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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.
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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.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“We observed a dose depen- dent inhibition of OCRs by itaconate in RAW 264.7 macrophages (Fig. 5a) and BMDMs (Fig. 5b)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Itaconate also failed to impact this complex IV-mediated respiration.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Notably, basal oxygen consumption rates (OCR) remained unchanged compared with resting macrophages (Fig. 1b).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“However, medium itaconate levels were not appreciably affected (Fig. 2g).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Because labeling of succinate after exposure to exogenous, unlabeled itaconate was unchanged (even in the physi-ological concentration used here) (Fig. 4d)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Loss of itaconate production in activated macrophages from Irg1 ؊/؊ mice decreases the accumulation of succinate in response to LPS exposure.”
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesA result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 10
- Probably not a substantial claim. 13
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Itaconate and Irg1-induced Succinate Accumulation Is Not
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“exposure to exogenous itaconate induces succinate accumulation in resting RAW 264.7 macrophages (Fig. 2e) as well as resting BMDMs (Fig. 2h)”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Succinate and Itaconate Accumulate in LPS-activated RAW 264.7 Macrophages-To better understand the relationship between
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Within our analyses, we did observe variability in succinate accumulation upon LPS stimulation when comparing RAW 264.7 macrophages and BMDMs.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:plain· not yet calibratedCausal:correlational· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“The first break occurs at isocitrate dehydrogenase, leading to the accumulation of citrate, the precursor for itaconate”
What the sources say
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Although itaconate has been shown previously to inhibit SDH ex vivo (26 -28)”
What the sources say
- Not checked yetcites [26] Booth, 1952, The inhibitory effects of itaconic acid in vitro and in vivo, J. Biol. Chem. source
- Not checked yetcites [27] Ackermann, 1949, Enzyme inhibition in relation to chemotherapy, Proc. Soc. Exp. Biol. Med. source
- Not checked yetcites [28] Dervartanian, 1964, Studies on succinate dehydrogenase: I: spectral properties of the purified enzyme and formation of enzyme-competitive inhibitor complexes, Biochim. Biophys. Acta.
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
In the paper
“although glycolytic metabolism is a prerequisite (14).”
What the sources say
- Not checked yetcites [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
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“the second break occurs at succinate dehydrogenase (SDH), which may allow for succinate accumulation.”
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim.
- Rests on an assumption: The cell models used are representative of macrophages in vivo for conclusions about immune cell metabolism.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [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
Strength:boosted· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [25] Jha, 2015, Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization, Immunity source
- Not checked yetcites [40] Chouchani, 2016, A unifying mechanism for mitochondrial superoxide production during ischemia-reperfusion injury, Cell Metab source
- Not checked yetcites [41] Chouchani, 2014, Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS, Nature source
Strength:plain· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Intracellular signaling pathways also play key roles in macrophage polarization and likely sustain inflammation to some degree in the absence of Irg1 (44).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [44] Sica, 2012, Macrophage plasticity and polarization: in vivo veritas, J. Clin. Invest. source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
In the paper
“Glutamine serves as a major carbon source for succinate production in LPSactivated macrophages via ␣-ketoglutarate or, alternatively, through the GABA shunt (9).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“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).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As such, itaconate may have pleiotropic effects on cells depending on the expression, K i , and compartment-specific impacts on succinate concentrations.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
None of the sources cited for this claim have been checked yet.
In the paper
“As noted above, various other pathways (e.g.GABA shunt, glutaminolysis) contribute to succinate synthesis in macrophages and could allow compensation (9, 13, 14).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [9] Tannahill, 2013, Succinate is an inflammatory signal that induces IL-1β through HIF-1α, Nature source
- Not checked yetcites [13] Mills, 2014, Succinate: a metabolic signal in inflammation, Trends Cell Biol source
- Not checked yetcites [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
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✗ Checkable: fails✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence. The paper’s conclusions may not depend on it.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“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.”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Loss of Irg1 Influences Succinate Levels in
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Discussion · plain
None of the sources cited for this claim have been checked yet.
In the paper
“Succinate inhibits HIF-1␣ signaling through inhibition of PHD2 but can also impact the activity of numerous ␣-ketoglutarate-dependent dioxygenases (42,43).”
§ Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels * > Discussion
What the sources say
- Not checked yetcites [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 yetcites [43] Metallo, 2013, Understanding metabolic regulation and its influence on cell physiology, Mol. Cell. source
Strength:plain· not yet calibratedCausal:direct· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✗ Load-bearing: fails✓ Based: passesProbably not a substantial claim. The paper’s conclusions may not depend on it. It may state two separate claims as one.
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?
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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]
In the citing paper
“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␣”
Citations
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Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS
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“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).”
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Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-α prolyl hydroxylase
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IntracellularSalmonellametabolism
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Influenza A induces lactate formation to inhibit type I IFN in primary human airway epithelium
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Self-citationThe promise and peril of targeting cell metabolism for cancer therapy
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Macrophage activation as an archetype of mitochondrial repurposing
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Spontaneous hydrolysis and spurious metabolic properties of α-ketoglutarate esters
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Metabolic Adaptation of Macrophages as Mechanism of Defense against Crystalline Silica
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Unlocking potential: the role of the electron transport chain in immunometabolism
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Nrf2—A Molecular Target for Sepsis Patients in Critical Care
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How could we forget immunometabolism in SARS-CoV2 infection or COVID-19?
