A Distal Locus Element Mediates IFN-γ Priming of Lipopolysaccharide-Stimulated TNF Gene Expression

Chow, Nancy A.; Jasenosky, Luke D.; Goldfeld, Anne E.

doi:10.1016/j.celrep.2014.11.011

Cited by 26 publications

(35 citation statements)

References 42 publications

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“…Despite increased TNF secretion in heme-trained Mφ, we could not find a difference in H3K27ac levels at the TNF promoter after heme treatment compared to control cells by ChIP-qPCR which is in line with our finding that the pan-innate immune training signature observed in both heme and β-glucan exposed Mφ involves the upregulation of mechanisms for cytokine release. This is in agreement with recent findings by other authors who used a model of IFNγ-priming 49 . Increased TNF release was also unrelated to H3K27ac in the TNF promotor itself as IFNγ dependent modifications occur at a region 8 kb upstream of the TNF promotor 49 .…”

Section: /37supporting

confidence: 94%

“…This is in agreement with recent findings by other authors who used a model of IFNγ-priming 49 . Increased TNF release was also unrelated to H3K27ac in the TNF promotor itself as IFNγ dependent modifications occur at a region 8 kb upstream of the TNF promotor 49 . Additionally, it was shown that innate immune memory does not only depend on H3K27ac but also involves histone methylation 18,50 .…”

Section: /37supporting

confidence: 94%

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Heme induces innate immune memory

Jentho

Novakovic

Ruiz-Moreno

et al. 2019

Preprint

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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.Jentho et al. 3/37

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Section: /37supporting

confidence: 94%

Section: /37supporting

confidence: 94%

Heme induces innate immune memory

Jentho

Novakovic

Ruiz-Moreno

et al. 2019

Preprint

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“…Previous studies have shown that IFN-g synergizes with TLR ligands to activate macrophages (22,23,34). In light of our findings that TLR engagement triggered the production of IFN-g by Agexperienced T cells, we examined whether the amount of IFN-g produced was sufficient to support the activation of macrophages.…”

Section: Tlr-dependent Activation Of T Cells Augments Macrophage Respmentioning

confidence: 99%

“…The production of IFN-g during this bystander activation supports the immune response against unrelated infections (14,16). To achieve this cross-protection, innate immune cells like dendritic cells and NK cells are recruited to the site of infection (7,21), and macrophages and neutrophils become activated by IFN-g (8,22,23).…”

Section: Tlr-mediated Innate Production Of Ifn-g By Cd8mentioning

confidence: 99%

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Salerno

Guislain

Cansever

et al. 2016

The Journal of Immunology

120

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CD8+ T cells can respond to unrelated infections in an Ag-independent manner. This rapid innate-like immune response allows Ag-experienced T cells to alert other immune cell types to pathogenic intruders. In this study, we show that murine CD8+ T cells can sense TLR2 and TLR7 ligands, resulting in rapid production of IFN-γ but not of TNF-α and IL-2. Importantly, Ag-experienced T cells activated by TLR ligands produce sufficient IFN-γ to augment the activation of macrophages. In contrast to Ag-specific reactivation, TLR-dependent production of IFN-γ by CD8+ T cells relies exclusively on newly synthesized transcripts without inducing mRNA stability. Furthermore, transcription of IFN-γ upon TLR triggering depends on the activation of PI3K and serine-threonine kinase Akt, and protein synthesis relies on the activation of the mechanistic target of rapamycin. We next investigated which energy source drives the TLR-induced production of IFN-γ. Although Ag-specific cytokine production requires a glycolytic switch for optimal cytokine release, glucose availability does not alter the rate of IFN-γ production upon TLR-mediated activation. Rather, mitochondrial respiration provides sufficient energy for TLR-induced IFN-γ production. To our knowledge, this is the first report describing that TLR-mediated bystander activation elicits a helper phenotype of CD8+ T cells. It induces a short boost of IFN-γ production that leads to a significant but limited activation of Ag-experienced CD8+ T cells. This activation suffices to prime macrophages but keeps T cell responses limited to unrelated infections.

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“…IFN-γ and STAT1 have been implicated in nucleosome remodeling and opening of chromatin (122). Recent genome-wide studies of human macrophages revealed that IFN-γ induced stable and coordinated recruitment of STAT1, IRF1, and associated histone acetylation to enhancers and promoters of genes that are synergistically activated by IFN-γ and LPS, such as TNF , IL6 , and IL12B (123, 124). Importantly, CRISPR-mediated deletion established the functional importance of IFN-γ-primed enhancer at the TNF locus.…”

Section: Epigenetics In Priming Macrophage Activation Statesmentioning

confidence: 99%

Epigenetic Regulation of Myeloid Cells

Ivashkiv

Park

2016

Microbiol Spectr

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Epigenetic regulation in myeloid cells is crucial for cell differentiation and activation in response to developmental and environmental cues. Epigenetic control involves posttranslational modification of DNA or chromatin, and is also coupled to upstream signaling pathways and transcription factors. In this review, we summarize key epigenetic events and how dynamics in the epigenetic landscape of myeloid cells shape the development, immune activation, and innate immune memory.

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A Distal Locus Element Mediates IFN-γ Priming of Lipopolysaccharide-Stimulated TNF Gene Expression

Cited by 26 publications

References 42 publications

Heme induces innate immune memory

Heme induces innate immune memory

TLR-Mediated Innate Production of IFN-γ by CD8+ T Cells Is Independent of Glycolysis

Epigenetic Regulation of Myeloid Cells

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