The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index; none of the 26 sources its claims cite is checked for support yet.
Pyruvate Kinase M2 Regulates Hif-1α Activity and IL-1β Induction and Is a Critical Determinant of the Warburg Effect in LPS-Activated Macrophages
Open accessAbstract
Macrophages activated by the TLR4 agonist LPS undergo dramatic changes in their metabolic activity. We here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2). Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes. Activation of PKM2 attenuated an LPS-induced proinflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage. We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2. Both compounds inhibited LPS-induced glycolytic reprogramming and succinate production. Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, while boosting production of IL-10. PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.
Overview
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Written from the paper’s full text.
TL;DR
LPS induces PKM2 in macrophages, where dimeric/monomeric PKM2 complexes with Hif-1α and binds the IL-1β promoter to promote Warburg-like glycolysis and pro-inflammatory activation. Forcing PKM2 into tetramers with DASA-58 or TEPP-46 inhibits Hif-1α activity, IL-1β induction, glycolytic reprogramming, and succinate accumulation, while shifting macrophages toward an M2-like/IL-10-high phenotype and impairing bacterial killing in vivo.
Key findings
- LPS induced PKM2 expression and tyrosine 105 phosphorylation in BMDMs; Pkm2 mRNA increased approximately 2.8-fold after 24 hours, and phospho-PKM2 showed a 10.3-fold increase in relative band intensity, consistent with inactive monomer/dimer formation.
- PKM2 activators DASA-58 and TEPP-46 promoted tetramerization, inhibited LPS-induced nuclear translocation of PKM2, and blocked LPS-induced Hif-1α protein, pro-IL-1β, Il1b mRNA, and the Hif-1α target Ldha, without affecting IL-6 or TNF.
- LPS increased PKM2–Hif-1α association and binding of both to the IL-1β promoter; TEPP-46/DASA-58 inhibited this binding. PKM2 deletion reduced LPS-induced Hif-1α, Il1β, and Ldha, and reduced glycolysis, while increasing oxidative phosphorylation.
- DASA-58 blocked LPS-induced succinate and glycolytic intermediates; LPS caused up to a ten-fold increase in glycolysis that was markedly inhibited by TEPP-46 and DASA-58. In vivo, TEPP-46 reduced LPS- and Salmonella typhimurium-induced IL-1β, boosted IL-10, and increased bacterial dissemination.
Methods
- Primary BMDMs and peritoneal cells from C57BL/6 mice, RAW 264.7 macrophages, and conditional PKM2fl/fl BMDMs were treated with LPS, TEPP-46, DASA-58, tamoxifen, Mtb, or S. typhimurium.
- Main assays included Western blotting, DSS crosslinking, size-exclusion chromatography, nuclear/cytosolic fractionation, ELISA, qPCR, co-immunoprecipitation, oligonucleotide pulldown, sequential ChIP, Seahorse extracellular flux analysis, microarray profiling, and LC-MS metabolomics.
- In vivo models used LPS-induced sepsis and S. typhimurium infection in mice treated with TEPP-46 or vehicle, measuring serum cytokines, peritoneal cell IL-1β, and bacterial CFU in liver/spleen.
Limitations
- The paper does not include a dedicated limitations section.
- Limitations evident from the text: most mechanistic work uses mouse BMDMs/PECs and RAW cells; in vivo infection experiments use TEPP-46 only because DASA-58 is not pharmacokinetically validated in vivo; some data are not shown; and the mechanism by which PKM2 promotes IL-10 production is stated to require further analysis.
- The Mtb ELISA results are described as means ± SEMs for one representative experiment with n=2, limiting statistical robustness.
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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 found that genes upregulated in M1 cells were significantly upregulated by LPS treatment compared to LPS+DASA-58 (Figure 2E).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 attenuates LPS-induced M1 macrophage polarization in BMDMs
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
“Neither TEPP-46 nor DASA-58 had a significant effect on oxidative phosphorylation as measured by oxygen consumption rate (data not shown).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > PKM2 activators inhibit glycolysis and the accumulation of succinate in LPS-activated macrophages
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ Based: passesNone of the sources cited for this claim have been checked yet.
In the paper
“Furthermore, LPS-induced IL-6 and TNF protein expression (Figure 1J) were unaffected by activation of PKM2 consistent with these cytokine responses not directly requiring Warburg metabolism (Tannahill et al., 2013).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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 found enrichment for several interferon associated factors (IRF1, IRF8, ISGF3) as well as NRF2 and Hif-1α amongst the top 10 candidate TFs (Table S5).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Strength:plain· not yet calibratedCausal:correlational· 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
“We identified a signature set of 100 genes (Figure S1, Table S1) for which the activation of PKM2 induced a markedly distinct response from that observed during LPS treatment alone.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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
“In addition we see a clear down regulation of PKM1 mRNA in these M1 macrophages.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 attenuates LPS-induced M1 macrophage polarization in BMDMs
Strength:boosted· not yet calibratedCausal:correlational· 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
“Several of the well-known targets of HIF1α, such as Vimentin, Plaur (uPAR), Stap1 (Art-27), Sort1, and PFKP were either down regulated or not expressed when BMDMs were stimulated with LPS in the presence of DASA-58.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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
“Disuccinimidyl suberate (DSS) crosslinking of lysates from LPS treated BMDMs suggest that LPS induced PKM2 is primarily of a monomeric configuration (Figure 1B).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
“This is further supported by results from the cross-linking experiments shown in Figure 1B, where DSS cross-linked lysates from LPS treated BMDMs failed to reveal any high molecular weight PKM2 complexes.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Load-bearingStrength:boosted· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
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
“In addition, there is an increased binding of both PKM2 and Hif-1α to this promoter site in response to LPS (compare lane 2 to lane 1).”
- Also stated in: § LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter · plain
“As seen in Figure 3C, LPS causes increased binding of endogenous Hif-1α to the IL-1β promoter (left panel), and interestingly after this sample was put through a second round of ChIP specific for PKM2 (right panel) we also see an increased binding of endogenous PKM2 to the same copy of DNA in response to LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes- Also stated in: § LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter · plain
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
“PKM2 activation also significantly inhibited LPS-induced expression of the Hif-1α target gene Ldha.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passes
- It may state two separate claims as one. 51
- Probably not a substantial claim. 9
- The quote only partly states this claim. 1
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
“LPS caused up to a ten-fold increase in glycolysis, which is markedly inhibited by both TEPP-46 and DASA-58.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > PKM2 activators inhibit glycolysis and the accumulation of succinate in LPS-activated macrophages
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
“As shown in Figure 1I, activation of PKM2 using DASA-58 also inhibited LPS-induced expression of Il1b mRNA but importantly had no effect on LPS-induced Il6 mRNA levels.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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
“Similarly, although not significant we consistently observed a boost in the expression of the M2 markers Arg-1 and Mrc-1 by TEPP-46 in M1 polarized macrophages.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 attenuates LPS-induced M1 macrophage polarization in BMDMs
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.
