., Gabandé‐Rodríguez, E., Oller, J., & Mittelbrunn, M. (2020) · FEBS Journal · doi:10.1111/febs.15327 · Cited by 645 · see citing works
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 624 · see citing works
Metabolic Regulation of Macrophage Polarization in Cancer
Mehla, K., & Singh, P. K. (2019) · Trends in cancer · doi:10.1016/j.trecan.2019.10.007 · Cited by 617 · see citing works
The Immunomodulatory Metabolite Itaconate Modifies NLRP3 and Inhibits Inflammasome Activation
Hooftman, A., Angiari, S., Hester, S., Corcoran, S. E., Runtsch, M. C., Ling, C., Ruzek, M. C., Slivka, P. F., McGettrick, A. F., Banahan, K., et al. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.07.016 · Cited by 620 · see citing works
Redox regulation of the immune response
Morris, G., Gevezova, M., Sarafian, V. S., & Maes, M. H. J. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00902-0 · Cited by 600 · see citing works
Williams, N. C., & O'Neill, L. A. J. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00141 · Cited by 569 · see citing works
Metabolism of tissue macrophages in homeostasis and pathology
Wculek, S. K., Dunphy, G., Heras-Murillo, I., Mastrangelo, A., & Sancho, D. (2022) · Cellular & Molecular Immunology · doi:10.1038/s41423-021-00791-9 · Cited by 501 · see citing works
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 · see citing works
The role of itaconate in host defense and inflammation
Peace, C. G., & O’Neill, L. A. J. (2022) · Journal of Clinical Investigation · doi:10.1172/jci148548 · Cited by 452 · see citing works
Krebs cycle Reborn in macrophage immunometabolism
Ryan, D. G., & O'Neill, L. A. J. (2020) · Annual Review of Immunology · doi:10.1146/annurev-immunol-081619-104850 · Cited by 444 · see citing works
Coupling Krebs cycle metabolites to signalling in immunity and cancer
Ryan, D. G., Murphy, M. P., Frezza, C., Prag, H. A., Chouchani, E. T., O’Neill, L. A., & Mills, E. L. (2018) · Nature Metabolism · doi:10.1038/s42255-018-0014-7 · Cited by 398 · see citing works
Domínguez‐Andrés, J., Novakovic, B., Li, Y., Scicluna, B. P., Gresnigt, M. S., Arts, R. J. W., Oosting, M., Moorlag, S. J. C. F. M., Groh, L. A., Zwaag, J., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.09.003 · Cited by 394 · see citing works
Self-citationKrebs Cycle Reimagined: The Emerging Roles of Succinate and Itaconate as Signal Transducers
Murphy, M. P., & O'Neill, L. A. J. (2018) · Cell · doi:10.1016/j.cell.2018.07.030 · Cited by 393 · see citing works
Gut Microbiome Dysbiosis and Immunometabolism: New Frontiers for Treatment of Metabolic Diseases
Belizário, J. E., Faintuch, J., & Garay-Malpartida, M. (2018) · Mediators of Inflammation · doi:10.1155/2018/2037838 · Cited by 341 · see citing works
Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation
Billingham, L. K., Stoolman, J. S., Vasan, K., Rodriguez, A. E., Poor, T. A., Szibor, M., Jacobs, H. T., Reczek, C. R., Rashidi, A., Zhang, P., et al. (2022) · Nature Immunology · doi:10.1038/s41590-022-01185-3 · Cited by 360 · see citing works
Metabolism as a guiding force for immunity
Jung, J., Zeng, H., & Horng, T. (2018) · Nature Cell Biology · doi:10.1038/s41556-018-0217-x · Cited by 345 · see citing works
Serine Metabolism Supports Macrophage IL-1β Production
Rodriguez, A. E., Ducker, G. S., Billingham, L. K., Martinez, C. A., Mainolfi, N., Suri, V., Friedman, A. A., Manfredi, M. G., Weinberg, S. E., Rabinowitz, J. D., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.01.014 · Cited by 346 · see citing works
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 · see citing works
