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Prolyl hydroxylase PHD3 is essential for hypoxic regulation of neutrophilic inflammation in humans and mice

ABSTRACT: Neutrophils were isolated form peripheral blood of wildtype and Phd3 null mice, cultured for 4 hours in hypoxia (3% O2) and micro array analysis performed The aim of the present study is to identify the mechanism by which phd3 is required for the hypoxia mediated survival of neutrophils

ORGANISM(S): Mus musculus

PROVIDER: GSE26023 | GEO | 2011/02/08

SECONDARY ACCESSION(S): PRJNA135485

REPOSITORIES: GEO

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Prolyl hydroxylase PHD3 is essential for hypoxic regulation of neutrophilic inflammation in humans and mice

Project description:Neutrophils were isolated form peripheral blood of wildtype and Phd3 null mice, cultured for 4 hours in hypoxia (3% O2) and micro array analysis performed The aim of the present study is to identify the mechanism by which phd3 is required for the hypoxia mediated survival of neutrophils Murine peripheral blood neutrophils were isolated from wildtype and phd3 null mice, cultured for 4 hours in hypoxia (3% O2) and micro array analysis performed

2011-02-08 | E-GEOD-26023 | biostudies-arrayexpress

Prolyl-4-hydroxylase domain 3 (PHD3) is a critical terminator for cell survival of macrophages under stress conditions

Project description:On molecular level cells sense changes in oxygen availability through the prolyl-4-hydroxylase domain enzymes (PHDs), which regulate the protein stability of the α-subunit of the transcription factor hypoxia inducible factor (HIF). Especially PHD3 has been additionally associated with apoptotic cell death. We hypothesized that PHD3 plays a role in cell-fate decisions in macrophages. Therefore myeloid-specific PHD3 knock out mice (PHD3-/-) were created and analysed. PHD3-deficient bone marrow-derived macrophages (BMDM) showed no altered HIF-1alpha or HIF-2alpha stabilization or increased HIF target genes expression in normoxia or hypoxia. Macrophage M1 and M2-polarization was unchanged likewise. Compared to macrophages from wild type littermates PHD3-/- BMDM exhibited a significant reduction in TUNEL positive cells after serum withdrawal or treatment with staurosporine and s-nitroso-N-acetylpenicillamine (SNAP). Under the same conditions PHD3-/- BMDM also showed less Annexin V staining which is representative for membrane disruption and indicated a reduced early apoptosis. In an unbiased transcriptome screen we found that angiopoietin like protein 2 (Angptl2) expression was reduced in PHD3-/- BMDM under stress conditions. Addition of recombinant Angptl2 rescued the anti-apoptotic phenotype demonstrating that it is involved in the PHD3-mediated response towards apoptotic stimuli in macrophages.

2014-12-31 | GSE55693 | GEO

Prolyl hydroxylase 3 (PHD3) is essential for hypoxic regulation of neutrophilic inflammation in humans and mice.

Project description: Not available

| S-EPMC3049381 | biostudies-literature

Prolyl hydroxylase 2 inactivation enhances glycogen storage and promotes excessive neutrophilic responses.

Project description: Not available

| S-EPMC5669581 | biostudies-literature

Transcriptional imprinting of transmigrating neutrophils on T84 intestinal epithelial cells

Project description:Neutrophil accumulation in crypt abscesses is a pathological hallmark of ulcerative colitis. Based on recent evidence that mucosal metabolic changes influence disease outcomes, we hypothesized that transmigrating neutrophils influence the transcriptional profile of intestinal epithelia. Microarray studies revealed a cohort of hypoxia-responsive genes regulated by neutrophil-epithelial crosstalk. Real-time O2 sensing indicated that transmigrating neutrophils rapidly deplete microenvironmental O2 sufficient enough to stabilize intestinal epithelial cell hypoxia-inducible factor (HIF). Utilizing HIF reporter mice in a TNBS colitis model, we investigated the relative contribution of neutrophils and the respiratory burst to “inflammatory hypoxia” in vivo. Gp91phox-null mice, which mirror human chronic granulomatous disease, developed accentuated colitis compared to control with exaggerated neutrophil infiltration and diminished inflammatory hypoxia. In conclusion, transcriptional imprinting of host tissue by infiltrating neutrophils modulates the host response to inflammation. Likewise, the respiratory burst contributes fundamentally to localized O2 depletion, resultant microenvironmental hypoxia and effective inflammatory resolution.