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
“Phosphofructokinase (PFKP), which catalyzes the irreversible conversion of fructose-6-phosphate to FBP, is relatively down-regulated by activation of PKM2 whereas the enzymes downstream of this metabolite, namely ALDOC and TPI1, are significantly up- regulated by DASA-58.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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.
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 here show that LPS induces expression of the key metabolic regulator Pyruvate Kinase M2 (PKM2).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
“LPS induced high levels of PKM2 in BMDMs up to 48 hours (Figure 1A).”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · boosted
“LPS strongly induced Pkm2 mRNA expression (Figure 1C), with expression levels increasing approximately 2.8 fold after 24 hours of LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
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
“As depicted in Figure 1E, LPS caused an increased expression level of PKM2 in the cytosol (compare lane 7 to lane 8) as well as in the nucleus (compare lane 1 to lane 2).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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
“we analyzed enrichment of metabolic networks and found 48 pathways to be significantly enriched (FDR < 0.05) with Glycolysis being the top ranking metabolic pathway (Table S4).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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
“LPS- induced expression of PKM2 causes concurrent phosphorylation of Tyrosine 105 to an extent comparable or greater to the increased expression levels.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
“This phosphorylation is evident after just one hour, with the strongest induction after 48 hours (Figure 1A middle panel, 10.3 fold increase in relative band intensity).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
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
“As shown in Figure 1D, PKM1 expression levels did not increase substantially in response to LPS but instead a slight decrease in PKM1 protein was observed after 24 hours of LPS, confirming that in relation to the Pkm gene, the effect of LPS is specific to PKM2.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
Strength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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
“As shown in Figure 1H, DASA-58 and TEPP-46 inhibited the induction of pro-IL-1β in LPS-activated BMDMs. Both compounds also inhibited LPS-induced pro-IL-1β in PECs (Figure 1H).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
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
“We show that LPS-induced PKM2 enters into a complex with Hif-1α, which can directly bind to the IL-1β promoter, an event that is inhibited by activation of PKM2.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
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
“In addition, Mtb-induced IL-1β but also TNFα protein levels were inhibited by TEPP-46, whereas IL-10 protein was significantly increased by activation of PKM2 (Figure 6I).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
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
“Activation of PKM2 using two well-characterized small molecules, DASA-58 and TEPP-46, inhibited LPS-induced Hif-1α and IL-1β, as well as the expression of a range of other Hif-1α-dependent genes.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
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
“Results from BMDMs treated with Mtb for 24 hours revealed an upregulation of PKM2 protein (Figure 6D, third panel, compare lanes 1 and 2) as well as PKM2 mRNA (Figure 6E).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
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
“however as expected Pkm1 expression was compensatorily increased (Figure 5B).”
- Also stated in: § Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages · plain
“whereas PKM1 protein was upregulated following Tamoxifen and LPS-treatment compared to control (Figure 5C second panel).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
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.
- Also stated in: § Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages · plain
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
“Activation of PKM2 attenuated an LPS-induced pro-inflammatory M1 macrophage phenotype while promoting traits typical of an M2 macrophage.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“However, although as expected LPS causes a reduction on OCR in PKM2+/+ cells (Tannahill et al., 2013), the same inhibitory effect was still observed in BMDMs derived from PKM2−/− cells (data not shown).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
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.
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
“Finally, activation of PKM2 by TEPP-46 in vivo inhibited LPS and Salmonella typhimurium-induced IL-1β production, whilst boosting production of IL-10.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
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
“We demonstrate PKM2 up-regulation and phosphorylation in an activated macrophage, with only a minor change in PKM1 protein expression.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
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
“LPS-induced Il1b expression was attenuated in PKM2 ablated cells, with no further inhibitory effect observed following pre-treatment with TEPP-46 or DASA-58.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
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
“In a model of macrophage infection using live Mtb (strain H37Ra), TEPP-46 inhibited Mtb-induced Il1b mRNA levels, boosted Mtb-induced levels of Il10 mRNA and had no effect on levels of Tnf (Figure 6H).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
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
“In addition, both FSL-1 and CpG induced pro-IL-1β and Hif-1α protein expression (Figure 6A).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
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.
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
“Both compounds inhibited LPS- induced glycolytic reprogramming and succinate production.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
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
“Additionally, the pentose phosphate pathway intermediate Ribose 5-phosphate (R5P), was significantly accumulated in response to LPS (Figure 4C; left panel), however this was alleviated by activation of PKM2 (right panel).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > PKM2 activators inhibit glycolysis and the accumulation of succinate in LPS-activated macrophages
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.
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
“As illustrated in Figure 6K BMDMs derived from IL-1 Type I Receptor knock out mice when infected with Mtb display an increased bacterial load compared to wild type cells, with no effect of TEPP-46”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
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
“In addition, TEPP-46 inhibited Mtb-induced pro-IL-1β and Hif-1α protein, (Figure 6D), as well as TNFα and IL-6 (Figure 6G), whilst significantly boosting Mtb induced IL-10 (Figure 6F).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“We confirmed that LPS stimulation leads to accumulation of upstream glycolytic intermediates, such as G6P, FBP, DHAP and 2-PG, and TCA cycle intermediates including succinate (Tannahill et al., 2013).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Tannahill et al., 2013 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“These events are all prevented by PKM2 activation by DASA-58 and TEPP-46, which thereby prevent macrophage activation by LPS.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“This impairs the ability of the PKM2 and Hif-1α complex to bind to the Hif-1α motif in the promoter of the known Hif-1α target gene IL-1β (Peyssonnaux et al., 2007; Zhang et al., 2006), thereby inhibiting the transcriptional activity of Hif-1α and induction of IL-1β”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
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
“Activation of PKM2 also inhibited induction of IL-1β and boosted IL-10 production in Mtb-infected macrophages promoting bacterial growth.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“In order to examine the functional relevance of PKM2 for LPS action we next examined the effect of two highly specific small-molecule PKM2 activators, TEPP-46 and DASA-58.”
