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Heme induces innate immune memory
Open accessAbstract
Trained immunity defines long-lasting adaptive responses of innate immunity, mediated by transcriptional and epigenetic modifications of myeloid cells. Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice. Heme-trainning in monocytes is associated with epigenetic and transcriptional profiles that overlap to some extent with those seen in β-glucan-training, the prototype agonist of trained immunity. In sharp contrast to β-glucan training however, heme-training relied on activation of the Syk/JNK-pathway. Heme training in mice was associated with long-lasting expansion of myeloid-biased progenitor cells as well as with altered chromatin accessibility in hematopoietic stem and progenitor cells. Finally, heme-induced training was protective against bacterial sepsis in mice. In conclusion, we reveal that heme, a bona fide alarmin, induces innate immune memory regulating host response to infection.
Checked 2026-11-11 · 1 reference not checked yet
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TL;DR
Labile heme acts as an alarmin that induces trained immunity in human and murine myeloid cells and in mice, with epigenetic and transcriptional overlap but a distinct Syk/JNK-dependent mechanism compared with β-glucan training. Heme training expands myeloid-biased hematopoietic progenitors and is protective in polymicrobial sepsis, yet worsens acute LPS endotoxemia.
Key findings
- Heme induced trained immunity in human and murine primary macrophages, increasing cytokine release upon secondary LPS or Pam3CSK4 challenge; training was also induced by iron-lacking protoporphyrin (PPIX) and was not prevented by N-acetyl cysteine.
- ChIP-seq showed that after heme exposure approximately 5% of all H3K27ac-marked regions increased versus untreated controls, with 497 peaks near 308 genes at 24 h; 98.6% of peaks occurred within 0.5 Mb of a gene TSS. RNA-seq at 24 h identified 201 genes commonly induced by heme and β-glucan, 140 heme-specific genes, and 346 β-glucan-specific genes.
- Heme training required Syk and JNK activation: Syk inhibition with R406 and JNK inhibition with SP600125 abolished training, while mTOR inhibition with rapamycin did not; Tlr4−/− BMDM were equally trained by heme.
- In mice, heme training increased myeloid-biased LT-HSCs (CD41+ LT-HSC) and MPP3 cells and decreased lymphoid-biased MPP4 cells, persisting 28 days after treatment; single-nuclei ATAC-seq of LSK cells showed altered chromatin accessibility. Heme-trained mice had reduced survival in LPS endotoxemia but faster weight recovery, higher temperature, and higher survival in polymicrobial sepsis.
Methods
- A 2-hit training model was used with human monocytes/macrophages and murine BMDM: first hit with heme (typically 50 µM) or β-glucan (1 µg/mL) for 24 h, washout and rest, then secondary challenge with LPS (10 ng/mL) or Pam3CSK4; cytokine release was measured by ELISA and LegendPlex.
- Epigenetic and transcriptional profiling included H3K27ac ChIP-seq, RNA-seq, ChIP-qPCR, Western blot, and single-nuclei ATAC-seq on sorted LSK cells; sequencing data were deposited under GEO accession GSE111003.
- Mouse experiments used C57Bl/6, Tlr4−/−, and Rag2−/− mice; heme was given at 2 mg/kg i.p., and LPS at 15 mg/kg one week later for survival, temperature, weight, clinical severity, and peritoneal flow cytometry. Statistical tests included log-rank, one-way/two-way ANOVA with Fisher’s LSD, and Student t-test.
Limitations
- Stated: how heme induces Syk phosphorylation independently of TLR4 is unknown; the authors speculate there may be no specific heme receptor and that Syk autophosphorylation could be enforced by heme–phospholipid interaction. It is also unclear how JNK signaling leads to histone modifications and which cofactors are involved.
- Stated: whether the observed effects rely on heme-driven modulation of BACH-1 remains to be established, and whether indirect cytokine effects mediate long-term myelopoiesis adaptation as proposed for β-glucan remains to be established. The analysis did not include H3K4me3 or H3K4me1 marks, although innate immune memory also involves histone methylation.
- Evident: the text is a preprint marked “not certified by peer review”; the single-nuclei ATAC-seq experiments used n = 2 mice per group at each time point, and the in vivo outcomes are context-dependent, with heme training deleterious in acute LPS endotoxemia but protective in polymicrobial sepsis.