Metabolic orchestration of the wound healing response
Eming, S. A., Murray, P. J., & Pearce, E. J. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.07.017 · Cited by 319 · see citing works
Macrophage Metabolism As Therapeutic Target for Cancer, Atherosclerosis, and Obesity
Geeraerts, X., Bolli, E., Fendt, S., & Ginderachter, J. A. V. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00289 · Cited by 315 · see citing works
Immunity, Hypoxia, and Metabolism–the Ménage à Trois of Cancer: Implications for Immunotherapy
Riera-Domingo, C., Audigé, A., Granja, S., Cheng, W.-C., Ho, P.-C., Baltazar, F., Stockmann, C., & Mazzone, M. (2020) · Physiological Reviews · doi:10.1152/physrev.00018.2019 · Cited by 310 · see citing works
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
Metabolic Modulation in Macrophage Effector Function
Diskin, C., & Pålsson‐McDermott, E. M. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00270 · Cited by 292 · see citing works
Olagnier, D., Brandtoft, A. M., Gunderstofte, C., Villadsen, N. L., Krapp, C., Thielke, A. L., Laustsen, A., Peri, S., Hansen, A. L., Bonefeld, L., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-05861-7 · Cited by 282 · see citing works
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 · see citing works
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 · see citing works
Cancer cell and macrophage cross-talk in the tumor microenvironment
Dehne, N., Mora, J., Namgaladze, D., Weigert, A., & Brüne, B. (2017) · Current Opinion in Pharmacology · doi:10.1016/j.coph.2017.04.007 · Cited by 265 · see citing works
Metabolic regulation of macrophage phenotype and function
Saha, S., Shalova, I. N., & Biswas, S. K. (2017) · Immunological Reviews · doi:10.1111/imr.12603 · Cited by 252 · see citing works
Papathanassiu, A. E., Ko, J., Imprialou, M., Bagnati, M., Srivastava, P. K., Vu, H., Cucchi, D., McAdoo, S. P., Ananieva, E. A., Mauro, C., et al. (2017) · Nature Communications · doi:10.1038/ncomms16040 · Cited by 250 · see citing works
Intracellular and Intercellular Aspects of Macrophage Immunometabolism in Atherosclerosis
Tabas, I. A., & Bornfeldt, K. (2020) · Circulation Research · doi:10.1161/circresaha.119.315939 · Cited by 249 · see citing works
How location and cellular signaling combine to activate the NLRP3 inflammasome
Akbal, A., Dernst, A., Lovotti, M., Mangan, M., McManus, R. M., & Latz, E. (2022) · Cellular and Molecular Immunology · doi:10.1038/s41423-022-00922-w · Cited by 250 · see citing works
Macrophage fumarate hydratase restrains mtRNA-mediated interferon production
Hooftman, A., Peace, C. G., Ryan, D. G., Day, E. A., Yang, M. H., McGettrick, A. F., Yin, M., Montano, E. N., Huo, L., Toller-Kawahisa, J. E., et al. (2023) · Nature · doi:10.1038/s41586-023-05720-6 · Cited by 246 · see citing works
Itaconate confers tolerance to late NLRP3 inflammasome activation
Bambousková, M., Potůčková, L., Paulenda, T., Kerndl, M., Mogilenko, D. A., Lizotte, K., Swain, A., Hayes, S., Sheldon, R. D., Kim, H., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.108756 · Cited by 246 · see citing works
Tricarboxylic Acid (TCA) Cycle Intermediates: Regulators of Immune Responses
Choi, I., Son, H., & Baek, J.-H. (2021) · Life · doi:10.3390/life11010069 · Cited by 244 · see citing works
Kieler, M., Hofmann, M., & Schabbauer, G. (2021) · FEBS Journal · doi:10.1111/febs.15715 · Cited by 246 · see citing works
Nitric Oxide in Macrophage Immunometabolism: Hiding in Plain Sight
