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Direct TLR2 signaling through mTOR and TBK1 induces C/EBPβ and IRF7-dependent macrophage differentiation in hematopoietic stem and progenitor cells

ABSTRACT: Direct TLR2 signaling through mTOR and TBK1 induces C/EBPβ and IRF7-dependent macrophage differentiation in hematopoietic stem and progenitor cells

PROVIDER: PRJNA851437 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR19769925_1.fastq.gz	Fastqsanger.gz
	SRR19769925_2.fastq.gz	Fastqsanger.gz
	SRR19769926_1.fastq.gz	Fastqsanger.gz
	SRR19769926_2.fastq.gz	Fastqsanger.gz
	SRR19769927_1.fastq.gz	Fastqsanger.gz

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Direct TLR2 signaling through mTOR and TBK1 induces C/EBPβ and IRF7-dependent macrophage differentiation in hematopoietic stem and progenitor cells

Project description:During an infection, hematopoiesis is altered to increase the output of mature myeloid cells to fight off the pathogen. Despite convincing evidence that hematopoietic stem and progenitor cells (HSPCs) can sense pathogens directly, more mechanistic studies are needed to reveal whether pattern recognition receptor (PRR) signaling initiates myeloid development directly, or indirectly through the production of cytokines by HSPCs that can act in an autocrine/paracrine manner, or by a combination of both direct and indirect mechanisms. In this study, we have used an in vitro model of murine HSPCs to study myeloid differentiation in response to the TLR2 ligand Pam3CSK4 and showed that, besides indirect mechanisms, TLR2 stimulation of HSPCs promotes myelopoiesis directly by initiating a MyD88-dependent signaling. This direct differentiation program involves a combined activation of the transcription factors PU.1, C/EBPβ and IRF7 driven by TBK1 and PI3K/mTOR. Notably, downstream of MyD88, the activated TBK1 kinase can activate mTOR directly and IRF7 induction is mediated by both TBK1 and mTOR. TLR2 signaling also induces NF-κB dependent IL-6 production that may further induce indirect myeloid differentiation. Our results have identified the direct signaling pathways and the transcription factors involved in macrophage development from HSPCs in response to TLR2 engagement, a critical process to trigger a rapid immune response during infection.

2023-01-09 | GSE206596 | GEO

Deregulation of the endogenous C/EBPβ LIP isoform predisposes to tumorigenesis

Project description:Two long and one truncated isoforms (termed LAP*, LAP, and LIP, respectively) of the transcription factor CCAAT enhancer binding protein beta (C/EBPβ) are expressed from a single intronless Cebpb gene by alternative translation initiation. Isoform expression is sensitive to mammalian target of rapamycin (mTOR)-mediated activation of the translation initiation machinery and relayed through an upstream open reading frame (uORF) on the C/EBPβ mRNA. The truncated C/EBPβ LIP, initiated by high mTOR activity, has been implied in neoplasia, but it was never shown whether endogenous C/EBPβ LIP may function as an oncogene. In this study, we examined spontaneous tumor formation in C/EBPβ knockin mice that constitutively express only the C/EBPβ LIP isoform from its own locus. Our data show that deregulated C/EBPβ LIP predisposes to oncogenesis in many tissues. Gene expression profiling suggests that C/EBPβ LIP supports a protumorigenic microenvironment, resistance to apoptosis, and alteration of cytokine/chemokine expression. The results imply that enhanced translation reinitiation of C/ EBPβ LIP promotes tumorigenesis. Accordingly, pharmacological restriction of mTOR function might be a therapeutic option in tumorigenesis that involves enhanced expression of the truncated C/EBPβ LIP isoform.

2014-12-16 | GSE53770 | GEO

Transcriptome analysis of microglia reveals the TLR2/IRF7 signaling axis mediates neuroinflammation after subarachnoid hemorrhage

Project description:Transcriptome analysis of microglia reveals the TLR2/IRF7 signaling axis mediates neuroinflammation after subarachnoid hemorrhage

| PRJNA705667 | ENA

Transcriptome analysis of microglia reveals the TLR2/IRF7 signaling axis mediates neuroinflammation after subarachnoid hemorrhage

Project description:Microglia-mediated neuroinflammatory response in the early brain injury after subarachnoid hemorrhage (SAH) has been reported to have an impact on progress and the mechanism is not completely understood. Here, we performed genome-wide transcriptome analysis of microglia purified from damaged hemisphere of adult mice at 3 days after SAH or sham operation. Robust transcriptional changes were observed between SAH-induced and healthy microglia, indicating rapid activation of microglia after suffering SAH. We identified 1576 differentially expressed genes (DEGs; 928 up-regulated and 648 down-regulated) in SAH-induced microglia compared with sham microglia, representing a strong alteration of the genome (6.85% of total ~23,000 genes). Functional enrichment of these DEGs indicated that cell division, inflammatory response, cytokine production and leukocyte chemotaxis were strongly activated in SAH-induced microglia. Moreover, we identified and proved the TLR2/IRF7 signaling axis was involved in regulation of this microglia-mediated inflammation in SAH mice, by performing flow cytometry, immunofluorescence. Together, these results provided a perspective of microglia-mediated neuroinflammatory response in the early stage of SAH and might give a new therapeutic target for SAH.