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47 Own result · 13 Own interpretation · 7 No full text of the sources · 5 Own method · 4 Not checked yet · 1 Check pending
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In the paper
“Accordingly, heme-induced trained immunity was not prevented by the glutathione precursor N-Acetyl Cysteine (NAC) (Suppl.Fig.1)”
§ Heme induces innate immune memory > 5/37
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“The deleterious effects of heme training on subsequent LPS-induced systemic inflammation persisted in Rag2 knock-out mice (Rag2 -/-) with a constitutive deficiency of mature B-and T-cells 45 as shown by significantly increased disease severity, significantly decreased temperature and decreased survival of heme-trained Rag2 -/-mice compared to control mice (Fig. 5g,h,i).”
§ Heme induces innate immune memory > 10/37
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“Furthermore, a significant increase of mature neutrophils and monocyte is observed at this time point.”
§ Heme induces innate immune memory > 9/37
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“Figure 2: Heme training evokes a specific transcriptional signature”
§ Heme induces innate immune memory > Dynamic H3K27ac
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“Our data show that primary human and murine myeloid cells can undergo heme-training resulting in specific changes of the expression of several hundred genes within 24 hours of exposure.”
§ Heme induces innate immune memory > CONCLUSION
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“In contrast, H3K27ac levels at genes related to adaptive immune regulation were downregulated by heme (Suppl.Fig.2).”
§ Heme induces innate immune memory > 6/37
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“Figure 5: Heme training in vivo”
§ Heme induces innate immune memory > Dynamic H3K27ac
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“Principial component analysis (PCA) plots based on the expression of common genes showed that heme and β-glucan exposed cells move faster along the differentiation trajectory (Fig. 2c)”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
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“We find that it can also be induced by protoporphyrin (PPIX), lacking iron (Suppl.Fig.1).”
§ Heme induces innate immune memory > 5/37
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“Gene ontology (GO) analysis showed that heme exposure elevated H3K27ac signal near genes involved in wounding and stress”
§ Heme induces innate immune memory > 6/37
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“After heme exposure, approximately 5% of all H3K27ac marked regions in the genome showed increased signal as compared to untreated controls (Fig. 1f; Suppl.Fig.2).”
§ Heme induces innate immune memory > 5/37
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“After seven days of heme exposure, there was a modest increase in the proportion of HSC-MPP3-4 cells compared with control mice (Fig. 4e,f).”
§ Heme induces innate immune memory > 9/37
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“Heme exposure rapidly increased JNK-phosphorylation in human monocytes (Fig. 3f; Suppl.Fig.3)”
§ Heme induces innate immune memory > 8/37
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“Myeloid-biased LT-HSCs (CD41 + LT-HSC) and MPP3 were still increased 28 days after heme treatment (Suppl.Fig.4).”
§ Heme induces innate immune memory > 9/37
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“Heme-training was independent of TLR4 signaling, previously shown to be induced by heme 11 as BMDM from C57Bl/6 mice with a constitutive deletion of Tlr4 (Tlr4 -/-) were equally trained by heme, using Pam-3-Cys as the second stimulus (Suppl.Fig.1).”
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“Common pathways included metabolic and lysosome regulation (Fig. 2e), indicating that these pathways may be fundamental for innate immune memory.”
§ Heme induces innate immune memory > 7/37
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“Moreover, Syk inhibition by R406 38 abolished heme-induced training (Fig. 3b;c).”
§ Heme induces innate immune memory > Heme training is mediated via a Syk/JNK dependent pathway
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“One-time exposure to heme, that did not affect vigor of the animals, resulted in enrichment of chromatin accessibility from genes defining early myeloid progenitors.”
§ Heme induces innate immune memory > 12/37
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“Induced H3K27ac regions could be separated into heme-specific and heme/β-glucan common (Fig. 1g; Suppl.Fig.2; Suppl.Tables 1;2).”
§ Heme induces innate immune memory > 5/37
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“Despite increased phosphorylation of the mTOR target S6 in heme-trained Mφ (Fig. 3j), inhibition of mTOR activity by rapamycin did not abolish heme training, as the increased TNF production of heme trained cells to a secondary challenge was not affected by the mTOR inhibitor (Fig. 3k).”