Palmieri, E. M., McGinity, C., Wink, D. A., & McVicar, D. W. (2020) · Metabolites · doi:10.3390/metabo10110429 · Cited by 237 · 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…”
BackgroundInfluentialThe 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 · see citing works
Itaconate inhibits TET DNA dioxygenases to dampen inflammatory responses
Chen, L., Morcelle, C., Cheng, Z., Chen, X., Xu, Y., Gao, Y., Song, J., Li, Z., Smith, M. D., Shi, M., et al. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00853-8 · Cited by 228 · see citing works
ACOD1 in immunometabolism and disease
Wu, R., Chen, F., Wang, N., Tang, D., & Kang, R. (2020) · Cellular and Molecular Immunology · doi:10.1038/s41423-020-0489-5 · Cited by 217 · see citing works
The role of macrophages polarization in sepsis-induced acute lung injury
Wang, Z., & Wang, Z. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1209438 · Cited by 219 · see citing works
Modification of Proteins by Metabolites in Immunity
Diskin, C., Ryan, T. A. J., & O'Neill, L. A. J. (2020) · Immunity · doi:10.1016/j.immuni.2020.09.014 · Cited by 214 · see citing works
Regulation of succinate dehydrogenase and role of succinate in cancer
Dalla Pozza, E., Dando, I., Pacchiana, R., Liboi, E., Scupoli, M. T., Donadelli, M., & Palmieri, M. (2020) · Seminars in Cell & Developmental Biology · doi:10.1016/j.semcdb.2019.04.013 · Cited by 212 · see citing works
Fleetwood, A. J., Lee, M. K. S., Singleton, W., Achuthan, A. A., Lee, M.-C., O’brien-simpson, N. M., Cook, A. D., Murphy, A. J., Dashper, S. G., Reynolds, E. C., et al. (2017) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2017.00351 · Cited by 206 · see citing works
Self-citationMetabolism Supports Macrophage Activation
Langston, P. K., Shibata, M., & Horng, T. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00061 · Cited by 185 · see citing works
The NLRP3 Inflammasome: Metabolic Regulation and Contribution to Inflammaging
Meyers, A. K., & Zhu, X. (2020) · Cells · doi:10.3390/cells9081808 · Cited by 203 · see citing works
Molecular Mechanisms Modulating the Phenotype of Macrophages and Microglia
Amici, S. A., Dong, J., & Guerau‐de‐Arellano, M. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01520 · Cited by 192 · see citing works
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 · see citing works
Chen, F., Elgaher, W. A. M., Winterhoff, M., Büssow, K., Waqas, S. F., Graner, E., Pires‐Afonso, Y., Perez, L. C., de la Vega, L., Sahini, N., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00577-x · Cited by 175 · see citing works
Self-citationMetabolic influence on macrophage polarization and pathogenesis
Thapa, B., & Lee, K. (2019) · BMB Reports · doi:10.5483/bmbrep.2019.52.6.140 · Cited by 173 · see citing works
Impact of intracellular innate immune receptors on immunometabolism
Chou, W.-C., Rampanelli, E., Li, X., & Ting, J. P. ‐. (2021) · Cellular and Molecular Immunology · doi:10.1038/s41423-021-00780-y · Cited by 170 · see citing works
Myeloid-derived itaconate suppresses cytotoxic CD8+ T cells and promotes tumour growth
Zhao, H., Teng, D., Yang, L., Xu, X., Chen, J., Jiang, T., Feng, A. Y., Zhang, Y., Frederick, D. T., Gu, L., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00676-9 · Cited by 173 · see citing works
Biphasic Dynamics of Macrophage Immunometabolism during Mycobacterium tuberculosis Infection
Shi, L., Jiang, Q., Bushkin, Y., Subbian, S., & Tyagi, S. (2019) · mBio · doi:10.1128/mbio.02550-18 · Cited by 169 · see citing works
Itaconate is an effector of a Rab GTPase cell-autonomous host defense pathway against Salmonella