2021-06-30 | GSE167957 | GEO

ChIP-seq for IRF7

Project description:We performed ChiP-Seq for IRF7 in GM-CSF induced bone-marrow cells. IRF7 ChIP-Seq in myeloid cells

2014-12-03 | E-GEOD-62697 | biostudies-arrayexpress

Genome-wide C/EBPβ traget genes in C/EBPβ-overexpressed HL-60 cells.

Project description:To characterize genome-wide C/EBPβ traget genes in C/EBPβ-overexpressed HL-60 cells by ChIP-seq.

2018-06-13 | GSE100486 | GEO

Transcription profiling of mouse wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses

Project description:B-DNA-induced gene expression profile in wild-type, TBK1, IKKi(Ikbke), or TBK1 IKKi doubly deficient embryonic fibroblats; to elucidate how TBK1 and/or IKKi mediates B-DNA-mediated innate immune responses. Experiment Overall Design: Total RNA was extracted from embryonic fibroblats transfected for 4 h with or without poly(dA-dT)-poly(dT-dA), after which cRNA was synthesized. Preparation of cRNA, hybridization and scanning of the microarray were done according to the manufacturer's instructions (Affymetrix). A microarray (MG U74A version 2; Affymetrix) was used with Microarray Suite software (version 5.0; Affymetrix) and GeneSpring software (Silicon Genetics).

2007-12-07 | E-GEOD-4171 | biostudies-arrayexpress

Transcription factor C/EBPβ orchestrates DC maturation and functionality under homeostatic and malignant conditions [CEBPbetaKO]

Project description:Dendritic cell (DC) maturation is a prerequisite for the induction of adaptive immune responses against pathogens and cancer. Transcription factor (TF) networks control differential aspects of early DC progenitor versus late stage DC cell fate decisions. Here, we identified the TF C/EBPβ as a key regulator for DC maturation and immunogenic functionality under homeostatic and lymphoma-transformed conditions. Gene expression profiles of splenic C/EBPβ-/- DCs showed a strong downregulation of E2F cell cycle target genes, whereas signatures of maturation were enriched. In accordance with E2F1 being a negative regulator of DC maturation, C/EBPβ-/- bone marrow-derived DCs matured much faster enabling them to strongly activate T cells. Conversely, the E2F transcriptional pathways were upregulated in lymphoma-exposed DCs and DC maturation was impaired. Pharmacological blockade of C/EBPβ/mTOR signaling in human DCs abrogated their pro-tumorigenic function in B-cell lymphoma co-cultures. Thus, C/EBPβ plays a unique role in DC maturation and functionality and emerges as a key factor of the microenvironment promoting lymphomagenesis.

2020-10-20 | GSE123591 | GEO

C/EBPβ deficiency reshapes microglial gene expression

Project description:CCAAT/enhancer binding protein β (C/EBPβ) is a transcription factor that regulates the expression of important pro-inflammatory genes in microglia. Mice deficient for C/EBPβ show protection against excitotoxic and ischemic CNS damage but the involvement of the various C/EBPβ expressing cell types in this neuroprotective effect is not solved. Since C/EBPβ-deficient microglia show attenuated neurotoxicity in culture we hypothesized that specific C/EBPβ deficiency in microglia could be neuroprotective in vivo. In this study we have tested this hypothesis by generating mice with myeloid C/EBPβ deficiency. Mice with myeloid C/EBPβ deficiency were generated by crossing LysMCre and C/EBPβfl/fl mice . Primary microglial cultures from C/EBPβfl/fl (named here as WT) and LysMCre-C/EBPβfl/fl (named here as KO) mice were treated with lipopolysaccharide ± interferon γ (IFNγ) for 6 h and gene expression was analyzed by RNA sequencing. LysMCre-C/EBPβfl/fl mice showed an efficiency of C/EBPβ deletion of 100% in cultured microglia. Transcriptomic analysis of C/EBPβ-deficient primary microglia revealed C/EBPβ-dependent expression of 1068 genes, significantly enriched in inflammatory and innate immune responses GO terms. This study provides new data that support a central role for C/EBPβ in the biology of activated microglia.

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Transcription factor C/EBPβ orchestrates DC maturation and functionality under homeostatic and malignant conditions [Emu-Myc]

2020-10-20 | GSE123592 | GEO