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“Consitent with previous reports 32 , heme appears to signal via the spleen tyrosine kinase (Syk), as assessed by its phosphorylation in human monocytes (Fig. 3a; Suppl.Fig.3).”
§ Heme induces innate immune memory > Heme training is mediated via a Syk/JNK dependent pathway
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“Of note, we identified a group of cells (refered to as enriched MPP (eMPP)) within the earliest progenitors with a low LT-HSC signature score but enriched for MPP (Fig. 4g,h).”
§ Heme induces innate immune memory > 9/37
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“We identified eight cell subpopulations (Fig. 4c) based on two approaches”
§ Heme induces innate immune memory > 9/37
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“Figure 4: Heme training expands myeloid-biased hematopoetic stem cells in mice”
§ Heme induces innate immune memory > Dynamic H3K27ac
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“Accordingly, hemeinduced training was significantly decreaed by acetylation and methylation inhibitors (Fig. 1e).”
§ Heme induces innate immune memory > 5/37
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“Overall, 24 h after heme application, 497 peaks in the proximity of 308 genes showed increased H3K27ac signal.”
§ Heme induces innate immune memory > 5/37
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“we found that heme increased cytokine release from human and murine primary Mφ upon secondary challenge by LPS (Fig. 1b,c; Supplementary (Suppl.).Fig1)”
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“Global increase in H3K27ac in response to heme treatment was also prevented by Syk-inhibition, as assessed by Western bBlot in human monocytes (Fig. 3d).”
§ Heme induces innate immune memory > Heme training is mediated via a Syk/JNK dependent pathway
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“Within the HSC/MPP3-4 cluster, we found a transition of progenitors from LT-HSC towards MPP3 and MMP4 (Fig. 4d).”
§ Heme induces innate immune memory > 9/37
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“Heme-trained bone marrowderived macrophages (BMDM) from C57Bl/6 mice increased HO-1 protein content after the 2 nd hit supporting our finding in human cells that heme induces epigenetic modifications of the HMOX1 promoter (Suppl.Fig. 1).”
§ Heme induces innate immune memory > 7/37
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“The common signature was related to lysosome maturation and metabolism, key processes required for increased cytokine production observed in trained Mφ.”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
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“Yet, using transcriptomic data from different time points, heme-trained Mφ did not display any of this typical polarization traits (Suppl.Fig.2).”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
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“The t-SNE plot (dimension 2) clearly separated heme and β-glucantrained and naïve Mφ by H3K27ac pattern (Fig. 1h).”
§ Heme induces innate immune memory > 5/37
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“Genes only induced by heme are mainly involved in inflammatory pathways (Fig. 2a).”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
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“As a first notion, heme-application alone did not lead to any phenotype in the mice.”
§ Heme induces innate immune memory > Heme-induced training improves immunity in bacterial sepsis
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“Heme-regulated genes can be segregated into genes encoding cytokines and chemokines versus genes regulating metabolism as well as lysosome and phagocytosis function.”
§ Heme induces innate immune memory > CONCLUSION
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“Seven days after heme administration, we found no difference in cell number or percentages of LSK cells (Lin -cKit + Sca1 + ), long-term (LT)-HSCs (CD48 -CD150 + LSK), or multipotent progenitors (MPP, CD48 + CD150 -LSK), as compared to control-treated mice.”
§ Heme induces innate immune memory > Heme training promotes myelopoiesis
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“This demonstrates that trained immunity can be induced by alarmins, such as heme, which provide long-lasting adaptation of innate immunity to modulate the pathophysiology of a variety of immune-mediated inflammatory diseases.”
§ Heme induces innate immune memory > CONCLUSION
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“In summary, these data suggest that heme-induced trained immunity promotes a myeloid bias in HPSCs involving self-renewing long term HPSCs.”
§ Heme induces innate immune memory > 9/37
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“Hence, epigenetic alterations in HSPCs may contribute to the persistence of the heme-induced training effects.”
§ Heme induces innate immune memory > 9/37
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“Figure 3: Heme training relies on Syk/JNK activation”
§ Heme induces innate immune memory > Dynamic H3K27ac
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“This suggest that hosts exposed to heme, such as would occur in malaria or other form of hemolysis, prime hematopoeitc stem cells towards adapted myelopoiesis.”