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
“They promote the formation of active PKM2 tetramers thereby boosting PKM2 enzymatic activity and limiting tumor growth in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs) · plain
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Figure 2A validates the polarizing conditions showing an upregulation of the markers Interleukin-12 p40 (Il12p40) and C-X-C chemokine 10 (Cxcl-10) in M1 macrophages and an increased expression of Arginase-1 (Arg-1) and Manose Receptor C, type 1 (Mrc-1) during M2 polarizing conditions.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 attenuates LPS-induced M1 macrophage polarization in BMDMs
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“Phosphorylation of PKM2 on Tyrosine 105 is indicative of monomer/dimer formation, as it prevents PKM2 tetramer configuration, further promoting the Warburg effect (Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Tetramerization of PKM2 using small molecule activators inhibits LPS-induced activation of primary bone marrow derived macrophages (BMDMs)
What the sources say
- Not checked yetcites Hitosugi et al., 2009 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“PKM2 has been shown to interact with Hif-1α and stimulate Hif-1α transactivation domain function and recruitment of p300 to the Hif Response Element (HRE) of Hif-1α target genes (Luo et al., 2011).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > LPS promotes binding of PKM2 and Hif-1α to the IL-1β promoter
What the sources say
- Not checked yetcites Luo et al., 2011 source
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
“This suggests that activation of PKM2 in vivo counteracts the inflammatory effects of LPS, most likely through inhibiting Warburg metabolism.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 results in increased bacterial dissemination in a Salmonella typhimurium model of infection
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
“PKM2 is therefore a critical determinant of macrophage activation by LPS, promoting the inflammatory response.”
- Also stated in: § INTRODUCTION · boosted
“This event is required for macrophage activation by LPS and we identify PKM2 as a critical modulator of IL-1β production, macrophage polarization, glycolytic reprogramming and Warburg metabolism in LPS-activated macrophages.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > Abstract
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Also stated in: § INTRODUCTION · boosted
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Pkm2 expression was successfully ablated (Figure 5A), however as expected Pkm1 expression was compensatorily increased (Figure 5B). In addition, PKM2 protein levels were successfully reduced following treatment with Tamoxifen (Figure 5C top panel, compare lanes 5 and 6 to lanes 7 and 8)”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Isoform-specific deletion of PKM2 inhibits LPS-mediated activation of Hif-1α and expression of Hif-1α target genes in macrophages
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers which are retained in the cytosol(Mazurek et al., 2005).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“The pyruvate kinase activity of the tetramers can be regulated by the concentration of the naturally occurring upstream glycolytic intermediate FBP (Ashizawa et al., 1991; Jurica et al., 1998), serine (Chaneton et al., 2012), as well as by a multitude of post-translational modifications (Wu and Le, 2013) including tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. 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
“These metabolomic changes are consistent with DASA-58 activating PKM2, which would lead to a decrease in glycolytic and pentose phosphate pathway intermediates.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > PKM2 activators inhibit glycolysis and the accumulation of succinate in LPS-activated macrophages
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
None of the sources cited for this claim have been checked yet.
In the paper
“As the main causative agent of tuberculosis, Mtb signals mainly through TLR 2, 6 and 9 (Bafica et al., 2005; Means et al., 1999).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 using TEPP-46 modulates the anti-Mycobacterium tuberculosis response of macrophages
What the sources say
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
“TEPP-46, but not DASA-58, is pharmacokinetically validated in vivo (Anastasiou et al., 2012).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > RESULTS > Activation of PKM2 results in increased bacterial dissemination in a Salmonella typhimurium model of infection
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Load-bearingStrength:plain· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“This event has been shown to be important for the Warburg effect in hypoxia and cancer(Hitosugi et al., 2009).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Hitosugi et al., 2009 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.
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
“Activation of PKM2 also limits this response and this will lead to Hif-1α destabilization.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.
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
“Firstly, it will limit the nuclear function of PKM2 and decrease Hif-1α-dependent gene expression.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
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
“This further implies the activation of PKM2 as a potential therapeutic target in inflammatory disease.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
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
“PKM2 in its dimeric, catalytically less active form, is therefore required for glycolytic reprogramming in response to LPS, most likely because of the role dimeric PKM2 plays in Hif-1α function.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
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
“We demonstrate the impact tetramerization of PKM2 has on limiting the host immune response in vivo, by attenuating both LPS and S. typhimurium-induced IL-1β whilst boosting IL-10, leading to impaired clearance of infection evident from increased bacterial dissemination.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
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
“In conclusion, we have revealed a novel role for PKM2 in LPS induced activation of macrophages and in macrophages infected with Mtb, as well as in an in vivo S.typhimurium model of infection”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
In the paper
“These well-characterized and highly specific compounds bind PKM2, which then forms a tight tetramer with PKM1-like kinetic properties, an event that is resistant to inhibition by tyrosine phosphorylation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Anastasiou et al., 2012 source
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Data was checked for correlation between replicates, (>0.96 on average within groups).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > EXPERIMENTAL PROCEDURES > Statistical analysis of microarray data
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.
In the paper
“This could explain the increase in IL-10 production, which in the case of M2 macrophage activity may require mitochondrial oxidative metabolism (Krawczyk et al., 2010).”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
What the sources say
- Not checked yetcites Krawczyk et al., 2010 source
Strength:hedged· not yet calibratedCausal:conditional· not yet calibratedTests✓ Asserted: passes✓ Checkable: passes? Load-bearing: unclear✓ 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 data indicates a combination of transcriptional regulation of key enzymes to increase flux into lactate, divert metabolites into the pentose phosphate pathway and thereby divert pyruvate away from the TCA cycle.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
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
“Secondly, the decrease in succinate will further limit Hif-1α through stabilization and degradation.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✓ Checkable: passes✓ Load-bearing: passes✓ Based: passesIt may state two separate claims as one. The quote only partly states this claim.
- Rests on an assumption: Hif-1α is stabilized by succinate inhibiting PHDs.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“p-values were corrected for multiple hypothesis testing by Benjamini- Hochberg’s method to control false discovery rate at 25%.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > EXPERIMENTAL PROCEDURES > Statistical analysis of microarray data
Strength:plain· 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
“Targeting PKM2 in order to inhibit glycolysis or re-engaging mitochondrial oxidative metabolism in an overactive macrophage may provide novel therapeutic approaches for inflammatory diseases.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > DISCUSSION
Tests✓ Asserted: passes✗ Checkable: fails✓ Load-bearing: passes✓ Based: passesProbably not a substantial claim. It may be too vague to check against evidence.
What the paper did — it cites no source for this, so there is none to check. The quote shows it is in the paper.