Chen, M., Sun, H., Boot, M., Shao, L., Chang, S.-J., Wang, W., Lam, T. T., Lara-Tejero, M., Rego, E. H., & Galán, J. E. (2020) · Science · doi:10.1126/science.aaz1333 · Cited by 169 · see citing works
Dambrova, M., Zuurbier, C. J., Borutaitė, V., Liepinsh, E., & Makrecka‐Kuka, M. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.01.036 · Cited by 165 · see citing works
Marrocco, A., & Ortiz, L. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.936167 · Cited by 166 · see citing works
Itaconate controls the severity of pulmonary fibrosis
Ogger, P. P., Albers, G. J., Hewitt, R. J., O’Sullivan, B., Powell, J. E., Calamita, E., Ghai, P., Walker, S. A., McErlean, P. K., Saunders, P. T., et al. (2020) · Science Immunology · doi:10.1126/sciimmunol.abc1884 · Cited by 159 · see citing works
Shi, X., Zhou, H., Wei, J., Mo, W., Li, Q., & Lv, X. (2022) · Redox Biology · doi:10.1016/j.redox.2022.102553 · Cited by 160 · see citing works
Inducible antibacterial responses in macrophages
Sweet, M. J., Ramnath, D., Singhal, A., & Kapétanovic, R. (2024) · Nature reviews. Immunology · doi:10.1038/s41577-024-01080-y · Cited by 163 · see citing works
Mitochondria reactive oxygen species signaling in immune responses
Weinberg, S. E., & Chandel, N. S. (2025) · Immunity · doi:10.1016/j.immuni.2025.07.012 · Cited by 166 · see citing works
Itaconate modulates tricarboxylic acid and redox metabolism to mitigate reperfusion injury
Cordes, T., Lucas, A., Divakaruni, A. S., Murphy, A. N., Cabrales, P., & Metallo, C. M. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.11.019 · Cited by 153 · see citing works
Self-citationSanta, F. D., Vitiello, L., Torcinaro, A., & Ferraro, E. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7420 · Cited by 154 · see citing works
The Human Knockout Gene CLYBL Connects Itaconate to Vitamin B12
Shen, H., Campanello, G. C., Flicker, D., Grabarek, Z., Hu, J., Luo, C., Banerjee, R. V., & Mootha, V. K. (2017) · Cell · doi:10.1016/j.cell.2017.09.051 · Cited by 152 · see citing works
Chen, Y., Li, G.-N., Li, X.-J., Wei, L.-X., Fu, M., Cheng, Z., Yang, Z., Zhu, G., Wang, X., Zhang, C., et al. (2023) · Science Advances · doi:10.1126/sciadv.adg0654 · Cited by 149 · see citing works
Krebs cycle rewired for macrophage and dendritic cell effector functions
Ryan, D. G., & O'Neill, L. A. J. (2017) · FEBS Letters · doi:10.1002/1873-3468.12744 · Cited by 150 · see citing works
Targeting macrophage immunometabolism: Dawn in the darkness of sepsis
Kumar, V. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.03.005 · Cited by 149 · see citing works
Macrophages are metabolically heterogeneous within the tumor microenvironment
Geeraerts, X., Fernández-García, J., Hartmann, F. J., de Goede, K. E., Martens, L., Elkrim, Y., Debraekeleer, A., Stijlemans, B., Vandekeere, A., Rinaldi, G., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.110171 · Cited by 144 · see citing works
PPARγ is a nexus controlling alternative activation of macrophages via glutamine metabolismPreprint
Nelson, V., Nguyen, H. C. B., García-Cañaveras, J., Briggs, E. R., Ho, W. Y., DiSpirito, J., Marinis, J. M., Hill, D. A., & Lazar, M. (2018) · Genes & Development · doi:10.1101/gad.312355.118 · Cited by 136 · see citing works
Mitochondrial metabolites: undercover signalling molecules
Frezza, C. (2017) · Interface Focus · doi:10.1098/rsfs.2016.0100 · Cited by 136 · see citing works
Freemerman, A. J., Zhao, L., Pingili, A. K., Teng, B., Cozzo, A. J., Fuller, A. M., Johnson, A., Milner, J. J., Lim, M. F., Galanko, J. A., et al. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1800002 · Cited by 132 · see citing works