§ Heme induces innate immune memory > 12/37
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“Heme-induced training is mediated by a signal transduction pathway involving Syk and JNK phosphorylation and H3K27 acetylation.”
§ Heme induces innate immune memory > 11/37
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“In further support of this notion, the Syk-inhibitor R406 decreased JNK phosphorylation, suggesting that heme-induced training is mediated via Syk-dependent JNKactivation (Fig. 3i).”
§ Heme induces innate immune memory > 8/37
hedgeddirect- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Consistently, application of the Syk-inhibitor R406 during heme training did not alter the S6-phosphorylation indicating that activation of mTOR by heme acts independently of Syk signaling (Suppl.Fig.3).”
§ Heme induces innate immune memory > 8/37
hedged- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 provided in this manuscript shows that extracellular labile heme, an ironcontaining tetrapyrrol alarmin released from red blod cells upon hemolysis acts as a potent inducer of innate immune memory.”
§ Heme induces innate immune memory > 11/37
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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 finding supports that heme-mediated trained immunity is predominantly mediated by effects on innate immune cells.”
§ Heme induces innate immune memory > 10/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption: Rag2-/- mice, lacking mature B and T cells, isolate innate immune-mediated effects.
- It may state two separate claims as one. 24
- Probably not a substantial claim. 8
- 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
“FACS analysis of immune cell subsets taken from peritoneum 6 hours after LPS application revealed no changes in total cell number, yet, numbers of classical monocytes and numbers of Mφ were significantly higher in heme-trained mice (Fig. 5e,f).”
§ Heme induces innate immune memory > 10/37
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Gene set enrichment analysis (GSEA) using the Molecular Signatures Database (MSigDB) (Fig. 2e) showed that common genes between heme and β-glucan induced pathways are involved in stress response, while the heme-specific response is related to inflammation and immune response and β-glucan induced pathways relate rather to metabolic processes.”
§ Heme induces innate immune memory > 7/37
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Strikingly, upon 28 days of heme treatment, several cell subpopulations were diminished, particularly MEP, and cells mostly concentrated on the HSC-MMP3-4 cluster (Fig. 4g,h; Suppl.Fig. 5,6).”
§ Heme induces innate immune memory > 9/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Training effects were specific to heme as i) different concentrations of LPS as a first stimulus resulted in immune tolerance”
§ Heme induces innate immune memory > 5/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Pathway analysis using GREAT 37 demonstrated that those pathways involved in cytokine-signaling and stress-response were up-regulated during heme training, in contrast to genes encoding metabolism and mitochondrial function in β-glucan training.”
§ Heme induces innate immune memory > 7/37
What the sources say
- Not checked yetcites [37] source
boostedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The largest number of differentially expressed genes occurred at 24 hours after stimulation, with 201 genes commonly induced by heme and β-glucan, 140 specifically induced by heme and 346 specifically induced by β-glucan (Fig. 2a; Suppl.Table 3;4;5).”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“However, we observed increased frequency of myeloid-biased LT-HSCs (CD41 + LT-HSC) 40 amongst the LT-HSC population as well as of myeloid-biased MPP3 cells (Flt3 -CD48 + CD150 -LSK) with a corresponding decrease of lymphoid-biased MPP4 cells (Flt3 + CD48 + CD150 -LSK) (Fig. 4a,b).”
§ Heme induces innate immune memory > 9/37
What the sources say
- Not checked — no full text of the sourcecites [40] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“However, when LPS was injected after 6 days, heme-trained mice displayed increased sickness behavior and increased temperature drops and significantly reduced survival when compared to control mice (Fig. 5b,c,d).”
§ Heme induces innate immune memory > 10/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“ii) neither the application of ATP as a first hit nor heme as a second hit altered TNF release (Suppl.Fig.1).”
§ Heme induces innate immune memory > 5/37
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“while application of the JNK-Inhibitor SP600125 39 abolished JNK phosphorylation and heme-induced training (Fig. 3g;h).”