In the paper
“Processed data was log transformed (base 2). Correlation between replicates were >0.94 on average within different treatment groups.”
§ Pyruvate Kinase M2 regulates Hif-1α activity and IL-1β induction, and is a critical determinant of the Warburg Effect in LPS-activated macrophages > EXPERIMENTAL PROCEDURES > Statistical analysis of metabolomics data
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. It may state two separate claims as one.
The paper relies on this without support.
There is only limited information on the precise molecular determinants of the profound metabolic change in LPS-activated macrophages.
“There is only limited information on the precise molecular determinants of this profound change in metabolism.”
The paper relies on this without support.
LPS-activated macrophages have a high demand for biosynthetic precursors and increased energy demand, and these events are required for the cells to respond to infection or tissue injury during inflammation.
“In macrophages activated with the TLR4 agonist LPS there is a high demand for biosynthetic precursors including proteins, lipids, and nucleic acids as well as increased energy demand. These events are required for the cells to respond to infection or tissue injury during inflammation.”
The paper relies on this without support.
PKM2 enters the nucleus as a dimer.
“Since previous reports have established that PKM2 enters the nucleus as a dimer, we then carried out further DSS cross-linking studies in order to support a model for nuclear exclusion of PKM2 following treatment with our small molecule activators.”
The paper relies on this without support.
Hif-1α is stabilized by succinate inhibiting PHDs.
“Hif-1α will also be stabilized by succinate inhibiting PHDs, providing further regulation of Hif-1α.”
The paper relies on this without support.
Mycobacterium tuberculosis utilizes TLR2, TLR6 and TLR9.
“This extended our observation beyond TLR4 and LPS to a bacterial pathogen that utilizes TLR2, TLR6 and TLR9.”
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
“although glycolytic metabolism is a prerequisite (14).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [14]
In the citing 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).”
From Immunoresponsive Gene 1 and Itaconate Inhibit Succinate Dehydrogenase to Modulate Intracellular Succinate Levels (2016) · cites this paper as [14]
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.
Chromatography treatment is named TEPP-58 instead of TEPP-46
MinorThe methods name TEPP-58 for the size-exclusion experiment, while the results identify TEPP-46 as the treatment in that experiment.
“2–3 mg protein from RAW 264.7 ±10μM TEPP-58 or DMSO (1 hr)”
“In addition, lysates from RAW cells treated with TEPP-46 were separated through size exclusion using fast protein liquid chromatography (FPLC) (Figure 1G).”
Citations
Cites
Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method
Livak, K. J., & Schmittgen, T. D. (2001) · Methods · doi:10.1006/meth.2001.1262 · Cited by 180,860 · cited 1×
“Relative quantitation values were calculated using the 2(−Delta Delta C(T)) method (Livak and Schmittgen, 2001).”
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 · cited 14×
“Furthermore, LPS-induced IL-6 and TNF protein expression (Figure 1J) were unaffected by activation of PKM2 consistent with these cytokine responses not directly requiring Warburg metabolism (Tannahill et al., 2013).”
InfluentialSelf-citationMutation of the mouse klotho gene leads to a syndrome resembling ageing
Kuro-o, M., Matsumura, Y., Aizawa, H., Kawaguchi, H., Suga, T., Utsugi, T., Ohyama, Y., Kurabayashi, M., Kaname, T., Kume, E., et al. (1997) · Nature · doi:10.1038/36285 · Cited by 3,837
The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumour growth
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“Current data indicates that PKM2, when highly expressed, exists in an equilibrium of enzymatically inactive pyruvate kinase dimers (or monomers) which can translocate into the nucleus(Christofk et al., 2008; Hitosugi et al., 2009), and enzymatically active tetramers Palsson-McDermott et al.”
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 · cited 1×
“This phenomenon, which has been described as ‘pseudo hypoxia’ takes place when excess succinate is transported out of the mitochondria into the cytosol where it can impair the activity of prolylhydroxylases (PHD) leading to stabilization and activation of Hif-1α (Selak et al., 2005).”
Pyruvate Kinase M2 Is a PHD3-Stimulated Coactivator for Hypoxia-Inducible Factor 1
Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O'Meally, R., Cole, R. N., Pandey, A., & Semenza, G. L. (2011) · Cell · doi:10.1016/j.cell.2011.03.054 · Cited by 1,463 · cited 5×
“The PKM2 dimer can translocate to the nucleus where it will interact with Hif-1α and regulate expression of numerous pro-glycolytic enzymes (Luo et al., 2011), an event that is dependent on ERK1/2 activity and regulated by Jumoji C domaincontaining dioxygenase (JMJD5) (Wang et al., 2014; Yang et…”
InfluentialMal (MyD88-adapter-like) is required for Toll-like receptor-4 signal transduction
Fitzgerald, K. A., Pålsson‐McDermott, E. M., Bowie, A., Jefferies, C. A., Mansell, A. S., Brady, G., Brint, E. K., Dunne, A., Gray, P., Harte, M. T., et al. (2001) · Nature · doi:10.1038/35092578 · Cited by 1,258 · cited 4×
“BMDMs (±LPS, 24 hrs) were lysed as previously described (Fitzgerald et al., 2001).”
InfluentialSelf-citationToll-like receptor–induced changes in glycolytic metabolism regulate dendritic cell activation
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript INTRODUCTION Insights into the critical role of metabolic reprogramming in host defense and inflammation have recently emerged (Krawczyk et al., 2010; O’Neill and Hardie, 2013).”
Metabolism of Inflammation Limited by AMPK and Pseudo-Starvation
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Self-citationNuclear PKM2 regulates β-catenin transactivation upon EGFR activation
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“Other nuclear functions of dimeric PKM2 includes the ability to act as a protein kinase, activating transcription of mek5 through phosphorylation of STAT3(Gao et al., 2012) as well as promoting β-catenin translocation, leading to expression of cyclinD1 and c-myc(Yang et al., 2011).”