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Nitric oxide-driven modifications of lipoic arm inhibit α-ketoacid dehydrogenases
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Metabolic flexibility ensures proper neuronal network function in moderate neuroinflammation
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The anti-inflammatory effects of itaconate and its derivatives in neurological disorders
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Pattern-Recognition Receptors and Immunometabolic Reprogramming: What We Know and What to Explore
Kumar, V., & Stewart, J. H. (2024) · Journal of Innate Immunity · doi:10.1159/000539278 · Cited by 39
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Harnessing metabolism of hepatic macrophages to aid liver regeneration
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TCA cycle-derived oncometabolites in cancer and the immune microenvironment
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Succinate in innate immunity: linking metabolic reprogramming to immune modulation
Atallah, R., Gindlhuber, J., & Heinemann, Á. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1661948 · Cited by 41
Endotoxin Preconditioning Reprograms S1 Tubules and Macrophages to Protect the Kidney
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Immunometabolism in fungal infections: the need to eat to compete
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Itaconic acid indicates cellular but not systemic immune system activation
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Immune-based therapies in cardiovascular and metabolic diseases: past, present and future
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Self-citationMetabolism in tumor-associated macrophages
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Mitochondria in innate immunity signaling and its therapeutic implications in autoimmune diseases
Jiao, Y., Yan, Z., & Yang, A. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1160035 · Cited by 35
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Integration of transcriptional and metabolic control in macrophage activation
Natoli, G., Pileri, F., Gualdrini, F., & Ghisletti, S. (2021) · EMBO Reports · doi:10.15252/embr.202153251 · Cited by 33
Mitochondrial metabolism in macrophages
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Self-citationNew Avenues of Heme Synthesis Regulation
Medlock, A. E., & Dailey, H. A. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23137467 · Cited by 33
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The mechanisms and cross-protection of trained innate immunity
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Immunoresponsive gene 1 modulates the severity of brain injury in cerebral ischaemia
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Macrophages inhibit Coxiella burnetii by the ACOD1‐itaconate pathway for containment of Q fever
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Protein targeting by the itaconate family in immunity and inflammation
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Itaconate modulates immune responses via inhibition of peroxiredoxin 5
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The IRG1-Itaconate axis: A regulatory hub for immunity and metabolism in macrophages
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Let’s Enter the Wonderful World of Immunometabolites
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The Dual Role of ACOD1 in Inflammation
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Targeting the ACOD1-itaconate axis stabilizes atherosclerotic plaques
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Self-citationMyD88-Dependent Glucose Restriction and Itaconate Production Control Brucella Infection
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Metabolic ROS Signaling: To Immunity and Beyond
Andreyev, A. Y., Kushnareva, Y. E., Starkova, N. N., & Starkov, A. A. (2020) · Biochemistry (Moscow) · doi:10.1134/s0006297920120160 · Cited by 28
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The evolutionary tug-of-war of macrophage metabolism during bacterial infection
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Itaconic Acid: A Regulator of Immune Responses and Inflammatory Metabolism
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Immune-responsive gene 1 (IRG1) and dimethyl itaconate are involved in the mussel immune response
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Self-citationMacrophages treated with non-digestible polysaccharides reveal a transcriptionally unique phenotype
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The yin and yang of itaconate metabolism and its impact on the tumor microenvironment
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Discovery of Protein Modifications Using Differential Tandem Mass Spectrometry Proteomics
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Immunometabolites Drive Bacterial Adaptation to the Airway
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Elastomeric Polyesters in Cardiovascular Tissue Engineering and Organs-on-a-Chip
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Glutaminases as a Novel Target for SDHB-Associated Pheochromocytomas/Paragangliomas
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Itaconate mechanism of action and dissimilation in Mycobacterium tuberculosis
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Intersection of Immunology and Metabolism in Myocardial Disease
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In vivo itaconate tracing reveals degradation pathway and turnover kinetics
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Self-citationBasic Mechanisms of Immunometabolites in Shaping the Immune Response
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Intestinal Metabolites Influence Macrophage Phagocytosis and Clearance of Bacterial Infection
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Immunometabolic Regulation of Bacterial Infection, Biofilms, and Antibiotic Susceptibility
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Mitochondrial metabolism: Inducer or therapeutic target in tumor immune-resistance?
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The crucial role of metabolic reprogramming in driving macrophage conversion in kidney disease
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Anti-Inflammatory Metabolites in the Pathogenesis of Bacterial Infection
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A matter of time: temporal structure and functional relevance of macrophage metabolic rewiring
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Metabolite signaling in the heart
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Salvia officinalis L. exerts oncostatic effects in rodent and in vitro models of breast carcinoma
Kubatka, P., Mazuráková, A., Koklesová, L., Kuruc, T., Samec, M., Kajo, K., Petrová, K., Adamkov, M., Šmejkal, K., Švajdlenka, E., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1216199 · Cited by 19
Bahl, A., Pandey, S., Rakshit, R., Kant, S., & Tripathi, D. (2024) · Infection and Immunity · doi:10.1128/iai.00472-24 · Cited by 22
Bang, B., Miki, H., & Kang, Y. J. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1243548 · Cited by 22
Zhou, M., Yu, H., Bai, M., Lu, S., Wang, C., Ke, S., Huang, J., Li, Z., Xu, Y., Yin, B., et al. (2024) · Cancer Science · doi:10.1111/cas.16068 · Cited by 18
Metadata
- 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.
A language model drew the claims from the paper on 2026-10-10, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-10-10 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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 ›
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