Bhlhe40 is an essential repressor of IL-10 during Mycobacterium tuberculosis infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA449905 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6988800.fastq.gz | Fastqsanger.gz | |||
| SRR6988801.fastq.gz | Fastqsanger.gz | |||
| SRR6988802.fastq.gz | Fastqsanger.gz | |||
| SRR6988803.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 4 of 4 |
Similar Datasets
Project description:The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss of function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor Bhlhe40 is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-g. Deletion of Il10 in Bhlhe40-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb. Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
2018-05-09 | GSE113054 | GEO
Project description:Better understanding of the host responses to Mycobacterium tuberculosis (Mtb) infections is required to prevent tuberculosis and develop new therapeutic interventions. The host transcription factor BHLHE40 is essential for controlling Mtb infection, in part by repressing Il10 expression, where excess IL-10 contributes to the early susceptibility of Bhlhe40-/- mice to Mtb infection. Deletion of Bhlhe40 in lung macrophages and dendritic cells is sufficient to increase the susceptibility of mice to Mtb infection, but how BHLHE40 impacts macrophage and dendritic cell responses to Mtb is unknown. Here we report that BHLHE40 is required in myeloid cells exposed to GM-CSF, an abundant cytokine in the lung, to promote the expression of genes associated with a pro-inflammatory state and better control of Mtb infection. Loss of Bhlhe40 expression in murine bone marrow derived myeloid cells cultured in the presence of GM-CSF results in lower levels of pro-inflammatory associated signaling molecules IL-1b, IL-6, IL-12, TNFα, iNOS, IL-2, KC, and RANTES, as well as higher levels of the anti-inflammatory associated molecules MCP-1 and IL-10 following exposure to heat-killed Mtb. Deletion of Il10 in Bhlhe40-/- myeloid cells restored some, but not all, pro-inflammatory signals, demonstrating that BHLHE40 promotes pro-inflammatory responses via both IL-10-dependent and independent mechanisms. In addition, we show that macrophages and neutrophils within the lungs of Mtb-infected Bhlhe40-/- mice exhibit defects in iNOS production compared to infected WT mice, supporting that BHLHE40 promotes pro-inflammatory responses in innate immune cells, which may contribute to the essential role for BHLHE40 during Mtb infection in vivo.
2024-07-02 | GSE265840 | GEO
Project description:The cytokine IL-10 antagonizes pathways that control Mycobacterium tuberculosis (Mtb) infection. Nevertheless, the impact of IL-10 during Mtb infection has been difficult to decipher because loss-of-function studies in animal models have yielded only mild phenotypes. We have discovered that the transcription factor basic helix-loop-helix family member e40 (Bhlhe40) is required to repress Il10 expression during Mtb infection. Loss of Bhlhe40 in mice results in higher Il10 expression, higher bacterial burden, and early susceptibility similar to that observed in mice lacking IFN-γ. Deletion of Il10 in Bhlhe40-/- mice reverses these phenotypes. Bhlhe40 deletion in T cells or CD11c+ cells is sufficient to cause susceptibility to Mtb Bhlhe40 represents the first transcription factor found to be essential during Mtb infection to specifically regulate Il10 expression, revealing the importance of strict control of IL-10 production by innate and adaptive immune cells during infection. Our findings uncover a previously elusive but significant role for IL-10 in Mtb pathogenesis.
| S-EPMC6028511 | biostudies-literature
Project description:To assess the impact of hypoxia on global gene expression of beta cells, we performed bulk RNA-seq on mouse islets, human islets and MIN6 cells. Bhlhe40 was transcriptional repressor which was highly induced by hypoxia in beta cells. Thus, we established Bhlhe40 overexpressing MIN6 cells and performed RNA-seq to identify the targets of Bhlhe40.