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Items 101–200 of 1,001
Fatty Acids and NLRP3 Inflammasome–Mediated Inflammation in Metabolic Tissues
Ralston, J. C., Lyons, C. L., Kennedy, E. B., Kirwan, A. M., & Roche, H. M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064836 · Cited by 231
iNOS as a metabolic enzyme under stress conditions
Anavi, S., & Tirosh, O. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.10.411 · Cited by 229
Feng, J., Dai, W., Mao, Y., Wu, L., Li, J., Chen, K., Yu, Q., Kong, R., Li, S., Zhang, J., et al. (2020) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-020-1528-x · Cited by 232
Rao, J., Wang, H., Ni, M., Wang, Z., Wang, Z., Wei, S., Liu, M., Wang, P., Qiu, J., Zhang, L., et al. (2022) · Gut · doi:10.1136/gutjnl-2021-325150 · Cited by 241
Dioscin ameliorates murine ulcerative colitis by regulating macrophage polarization
Wu, M., Wang, Q.-M., Huang, B.-Y., Mai, C.-T., Wang, C., Wang, T., & Zhang, X. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105796 · Cited by 223
Lactate and Immunosuppression in Sepsis
Nolt, B., Tu, F., Wang, X., Ha, T., Winter, R. P., Williams, D. L., & Li, C. (2017) · Shock · doi:10.1097/shk.0000000000000958 · Cited by 229
Inhibition of glycolysis alleviates lipopolysaccharide‐induced acute lung injury in a mouse model
Zhong, W., Yang, H., Guan, X., Xiong, J., Sun, C., Zhang, C., Luo, X., Zhang, Y., Zhang, J., Duan, J., et al. (2018) · Journal of Cellular Physiology · doi:10.1002/jcp.27261 · Cited by 216
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 215
Self-citationOxygen availability and metabolic reprogramming in cancer
Xie, H. J., & Simon, M. C. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.r117.799973 · Cited by 207
Cell Origin Dictates Programming of Resident versus Recruited Macrophages during Acute Lung Injury
Mould, K. J., Barthel, L., Mohning, M. P., Thomas, S. M., McCubbrey, A. L., Danhorn, T., Leach, S. M., Fingerlin, T. E., O’Connor, B. P., Reisz, J. A., et al. (2017) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2017-0061oc · Cited by 204
Immunometabolism in the Single-Cell Era
Artyomov, M. N., & den Bossche, J. V. (2020) · Cell Metabolism · doi:10.1016/j.cmet.2020.09.013 · Cited by 217
Metabolism Supports Macrophage Activation
Langston, P. K., Shibata, M., & Horng, T. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00061 · Cited by 185
Cytokine-like Roles for Metabolites in Immunity
Zasłona, Z., & O'Neill, L. A. J. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.04.002 · Cited by 202
Self-citationThe Cellular and Molecular Basis of Translational Immunometabolism
Norata, G. D., Caligiuri, G., Chavakis, T., Matarese, G., Netea, M. G., Nicoletti, A., O'Neill, L. A. J., & Marelli‐Berg, F. M. (2015) · Immunity · doi:10.1016/j.immuni.2015.08.023 · Cited by 197
Self-citationStienstra, R., Netea-Maier, R. T., Riksen, N. P., Joosten, L. A. B., & Netea, M. G. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.001 · Cited by 206
Li, Y., Shen, Y., Jin, K., Wen, Z., Cao, W., Wu, B., Wen, R. M., Tian, L., Berry, G. J., Goronzy, J. J., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.06.016 · Cited by 190
“Being histone-free and close to the ROS source, mtDNA is highly susceptible to oxidative modification (Apel and Hirt, 2004), but cytosolic misplacement of mtDNA appears sufficient to trigger inflammasome assembly and caspase activation.”
BackgroundInfluentialIntegration of Innate Immune Signaling
Thaiss, C. A., Levy, M., Itav, S., & Elinav, E. (2016) · Trends in Immunology · doi:10.1016/j.it.2015.12.003 · Cited by 189
Bai, L., Chen, P., Zhao, Y., Hang, R., Yao, X., Tang, B. H., Liu, C., Xiao, Y., & Hang, R. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121162 · Cited by 189
Kong, Y., Liu, F., Ma, B., Duan, J., Yuan, W., Sang, Y., Lin, H., Wang, S., & Liu, H. (2021) · Advanced Science · doi:10.1002/advs.202100962 · Cited by 182
Metabolic Regulation of Macrophage Activation
Kolliniati, O., Ieronymaki, E., Vergadi, E., & Tsatsanis, C. (2021) · Journal of Innate Immunity · doi:10.1159/000516780 · Cited by 183
Hsu, M., & Hung, W. (2018) · Molecular Cancer · doi:10.1186/s12943-018-0791-3 · Cited by 184
Dhanesha, N., Patel, R. B., Doddapattar, P., Ghatge, M., Flora, G. D., Jain, M. K., Thedens, D. R., Olalde, H. M., Kumskova, M., Leira, E. C. C., et al. (2021) · Blood · doi:10.1182/blood.2021012322 · Cited by 180
Renaudin, F., Orliaguet, L., Castelli, F. A., Fenaille, F., Prignon, A., Alzaïd, F., Combes, C., Delvaux, A., Adimy, Y., Cohen-Solal, M. E., et al. (2020) · Annals of the Rheumatic Diseases · doi:10.1136/annrheumdis-2020-217342 · Cited by 189
Xu, F., Guo, M., Huang, W., Feng, L., Zhu, J., Luo, K., Gao, J., Zheng, B., Kong, L.-D., Pang, T., et al. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101634 · Cited by 196
Pyruvate kinase M2: A simple molecule with complex functions
Alquraishi, M. I., Puckett, D. L., Alani, D., Humidat, A. S., Frankel, V. D., Donohoe, D. R., Whelan, J. N., & Bettaieb, A. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.08.007 · Cited by 185
SIRT3 deficiency leads to induction of abnormal glycolysis in diabetic kidney with fibrosis
Srivastava, S. P., Li, J., Kitada, M., Fujita, H., Yamada, Y., Goodwin, J. E., Kanasaki, K., & Koya, D. (2018) · Cell Death and Disease · doi:10.1038/s41419-018-1057-0 · Cited by 175
Mycobacterium tuberculosis Limits Host Glycolysis and IL-1β by Restriction of PFK-M via MicroRNA-21
Hackett, E. E., Charles‐Messance, H., O’Leary, S. M., Gleeson, L. E., Muñoz‐Wolf, N., Case, S., Wedderburn, A., Johnston, D. G. W., Williams, M. A., Smyth, A., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2019.12.015 · Cited by 174
“Consistent with this, IFN-g-driven HIF-1a and nitric oxide (NO) production have emerged as key processes sensitive to changes in glycolysis (Braverman et al., 2016; Braverman and Stanley, 2017) that miR-21 also impact.”