§ Heme induces innate immune memory > 8/37
What the sources say
- Not checked yetcites [39] source
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Heme application specifically induced transcription of heme/iron related genes HMOX1, FTH1, HRG1 but not of the iron exporter ferroportin (FPN1) (Suppl.Fig.3).”
§ Heme induces innate immune memory > 7/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“Motif analysis of the gene promoter regions indicated that there is a β-glucan-specific signature (recognised by: USF and ELK1), hemespecific signature (e.g.NF-κB, BATF) and a common signature (AP-1, PPAR and MITF) (Fig. 2b).”
§ Heme induces innate immune memory > Heme induces distinct transcripts and common markers of innate immune memory
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“We also observed the expected upregulation of Dectin-1 target EGR2 by β-glucan exposure and upregulation of MITF and PPARG by both β-glucan and heme (Fig. 2d; Suppl.Fig.3).”
§ Heme induces innate immune memory > 7/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“JUN and FOSL were induced by heme, while ELK1 mRNA was induced exclusively by βglucan (Suppl.Fig.3).”
§ Heme induces innate immune memory > 7/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“In contrast to the endotoxemia model, heme-induced trained immunity was protective in polymicrobial sepsis as seen by a faster recovery of weight of heme pre-treated animals as well as a significantly higher temperature and a higher survival rate (Fig. 5j,k,l).”
§ Heme induces innate immune memory > 10/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“The increased cytokine release was non-specific to TLR-4 signaling as activation of TLR1/2 signaling by the synthetic receptor agonist Pam3CSK4 used as the secondary challenge, also resulting in increased TNF-release (Fig. 1d).”
§ Heme induces innate immune memory > 5/37
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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
“H3K27ac dynamics are observed at both promoters and distal enhancer regions, with 98.6% of peaks occurring within 0.5Mb of a gene TSS (Suppl.Fig.2).”
§ Heme induces innate immune memory > 6/37
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“The nuclei concentration was between 6,000 to 8,000 nuclei per µL.”
§ Heme induces innate immune memory > Nuclei isolation and single-nuclei ATAC library construction
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“The heme-dependent transcriptional repressor BACH-1 plays an essential role in the heme induced increase of myeloid cells, since it was shown that heme binding to BACH-1 causes a shift from erythropoiesis towards myelopoiesis in the bone marrow 52 , similar to observed in this study.”
§ Heme induces innate immune memory > 12/37
What the sources say
- Not checked — no full text of the sourcecites [52] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim.
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
“The samples were processed on the same day to avoid potential technical bias.”
§ Heme induces innate immune memory > 21/37
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it. The quote only partly states this claim.
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
“Since the peak calling was performed separately, peaks do not overlap perfectly and might be treated as entirely different features.”
§ Heme induces innate immune memory > 25/37
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“Heme imposes histone modifications and chromatin accessibility patterns and relies on signal transduction pathways involving the spleen tyrosine kinase mediated pathway, which is clearly distict from β-glucan-training.”
§ Heme induces innate immune memory > CONCLUSION
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It 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
“Only samples which clearly showed training in TNF ELISA after normalization to protein were taken for the LegendPlex TM analysis.”
§ Heme induces innate immune memory > Cytokine measurements
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
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
“Cell purity was above 95%.”
§ Heme induces innate immune memory > 23/37
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“The later have also been associated with β-glucan training and may therefore represent a pan-trained immunity signature.”
§ Heme induces innate immune memory > CONCLUSION
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“In mice, innate immune memory induced by β-glucan or BCG was mostly protective 17,18,23,31 and is associated with increased myelopoiesis 25,26 which is also seen in heme induced innate immune memory.”
§ Heme induces innate immune memory > 12/37
What the sources say
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“Here, we report that labile heme, an alarmin released extracellularily upon tissue damage and hemolysis, induces trained immunity in human and murine primary cells and in mice.”
- Also stated in: § 4/37 · boosted
“Here, we report that labile heme 9 induces potent trained immunity in vitro in human monocytes and Mφ, as well as in vivo in mice.”
§ Heme induces innate immune memory > Abstract
What the sources say
- Not checked — no full text of the sourcecites [9] source
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Also stated in: § 4/37 · boosted
In the paper
“Cells were filtered, keeping those with a TSS enrichment of at least five and more than 1,000 unique fragments.”