2023-05-01 | GSE202603 | GEO
Project description:BHLHE40 is key hypoxia-induced transcriptional repressor in beta cells
| PRJNA836763 | ENA
Project description:Microarray data on TH17 cells from Bhlhe40-GFP reporter mice We used microarrays to detail the global programme of gene expression in polarized Bhlhe40-GFPneg and Bhlhe40-GFPpos TH17 cells Purified naïve CD4 T cells from spleen were polarized under TH17 condition in vitro. On day 4, cells were stimulated with PMA and ionomycin, and sorted by their Bhlhe40-GFP expression prior to microarray analysis
2016-01-04 | E-GEOD-75407 | biostudies-arrayexpress
Project description:BHLHE40 regulates myeloid cell polarization through IL-10-dependent and independent mechanisms
| PRJNA1104364 | ENA
Project description:NK cells represent a cellular component of the mammalian innate immune system, and mount rapid responses against viral infection, including the secretion of the potent anti-viral effector cytokine IFN-g. Following mouse cytomegalovirus (MCMV) infection, Bhlhe40 was the most highly induced transcription factor in NK cells among the basic helix-loop-helix family. Bhlhe40 upregulation in NK cells depended upon IL-12 and IL-18 signals, with the promoter of Bhlhe40 enriched for STAT4 and the permissive histone H3K4me3, and STAT4-deficient NK cells showing an impairment of Bhlhe40 induction and diminished H3K4me3. Transcriptomic and protein analysis of Bhlhe40-deficient NK cells revealed a defect in IFN-g production during MCMV infection, resulting in diminished protective immunity following viral challenge. Finally, we provide evidence that Bhlhe40 directly promotes IFN-g by binding throughout the Ifng loci in activated NK cells. Thus, our study reveals how STAT4-mediated control of Bhlhe40 drives protective IFN-g secretion by NK cells during viral infection.
2023-09-13 | GSE242900 | GEO
Project description:Most tissue-resident macrophage populations develop during embryogenesis, self-renew in the steady state, and can expand during type 2 immunity. Whether shared mechanisms regulate macrophage proliferation in homeostasis and disease is unclear. We found that the transcription factor Bhlhe40 was cell-intrinsically required in large peritoneal macrophages (LPMs) for self-renewal and maintenance, but was not required in other resident macrophages. Bhlhe40 was selectively necessary in LPMs for proliferation, but not polarization, in response to IL-4. During a helminth infection, Bhlhe40 was required for normal LPM cell cycling. Bhlhe40 repressed the expression of Maf and Mafb and directly promoted expression of cell cycle-related transcripts to enable proliferation of LPMs. Genomic sites bound by Bhlhe40 in LPMs included some co-bound by the macrophage lineage-determining factor PU.1 and others uniquely bound by Bhlhe40, including Maf and cell cycle-related loci. Our findings demonstrate a tissue-specific control mechanism regulating resident macrophage proliferation in homeostasis and type 2 immunity.
2019-04-30 | GSE125729 | GEO
Project description:Tuberculosis remains a major cause of death from an infectious disease worldwide, yet only 10% of people infected with Mycobacterium tuberculosis develop disease. Defining both necessary and sufficient immunologic determinants of protection remains a great scientific challenge. Analysis of peripheral blood gene expression profiles of active tuberculosis patients has identified correlates of risk for disease or pathogenesis. We sought to identify human potential candidate markers of host defense by studying gene expression profiles of macrophages, cells which, upon infection by M. tuberculosis, can mount an antimicrobial response. Weighted gene co-expression network analysis revealed an association between the cytokine, IL-32, and the vitamin D antimicrobial pathway in a network of IFN-γ and IL-15 induced ‘defense response’ genes. IL-32 was sufficient for induction of the vitamin D-dependent antimicrobial peptides, cathelicidin and DEFB4, and generation of antimicrobial activity in vitro, dependent on the presence of adequate 25-hydroxyvitamin D. The IL-15 induced ‘defense response’ macrophage gene network was integrated with ranked pairwise comparisons of gene expression from five different clinical data sets of latent vs. active tuberculosis or healthy controls, and a co-expression network derived from gene expression in patients with tuberculosis undergoing chemotherapy. Together, these analyses identified eight common genes, including IL-32, as molecular markers of latent tuberculosis and the IL-15 induced gene network. Inferring that maintaining M. tuberculosis in a latent state and preventing transition to active disease represents host resistance, we believe these results identify IL-32 as one functional marker and potential correlate of protection against active tuberculosis.
2014-08-20 | GSE59184 | GEO