BackgroundInfluentialSelf-citationAndrographolide, an Anti-Inflammatory Multitarget Drug: All Roads Lead to Cellular Metabolism
Burgos, R. A., Alarcón, P., Quiroga, J., Manosalva, C., & Hancke, J. L. (2020) · Molecules · doi:10.3390/molecules26010005 · Cited by 177
Zhang, Y., Zhu, L., Li, X., Ge, C., Pei, W., Zhang, M., Zhong, M., Zhu, X., & Lv, K. (2023) · Redox Biology · doi:10.1016/j.redox.2023.103016 · Cited by 175
Pålsson‐McDermott, E. M., Dyck, L., Zasłona, Z., Menon, D., McGettrick, A. F., Mills, K. H. G., & O'Neill, L. A. J. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.01300 · Cited by 173
Self-citationEscoll, P., & Buchrieser, C. (2018) · FEBS Journal · doi:10.1111/febs.14446 · Cited by 179
The Circadian Clock Controls Immune Checkpoint Pathway in Sepsis
Deng, W., Zhu, S., Zeng, L., Liu, J., Kang, R., Yang, M., Cao, L., Wang, H., Billiar, T. R., Jiang, J., et al. (2018) · Cell Reports · doi:10.1016/j.celrep.2018.06.026 · Cited by 173
“We and others have demonstrated that PKM2-mediated lactate metabolism in macrophages contributes to the inflammatory response, organ injury, and septic death (Huang et al., 2017; Palsson-McDermott et al., 2015; Xie et al., 2016; Yang et al., 2014; Zhang et al., 2016).”
Self-citationImpact 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 173
Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation
Gioia, M. D., Spreafico, R., Springstead, J. R., Mendelson, M., Joehanes, R., Levy, D. A., & Zanoni, I. (2019) · Nature Immunology · doi:10.1038/s41590-019-0539-2 · Cited by 176
Tissue-resident macrophages: guardians of organ homeostasis
Nobs, S. P., & Köpf, M. (2021) · Trends in Immunology · doi:10.1016/j.it.2021.04.007 · Cited by 179
Pyruvate Kinase M2: A Potential Target for Regulating Inflammation
Alves-Filho, J. C., & Pålsson‐McDermott, E. M. (2016) · Frontiers in Immunology · doi:10.3389/fimmu.2016.00145 · Cited by 172
Chen, D., Ning, W.-R., Jiang, Z.-Z., Peng, Z.-P., Zhu, L., Zhuang, S., Kuang, D., Zheng, L., & Wu, Y. (2019) · Journal of Hepatology · doi:10.1016/j.jhep.2019.04.007 · Cited by 170
Emerging roles of lactate in acute and chronic inflammation
Fang, Y., Li, Z., Yang, L., Li, W., Wang, Y., Kong, Z., Miao, J., Chen, Y., Bian, Y., & Zeng, L. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-024-01624-8 · Cited by 186
Nagy, C., & Haschemi, A. (2015) · Frontiers in Immunology · doi:10.3389/fimmu.2015.00164 · Cited by 171
Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation
Lyons, C. L., & Roche, H. M. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19103092 · Cited by 168
“Thus, to explore the extent to which AMPK metabolic-inflammation may be either up- or down-regulated by different nutritional components, and how metabolic switching can also lead to beneficial changes in the cell [65]”
BackgroundVasculature-associated fat macrophages readily adapt to inflammatory and metabolic challenges
Silva, H. M., Báfica, A. L. B., Rodrigues-Luiz, G. F., Chi, J., Santos, P. D. A., Reis, B. S., van Konijnenburg, D. P. H., Crane, A., Arifa, R. D. D. N., Martin, P. K., et al. (2019) · The Journal of Experimental Medicine · doi:10.1084/jem.20181049 · Cited by 168
Marrocco, A., & Ortiz, L. A. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.936167 · Cited by 173
From periphery to center stage: 50 years of advancements in innate immunity
Carpenter, S. B., & O'Neill, L. A. J. (2024) · Cell · doi:10.1016/j.cell.2024.03.036 · Cited by 171
Self-citationLiu, R., Li, X., Ma, H., Yang, Q., Shang, Q., Song, L., Zheng, Z., Zhang, S., Pan, Y., Huang, P., et al. (2020) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2020.10.029 · Cited by 165
ROS signaling in innate immunity via oxidative protein modifications
Manoharan, R. R., Prasad, A., Pospı́šil, P., & Kzhyshkowska, J. G. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1359600 · Cited by 169
Metabolic reprogramming and immune evasion: the interplay in the tumor microenvironment
Zhang, H., Li, S., Wang, D., Liu, S. M., Xiao, T., Gu, W., Yang, H., Wang, H. Z., Yang, M., & Chen, P. (2024) · Biomarker Research · doi:10.1186/s40364-024-00646-1 · Cited by 178
The Role of Reactive Oxygen Species in the Rheumatoid Arthritis-Associated Synovial Microenvironment
Wang, X., Fan, D., Cao, X., Ye, Q., Wang, Q., Zhang, M., & Xiao, C. (2022) · Antioxidants · doi:10.3390/antiox11061153 · Cited by 176
“In addition, the ROS induced by macrophage activation upregulated the dimeric PKM2 and then attenuated the pro-inflammatory M1 macrophage phenotype while promoting the typical M2 macrophage characteristics [92].”
BackgroundPFKFB2-mediated glycolysis promotes lactate-driven continual efferocytosis by macrophages
Schilperoort, M., Ngai, D., Katerelos, M., Power, D. A., & Tabas, I. A. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00736-8 · Cited by 166
Liu, Z., Xu, J., Ma, Q., Zhang, X., Yang, Q., Wang, L., Cao, Y., Xu, Z., Tawfik, A. M., Sun, Y., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay1371 · Cited by 156
Wu, K. K.-L., Xu, X., Wu, M., Li, X., Hoque, M., Li, G. H., Lian, Q., Long, K., Zhou, T., Piao, H., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53006-w · Cited by 160
Li, M., Riddle, S. R., Zhang, H., D’Alessandro, A., Flockton, A. R., Serkova, N. J., Hansen, K. C., Moldovan, R., McKeon, B. A., Frid, M. G., et al. (2016) · Circulation · doi:10.1161/circulationaha.116.023171 · Cited by 154
Santa, F. D., Vitiello, L., Torcinaro, A., & Ferraro, E. (2018) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7420 · Cited by 157
Altered glucose metabolism and cell function in keloid fibroblasts under hypoxia
Wang, Q., Wang, P., Qin, Z., Yang, X. C., Pan, B., Nie, F., & Bi, H. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101815 · Cited by 153
Zhang, W., Zhang, S., Hu, X., & Tam, K. Y. (2015) · International Journal of Biological Sciences · doi:10.7150/ijbs.13325 · Cited by 153
Chi, Z., Chen, S., Xu, T., Zhen, W., Yu, W., Jiang, D., Guo, X., Wang, Z., Zhang, K., Li, M., et al. (2020) · Molecular Cell · doi:10.1016/j.molcel.2020.08.015 · Cited by 156
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 154
Self-citationTargeting macrophage immunometabolism: Dawn in the darkness of sepsis
Kumar, V. (2018) · International Immunopharmacology · doi:10.1016/j.intimp.2018.03.005 · Cited by 150
Li, C., Deng, C., Wang, S., Dong, X. D., Dai, B., Guo, W., Guo, Q., Feng, Y., Xu, H., Song, X., et al. (2024) · Redox Biology · doi:10.1016/j.redox.2024.103059 · Cited by 154
“PKM2 forms a complex with HIF1 α during inflammatory activation of macrophages and directly binds to the IL-1 β promoter to promote its expression [52].”