2012-10-31 | GSE39681 | GEO

Time-course bulk RNA sequencing of endothelial colony forming cells in hypoxic and non-hypoxic hydrogels

Project description:With the increased realization of the effect of oxygen (O2) deprivation (hypoxia) on cellular processes, recent efforts have focused on the development of engineered systems to control O2 concentrations and establish biomimetic O2 gradients to study and manipulate cellular behavior. Nonetheless, O2 gradients present in 3D engineered platforms result in diverse cell behavior across the O2 gradient, making it difficult to identify and study O2 sensitive signaling pathways. Using a layer‐by‐layer assembled O2‐controllable hydrogel, the authors precisely control O2 concentrations and study uniform cell behavior in discretized O2 gradients, then recapitulate the dynamics of cluster‐based vasculogenesis, one mechanism for neovessel formation, and show distinctive gene expression patterns remarkably correlate to O2 concentrations. Using RNA sequencing, it is found that time‐dependent regulation of cyclic adenosine monophosphate signaling enables cell survival and clustering in the high stress microenvironments. Various extracellular matrix modulators orchestrate hypoxia‐driven endothelial cell clustering. Finally, clustering is facilitated by regulators of cell–cell interactions, mainly vascular cell adhesion molecule 1. Taken together, novel regulators of hypoxic cluster‐based vasculogenesis are identified, and evidence for the utility of a unique platform is provided to study dynamic cellular responses to 3D hypoxic environments, with broad applicability in development, regeneration, and disease.

2021-06-04 | GSE176123 | GEO

TET1-mediated hydroxymethylation facilitates hypoxic gene induction in neuroblastoma

Project description:Analysis of 5-hydroxymethylcytosine changes in hypoxia in neuroblastoma cells 5-hmC distribution was analyzed from cells exposed to hypoxia (1% O2) or normoxia (20% O2); mRNA was sequenced in parallel for expression analysis.

2014-05-19 | E-GEOD-55391 | biostudies-arrayexpress

Histone methylation landscape in response to short hypoxic exposure

Project description:H3K4me3 and H3K36me3 ChIP seq in HeLa cells exposed to 0H (normoxia) or 1H of 1%O2 (hypoxia)

2019-01-16 | GSE120339 | GEO

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition:Sequencing Data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an /-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIF levels and FIH catalysis regulates HIF activity. How differences in HIF hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-10-25 | E-MTAB-4264 | biostudies-arrayexpress

Tuning the transcriptional response to hypoxia through HIF prolyl- and asparaginyl-hydroxylase inhibition: Microarray data

Project description:The hypoxia inducible factor (HIF) system orchestrates cellular responses to hypoxia in animals. HIF is an Î±/Î²-heterodimeric transcription factor that regulates the expression of hundreds of genes in a context dependent manner. A hypoxia-sensing component of the HIF system involves oxygen-dependent catalysis by the HIF hydroxylases; in humans there are three HIF prolyl hydroxylases (PHD1-3) and an asparaginyl hydroxylase (FIH). PHD catalysis regulates HIFÎ± levels and FIH catalysis regulates HIF activity. How differences in HIFÎ± hydroxylation status relate to variations in the induction of HIF target gene transcription is unknown. We report studies using small molecule inhibitors of the HIF hydroxylases to investigate the extent to which HIF target gene upregulation is induced by reduced PHD catalysis. The results reveal substantial differences in the role of prolyl- and asparaginyl-hydroxylation in regulating hypoxia responsive genes in cells. Selective PHD inhibitors with different structural scaffolds behave similarly. However, under the tested conditions, a broad-spectrum 2OG dioxygenase inhibitor is a better mimic of the transcriptional response to hypoxia than the selective PHD inhibitors, consistent with an important role for FIH in the hypoxic transcriptional response. Indeed, combined application of selective PHD and FIH inhibitors resulted in transcriptional induction of a subset of genes that were not fully responsive to PHD inhibition alone. Thus, for the therapeutic regulation of HIF target genes, it is important to consider both PHD and FIH activity, and in the case of some sets of target genes, simultaneous inhibition of the PHDs and FIH catalysis may be preferable.

2016-08-31 | E-MTAB-4300 | biostudies-arrayexpress

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