Metabolic programming of macrophage functions and pathogens control
Koo, S.-J., & Garg, N. J. (2019) · Redox Biology · doi:10.1016/j.redox.2019.101198 · Cited by 132 · see citing works
Huang, H., Li, G., He, Y., Chen, J., Yan, J., Zhang, Q., Li, L., & Cai, X. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1404441 · Cited by 141 · see citing works
Food Fight: Role of Itaconate and Other Metabolites in Antimicrobial Defense
Luan, H. H., & Medzhitov, R. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.08.013 · Cited by 130 · see citing works
Dimethyl Itaconate Is Not Metabolized into Itaconate Intracellularly
ElAzzouny, M., Tom, C. T. M. B., Evans, C. R., Olson, L. L., Tanga, M. J., Gallagher, K. A., Martin, B. R., & Burant, C. F. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.c117.775270 · Cited by 125 · see citing works
Pålsson‐McDermott, E. M., & O'Neill, L. A. J. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.03.004 · Cited by 122 · see citing works
An Epigenetic Role of Mitochondria in Cancer
Liu, Y., Chen, C., Wang, X., Sun, Y., Zhang, J., Chen, J., & Shi, Y. (2022) · Cells · doi:10.3390/cells11162518 · Cited by 125 · see citing works
Macrophage metabolic reprogramming during chronic lung disease
Ogger, P. P., & Byrne, A. J. (2020) · Mucosal Immunology · doi:10.1038/s41385-020-00356-5 · Cited by 119 · see citing works
Mesaconate is synthesized from itaconate and exerts immunomodulatory effects in macrophages
He, W., Henne, A., Lauterbach, M., Geißmar, E., Nikolka, F., Kho, C., Heinz, A., Dostert, C., Grusdat, M., Cordes, T., et al. (2022) · Nature Metabolism · doi:10.1038/s42255-022-00565-1 · Cited by 99 · see citing works
Self-citationThe Metabolic Basis of Immune Dysfunction Following Sepsis and Trauma
McBride, M. A., Owen, A. M., Stothers, C. L., Hernandez, A., Luan, L., Burelbach, K. R., Patil, T. K., Bohannon, J. K., Sherwood, E. R., & Patil, N. K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01043 · Cited by 116 · see citing works
The Dynamic Inflammatory Tissue Microenvironment: Signality and Disease Therapy by Biomaterials
Mata, R., Yao, Y., Cao, W., Ding, J., Zhou, T., Zhai, Z., & Gao, C.-Y. (2021) · Research · doi:10.34133/2021/4189516 · Cited by 112 · see citing works
Kuo, P., Weng, W., Scofield, B. A., Paraiso, H. C., Brown, D. A., Wang, P., Yu, I.-C. I., & Yen, J.-H. J. (2020) · Journal of Neuroinflammation · doi:10.1186/s12974-020-01768-7 · Cited by 112 · see citing works
Hallmarks of Pulmonary Hypertension: Mesenchymal and Inflammatory Cell Metabolic Reprogramming
D’Alessandro, A., Kasmi, K. C. E., Plecitá‐Hlavatá, L., Ježek, P., Li, M., Zhang, H., Gupte, S. A., & Stenmark, K. R. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7217 · Cited by 110 · see citing works
Biochemistry of proinflammatory macrophage activation
Nonnenmacher, Y., & Hiller, K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2784-1 · Cited by 110 · see citing works
Self-citationSohail, A., Iqbal, A., Sahini, N., Chen, F., Tantawy, M. A., Waqas, S. F., Winterhoff, M., Ebensen, T., Schultz, K., Geffers, R., et al. (2022) · PLoS Pathogens · doi:10.1371/journal.ppat.1010219 · Cited by 105 · see citing works
Self-citationIntegrated Molecular Characterization of Fumarate Hydratase–deficient Renal Cell Carcinoma
Sun, G., Zhang, X., Liang, J., Pan, X., Zhu, S., Liu, Z., Armstrong, C. M., Chen, J., Lin, W., Liao, B., et al. (2021) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-20-3788 · Cited by 102 · see citing works
Bettencourt, I. A., & Powell, J. D. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1601318 · Cited by 104 · see citing works