BackgroundAncillary Activity: Beyond Core Metabolism in Immune Cells
Puleston, D. J., Villa, M., & Pearce, E. L. (2017) · Cell Metabolism · doi:10.1016/j.cmet.2017.06.019 · Cited by 150
“By binding DNA, polyamines influence gene expression through multiple mechanisms (reviewed by Childs et al., 2003), including by controlling the expression of transcription factors such as Myc (Celano et al., 1989; Patel and Wang, 1997).”
BackgroundMetabolic Regulation of Adipose Tissue Macrophage Function in Obesity and Diabetes
Appari, M., Channon, K. M., & McNeill, E. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7060 · Cited by 154
Li, Y., Lu, B., Sheng, L., Zhu, Z., Sun, H., Zhou, Y., Yang, Y., Xue, D., Chen, W., Tian, X., et al. (2017) · Journal of Neurochemistry · doi:10.1111/jnc.14267 · Cited by 145
Immunometabolic crosstalk during bacterial infection
Rosenberg, G., Riquelme, S. A., Prince, A. S., & Avraham, R. (2022) · Nature Microbiology · doi:10.1038/s41564-022-01080-5 · Cited by 152
Tissue-Resident Alveolar Macrophages Do Not Rely on Glycolysis for LPS-induced Inflammation
Woods, P. S., Kimmig, L. M., Meliton, A. Y., Sun, K. A., Tian, Y., O’Leary, E. M., Gökalp, G. A., Hamanaka, R. B., & Mutlu, G. M. (2019) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2019-0244oc · Cited by 145
Casey, A. M., Ryan, D. G., Prag, H. A., Chowdhury, S. R., Marques, E., Turner, K., Gruszczyk, A. V., Yang, M. H., Wolf, D. M., Miljković, J. L., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01224-x · Cited by 171
“3e,h) as has been reported 17 .”
Mechanisms of Macrophage Polarization in Insulin Signaling and Sensitivity
Orliaguet, L., Dalmas, É., Drareni, K., Venteclef, N., & Alzaïd, F. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.00062 · Cited by 151
Systemic Immunometabolism: Challenges and Opportunities
Lercher, A., Baazim, H., & Bergthaler, A. (2020) · Immunity · doi:10.1016/j.immuni.2020.08.012 · Cited by 144
Lactylation: a Passing Fad or the Future of Posttranslational Modification
Qi, X., Wang, H., Li, Q., Liu, S., Qu, K., Liu, C., & Zhang, J. (2022) · Inflammation · doi:10.1007/s10753-022-01637-w · Cited by 150
Role of SLC7A5 in Metabolic Reprogramming of Human Monocyte/Macrophage Immune Responses
Yoon, B. R., Oh, Y.-J., Kang, S. W., Lee, E. B., & Lee, W. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00053 · Cited by 144
Gao, C., Hou, G., Liu, J., Ru, T., Xu, Y., Zhao, S., Ye, H., Zhang, L., Chen, K., Guo, Y., et al. (2019) · Angewandte Chemie International Edition · doi:10.1002/anie.201912489 · Cited by 143
Glucose Metabolism in the Progression of Prostate Cancer
Cutruzzolà, F., Giardina, G., Marani, M., Macone, A., Paiardini, A., Rinaldo, S., & Paone, A. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00097 · Cited by 143
“…the retina and in the choroid plexus, MCT1, MCT2 and MCT4 have been demonstrated to transport important monocarboxylates like lactate, pyruvate, ketone bodies (acetoacetate, β-idroxybutyrate) in several tissues including prostate cancer (Halestrap and Price, 1999; Pértega-Gomes and Baltazar, 2014).”
Macrophage metabolism in atherosclerosis
Bories, G. F. P., & Leitinger, N. (2017) · FEBS Letters · doi:10.1002/1873-3468.12786 · Cited by 145
Arbore, G., & Kemper, C. (2016) · European Journal of Immunology · doi:10.1002/eji.201546131 · Cited by 145
Awasthi, D., Nagarkoti, S., Sadaf, S., Chandra, T., Kumar, S., & Dikshit, M. (2019) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2019.165542 · Cited by 149
Sangineto, M., Ciarnelli, M., Cassano, T., Radesco, A., Moola, A., Bukke, V. N., Romano, A., Villani, R., Kanwal, H., Capitanio, N., et al. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102846 · Cited by 142
Modulation of Macrophage Immunometabolism: A New Approach to Fight Infections
Gauthier, T., & Chen, W. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.780839 · Cited by 137
Control of tumor-associated macrophage responses by nutrient acquisition and metabolism
Zhang, X., Ji, L., & Li, M. O. (2023) · Immunity · doi:10.1016/j.immuni.2022.12.003 · Cited by 136
Transcriptional Response to Hypoxia: The Role of HIF-1-Associated Co-Regulators
Yfantis, A., Mylonis, I., Chachami, G., Nikolaidis, M., Amoutzias, G. D., Paraskeva, E., & Simos, G. (2023) · Cells · doi:10.3390/cells12050798 · Cited by 144
Molecular mechanisms in liver repair and regeneration: from physiology to therapeutics
Ma, X., Huang, T., Chen, X., Li, Q., Liao, M., Fu, L., Huang, J., Yuan, K., Wang, Z., & Zeng, Y. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02104-8 · Cited by 133
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 135
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 155
Zhang, B., Chen, H., Ouyang, J., Xie, Y., Chen, L., Tan, Q., Du, X., Su, N. Y., Ni, Z., & Chen, L. (2019) · Autophagy · doi:10.1080/15548627.2019.1664705 · Cited by 135
Macrophage polarization and its impact on idiopathic pulmonary fibrosis
Ge, Z., Chen, Y. Q., Ma, L., Hu, F., & Xie, L. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1444964 · Cited by 147
Immunometabolism during Mycobacterium tuberculosis Infection
Howard, N. C., & Khader, S. A. (2020) · Trends in Microbiology · doi:10.1016/j.tim.2020.04.010 · Cited by 134
“During aerobic glycolysis, however, pyruvate can instead be converted into lactate and secreted from the cell [24,34,35].”