§ Heme induces innate immune memory > 25/37
What the sources say
- Not checked yetcites [58] source
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably not a substantial claim. The paper’s conclusions may not depend on it.
In the paper
“Mitroulis et al. showed that β-glucan training was associated with a specific expansion of myeloid-biased hematopoietic stem cells (HSC) 26 although HSC do not express the β-glucan receptor Dectin-1.”
§ Heme induces innate immune memory > 12/37
What the sources say
- Not checked yetcites [26] source
plaincorrelational- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: fails — The paper’s conclusions may not depend on it.
- Based: passes — The paper gives a reason why it holds.
Probably 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
“We coclude that heme-induced trained immunity can be deleterious in acute inflammatory stress but improve the host defense against infections of sutle onset.”
§ Heme induces innate immune memory > 10/37
plainconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
- Rests on an assumption: The mouse endotoxemia and polymicrobial sepsis models reflect human acute inflammatory stress and infection sufficiently to support conclusions about host defense.
The paper relies on this without support.
The mouse endotoxemia and polymicrobial sepsis models reflect human acute inflammatory stress and infection sufficiently to support conclusions about host defense.
“We then assessed the effects of heme training in vivo using a mouse endotoxemia model (Fig. 5a).”
“we induced a smoldering bacterial sepsis.”
The paper relies on this without support.
Pharmacological inhibitors R406, SP600125, and rapamycin specifically inhibit Syk, JNK, and mTOR, respectively, at the concentrations used.
“Syk inhibition by R406 38 abolished heme-induced training (Fig. 3b;c).”
“application of the JNK-Inhibitor SP600125 39 abolished JNK phosphorylation and heme-induced training (Fig. 3g;h).”
“inhibition of mTOR activity by rapamycin did not abolish heme training”
The paper relies on this without support.
Changes in H3K27ac and chromatin accessibility measured at the assayed time points reflect functional epigenetic memory that mediates the long-lasting trained immunity phenotype.
“Heme imposes histone modifications and chromatin accessibility patterns”
“epigenetic alterations in HSPCs may contribute to the persistence of the heme-induced training effects.”
The paper relies on this without support.
Rag2-/- mice, lacking mature B and T cells, isolate innate immune-mediated effects.
“The deleterious effects of heme training on subsequent LPS-induced systemic inflammation persisted in Rag2 knock-out mice (Rag2 -/-) with a constitutive deficiency of mature B-and T-cells 45”
“This finding supports that heme-mediated trained immunity is predominantly mediated by effects on innate immune cells.”
Citations
Cites
Comprehensive Integration of Single-Cell Data
Stuart, T., Butler, A., Hoffman, P., Hafemeister, C., Papalexi, E., Mauck, W. M., Hao, Y., Stoeckius, M., Smibert, P., & Satija, R. (2019) · Cell · doi:10.1016/j.cell.2019.05.031 · Cited by 15,453
Janeway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394
GREAT improves functional interpretation of cis-regulatory regions
McLean, C. Y., Bristor, D., Hiller, M., Clarke, S. L., Schaar, B. T., Lowe, C. B., Wenger, A. M., & Bejerano, G. (2010) · Nature Biotechnology · doi:10.1038/nbt.1630 · Cited by 4,502
The Danger Model: A Renewed Sense of Self
Matzinger, P. (2002) · Science · doi:10.1126/science.1071059 · Cited by 4,205
Sterile inflammation: sensing and reacting to damage
Chen, G. Y., & Nuñez, G. (2010) · Nature Reviews Immunology · doi:10.1038/nri2873 · Cited by 3,051
Trained immunity: A program of innate immune memory in health and– disease
Netea, M. G., Joosten, L. A. B., Latz, E., Mills, K. H. G., Natoli, G., Stunnenberg, H. G., O’Neill, L. A. J., & Xavier, R. J. (2016) · Science · doi:10.1126/science.aaf1098 · Cited by 2,768
Self-citationSP600125, an anthrapyrazolone inhibitor of Jun N-terminal kinase