Local Treatment with Lactate Prevents Intestinal Inflammation in the TNBS-Induced Colitis Model
Iraporda, C., Romanin, D., Bengoa, A. A., Errea, A. J., Cayet, D., Foligné, B., Sirard, J., Garrote, G. L., Abraham, A. G., & Rumbo, M. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00651 · Cited by 102 · see citing works
Alam, M. S., & Czajkowsky, D. M. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.11.001 · Cited by 101 · see citing works
Staphylococcus aureus stimulates neutrophil itaconate production that suppresses the oxidative burst
Tomlinson, K. L., Riquelme, S. A., Baskota, S. U., Drikic, M., Monk, I. R., Stinear, T. P., Lewis, I. A., & Prince, A. S. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112064 · Cited by 101 · see citing works
Zhu, X., Guo, Y., Liu, Z., Yang, J., Tang, H., & Wang, Y. (2021) · Scientific Reports · doi:10.1038/s41598-021-97352-x · Cited by 101 · see citing works
4-octyl itaconate as a metabolite derivative inhibits inflammation via alkylation of STING
Li, W., Li, Y., Kang, J., Jiang, H., Gong, W., Chen, L., Wu, C., Liu, M., Wu, X., Zhao, Y., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112145 · Cited by 117 · see citing works
Léveillard, T., Philp, N. J., & Sennlaub, F. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030762 · Cited by 100 · see citing works
Metabolic Regulation in the Induction of Trained Immunity
Ferreira, A. V., Domínguez‐Andrés, J., Pich, L. M. M., Joosten, L. A. B., & Netea, M. G. (2024) · Seminars in Immunopathology · doi:10.1007/s00281-024-01015-8 · Cited by 100 · see citing works
Chen, F., Lukat, P., Iqbal, A., Saile, K., Kaever, V., van den Heuvel, J., Blankenfeldt, W., Büssow, K., & Peßler, F. (2019) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1908770116 · Cited by 93 · see citing works
- Authors
- Cordes, T., Wallace, M., Michelucci, A., Divakaruni, A. S., Sapcariu, S. C., Sousa, C., Koseki, H., Cabrales, P., Murphy, A. N., Hiller, K., & Metallo, C. M.
- Affiliations
- University of California San Diego (US)
- University of Luxembourg (LU)
- RIKEN Center for Integrative Medical Sciences (JP)
- Corresponding author
- Metallo, Christian M.
- ORCID
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 291
- Issue
- 27
- Pages
- 14274-14284
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC4933182
- OpenAlex
- W2361586644
- Semantic Scholar
- e5517dd16c4dff72218eace800e1b0913a233bce
- Cited by
- 526
- References
- 52
- Citations by year
- 2026: 55 · 2025: 60 · 2024: 68 · 2023: 55 · 2022: 58 · 2021: 69 · 2020: 64 · 2019: 42 · 2018: 27 · 2017: 23 · 2016: 5
- FWCI
- 19.57
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, cc-by-nc-sa)
- Funders
- National Institutes of Health (R01CA188652, P01DK054441)
- National Institute of Allergy and Infectious Diseases (R01AI082610)
- National Heart, Lung, and Blood Institute (R53HL123015, P01HL110900, R01HL052684)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Microbial metabolism and enzyme function
- Keywords
- IRG1, itaconate, succinate accumulation, succinate dehydrogenase inhibition, cis-aconitate decarboxylase, TCA cycle, metabolic reprogramming, innate immunity, macrophages, lipopolysaccharide, electron transport chain, immunometabolism
- MeSH terms
- Animals, Cell Line, Hydro-Lyases, Lipopolysaccharides, Macrophages, Succinate Dehydrogenase, Succinates, Succinic Acid, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-10.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-10.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