BackgroundTranscriptional, Epigenetic and Metabolic Programming of Tumor-Associated Macrophages
Larionova, I., Kazakova, E., Patysheva, M. R., & Kzhyshkowska, J. G. (2020) · Cancers · doi:10.3390/cancers12061411 · Cited by 126
“PKM2 was found to activate the LPS-induced pro-inflammatory phenotype of M1 macrophages in murine model via the production of HIF-1α, IL-1β and other HIF-1α-dependent genes as well as to promote inflammasome activation by modulating eukaryotic translation initiation factor 2 alpha kinase 2 (EIF2AK2) phosphorylation in…”
BackgroundInfluentialMyeloid Cell PKM2 Deletion Enhances Efferocytosis and Reduces Atherosclerosis
Doddapattar, P., Dev, R., Ghatge, M., Patel, R. B., Jain, M. K., Dhanesha, N., Lentz, S. R., & Chauhan, A. K. (2022) · Circulation Research · doi:10.1161/circresaha.121.320704 · Cited by 126
Zhang, Q., Luo, P., Xia, F., Tang, H., Chen, J., Zhang, J., Liu, D., Zhu, Y., Liu, Y., Gu, L., et al. (2022) · Cell chemical biology · doi:10.1016/j.chembiol.2022.06.011 · Cited by 126
Amin, S., Yang, P., & Li, Z. (2019) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2019.02.003 · Cited by 128
Immune cell metabolism and metabolic reprogramming
Hu, C., Xuan, Y., Zhang, X., Liu, Y., Yang, S., & Yang, K. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07474-2 · Cited by 132
Metabolic Switch in the Tumor Microenvironment Determines Immune Responses to Anti-cancer Therapy
Wegiel, B., Vuerich, M., Daneshmandi, S., & Seth, P. (2018) · Frontiers in Oncology · doi:10.3389/fonc.2018.00284 · Cited by 129
Siska, P. J., Singer, K., Evert, K., Renner, K., & Kreutz, M. P. (2020) · Immunological Reviews · doi:10.1111/imr.12846 · Cited by 125
Cellular metabolism of myeloid cells in sepsis
Arts, R. J. W., Gresnigt, M. S., Joosten, L. A. B., & Netea, M. G. (2016) · Journal of Leukocyte Biology · doi:10.1189/jlb.4mr0216-066r · Cited by 126
“PKM2 stabilizes Hif1a to activate essential enzymes in the glycolysis pathway leading to lactate production [38].”
BackgroundLü, J., Wei, Z., Jiang, H., Cheng, L., Chen, Q., Chen, M., Yan, J., & Sun, Z. (2018) · Journal of Surgical Research · doi:10.1016/j.jss.2018.03.035 · Cited by 120
TREM2 inhibition triggers antitumor cell activity of myeloid cells in glioblastoma
Sun, R., Han, R., McCornack, C., Khan, S., Tabor, G. T., Chen, Y., Hou, J., Jiang, H., Schoch, K. M., Mao, D. D., et al. (2023) · Science Advances · doi:10.1126/sciadv.ade3559 · Cited by 119
Xu, W., Zhang, Z., Zou, K., Cheng, Y., Yang, M., Chen, H., Wang, H., Zhao, J., Chen, P., He, L., et al. (2017) · Cell Death and Disease · doi:10.1038/cddis.2017.60 · Cited by 118
PFKFB3-Driven Macrophage Glycolytic Metabolism Is a Crucial Component of Innate Antiviral Defense
Jiang, H., Shi, H., Sun, M., Wang, Y., Meng, Q., Guo, P., Cao, Y., Chen, J., Gao, X., Li, E., et al. (2016) · The Journal of Immunology · doi:10.4049/jimmunol.1600474 · Cited by 117
Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1α Transactivation in Steatohepatitis
Ouyang, X., Han, S., Zhang, J., Dioletis, E., Németh, B. T., Pacher, P., Feng, D., Bataller, R. A., Cabezas, J., Stärkel, P., et al. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2018.01.007 · Cited by 116
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Metadata
- Authors
- 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., Jiang, J.-K., Israelsen, W. J., Keane, J., Thomas, C., Clish, C., Vander Heiden, M., Xavier, R. J., & O’Neill, L. A. J.
- Affiliations
- Broad Institute (US)
- Trinity College Dublin (IE)
- National Institutes of Health (US)
- Koch Institute for Integrative Cancer Research At MIT (US)
- ORCID
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2015-01
- Volume
- 21
- Issue
- 1
- Pages
- 65-80
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5198835
- OpenAlex
- W2153586956
- Cited by
- 1,397
- References
- 38
- Citations by year
- 2026: 154 · 2025: 177 · 2024: 186 · 2023: 133 · 2022: 132 · 2021: 161 · 2020: 140 · 2019: 81 · 2018: 85 · 2017: 77 · 2016: 51 · 2015: 19
- FWCI
- 38.04
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-02-03)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Trinity's Access to Research Output (TARA) (Trinity College Dublin) (submittedVersion)
- Funders
- Health Research Board
- Seventh Framework Programme (FP7-2007-2013, HEALTH-14-2011-281608)
- National Institutes of Health
- European Research Council
- Science Foundation Ireland
- Wellcome Trust
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Keywords
- PKM2, HIF-1α, IL-1β, Warburg effect, macrophage polarization, M1/M2 macrophages, lipopolysaccharide stimulation, TLR4, glycolytic reprogramming, succinic acid, TEPP-46, IL-10, Salmonella typhimurium, inflammation, macrophage metabolism
- MeSH terms
- Animals, Bone Marrow Cells, Cells, Cultured, Glycolysis, Lipopolysaccharides, Macrophage Activation, Macrophages, Mice, Inbred C57BL, Promoter Regions, Genetic, Protein Binding, Pyruvate Kinase, RNA, Messenger, Salmonella typhimurium, Gene Expression, Enzyme Activators, Toll-Like Receptor 4, Mice, Hypoxia-Inducible Factor 1, alpha Subunit, Interleukin-1beta
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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.
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