Bennett, B. L., Sasaki, D. T., Murray, B. W., O'Leary, E. C., Sakata, S. T., Xu, W., Leisten, J. C., Motiwala, A., Pierce, S., Satoh, Y., et al. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.251194298 · Cited by 2,558
mTOR- and HIF-1α–mediated aerobic glycolysis as metabolic basis for trained immunity
Cheng, S.-C., Quintin, J., Cramer, R. A., Shepardson, K. M., Saeed, S., Kumar, V., Giamarellos-Bourboulis, E. J., Martens, J. H. A., Rao, N. A., Aghajanirefah, A., et al. (2014) · Science · doi:10.1126/science.1250684 · Cited by 2,224
Self-citationRAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement
Shinkai, Y. (1992) · Cell · doi:10.1016/0092-8674(92)90029-c · Cited by 2,150
Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity
Saeed, S., Quintin, J., Kerstens, H. H. D., Rao, N. A., Aghajanirefah, A., Matarese, F., Cheng, S.-C., Ratter, J., Berentsen, K., van der Ent, M. A., et al. (2014) · Science · doi:10.1126/science.1251086 · Cited by 1,761
Self-citation
Cited by
Sorted by citations
Sexual Dimorphism in Innate Immunity: The Role of Sex Hormones and Epigenetics
Shepherd, R., Cheung, A. S., Pang, K. C., Saffery, R., & Novakovic, B. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2020.604000 · Cited by 326
Self-citationPro-inflammatory Actions of Heme and Other Hemoglobin-Derived DAMPs
Bozza, M. T., & Jeney, V. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01323 · Cited by 214
Lysine methyltransferase G9a is an important modulator of trained immunity
Mourits, V. P., van Puffelen, J. H., Novakovic, B., Bruno, M., Ferreira, A. V., Arts, R. J. W., Groh, L. A., Crișan, T. O., Zwaag, J., Jentho, E., et al. (2021) · Clinical & Translational Immunology · doi:10.1002/cti2.1253 · Cited by 45
Self-citationChen, L., & Ozato, K. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.621333 · Cited by 41
Heme oxygenase-1 in protozoan infections: A tale of resistance and disease tolerance
Silva, R. C. M. C., Travassos, L. H., Paiva, C. N., & Bozza, M. T. (2020) · PLoS Pathogens · doi:10.1371/journal.ppat.1008599 · Cited by 31
Metadata
- Authors
- Jentho, E., Novakovic, B., Ruiz-Moreno, C., Kourtzelis, I., Martins, R., Chavakis, T., Soares, M. P., Kalafati, L., Guerra, J., Roestel, F., Bohm, P., Godmann, M., Grinenko, T., Eugster, A., Beretta, M., Joosten, L. A. B., Netea, M. G., Stunnenberg, H. G., Bauer, M., & Weis, S.
- Affiliations
- Jena University Hospital (DE)
- Radboud University Nijmegen (NL)
- Princess Máxima Center (NL)
- German Cancer Research Center (DE)
- Instituto Gulbenkian de Ciência (PT)
- Technische Universität Dresden (DE)
- Friedrich Schiller University Jena (DE)
- University of Bonn (DE)
- Corresponding author
- Weis, Sebastian
- ORCID
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2019-12-13
- OpenAlex
- W2995454016
- Semantic Scholar
- 965f2b755c4d514a0003c909b4203019551d6e17
- Cited by
- 10
- References
- 60
- Citations by year
- 2025: 1 · 2024: 1 · 2022: 1 · 2021: 4 · 2020: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (submittedVersion)
- Funders
- East Tennessee State University
- Deutsche Forschungsgemeinschaft (SFB-TRR 205, FOR1738, SFB1181, 01EO1502, Project A3, GRK1715, 1715/2)
- Bundesministerium für Bildung und Forschung (FOR 1738, 01EO1502)
- Universitätsklinikum Jena (01EO1502)
- Quillen College of Medicine, East Tennessee State University
- National Health and Medical Research Council (1173314)
- Center for Sepsis Control and Care (01EO1502)
- H2020 European Research Council (833247)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Immunology and Microbiology › Immunology › Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Keywords
- heme, trained immunity, alarmins, monocytes, epigenetic modifications, chromatin accessibility, hematopoietic stem and progenitor cells, β-glucan, bacterial sepsis, myeloid progenitor cells
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 2026-11-11, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-11 (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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