Beneficial and detrimental consequences of AHR stimulation in intestinal infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1265726 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR33645600_1.fastq.gz | Fastqsanger.gz | |||
| SRR33645600_2.fastq.gz | Fastqsanger.gz | |||
| SRR33645601_1.fastq.gz | Fastqsanger.gz | |||
| SRR33645601_2.fastq.gz | Fastqsanger.gz |
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Project description:The ligand dependent transcription factor aryl hydrocarbon receptor (AHR) is an environmental sensor whose activation can have physiologically beneficial or detrimental consequences for host immune responses depending on the ligand. Here we investigated the hypothesis that prolonged AHR activation either due to inefficient ligand metabolism or due to genetic manipulation may underlie the distinction between beneficial and detrimental effects. Our data indicate that prolonged AHR activation caused toxic endpoints for liver and thymus but was not per se interfering with the host response to infection with the intestinal pathogen C.rodentium. Genetically driven constitutive AHR activation improved resistance to infection, whereas prolonged AHR activation by the pollutant TCDD resulted in delayed clearance of C.rodentium. This was associated to a suppression in antibody production. Combined single cell RNAseq and ATAC-seq analysis provided evidence that TCDD, but not genetic AHR overactivation, affected dendritic cell functions such as activation, maturation and antigen presentation. Thus, the detrimental impact of environmental pollutants such as TCDD on immune responses cannot solely be attributed to aberrantly prolonged activation of AHR.
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Project description:We have generated transgenic mice expressing constitutively activated aryl hydrocarbon receptor (CA-AhR) to examine the biological consequences of AhR activation.. We used microarrays to identify genes that are regulated by AhR. Livers or intestines from three female mice were pooled at 5-6 week-old for RNA extraction and hybridization on Affymetrix Mouse Genome 430 2.0 Array.
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Project description:We have generated transgenic mice expressing constitutively activated aryl hydrocarbon receptor (CA-AhR) to examine the biological consequences of AhR activation.. We used microarrays to identify genes that are regulated by AhR.
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Project description:Sometimes biological research is an act of faith, a belief that untangling complex biologic interactions on a very basic level in-and-of itself eventually leads to larger and broader implications for human health. Indeed, sometimes focusing on the trees leads to a better view of the forest. This has been the case for the aryl hydrocarbon receptor (AHR). For decades, the AHR was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a “normal” physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus was placed on the association between AHR activity and poor outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.
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Project description:The bioactive lipid intermediate palmitoyl CoA (PCoA) can inhibit mitochondrial ADP/ATP transport, though the physiological relevance of this regulation remains unclear. We questioned whether myocardial ischaemia was a pathological setting in which PCoA regulation of ADP/ATP transport would be beneficial. Secondly, whether the chronically elevated lipid content within the diabetic heart would make the mitochondria less sensitive to the inhibitory effects of PCoA, with detrimental consequences during ischaemia. Palmitoyl CoA acutely decreased ADP-stimulated state 3 respiration, increasing the Km for ADP 2-fold. The half maximal inhibitory concentration (IC50) of PCoA in control mitochondria was 22 µM. This inhibitory effect of PCoA on respiration was blunted in the diabetic mitochondria, with no significant difference in the Km in the presence of PCoA, and the IC50 increased to 32 µM PCoA. The competitive inhibition by PCoA was localised to the phosphorylation apparatus, particularly the ADP/ATP carrier (AAC). During ischaemia, the AAC imports ATP into the mitochondria, where it is hydrolysed by reversal of the ATP synthase, to regenerate the membrane potential. Addition of PCoA dose-dependently prevented this wasteful ATP hydrolysis for membrane repolarisation during ischaemia. However, this beneficial effect was blunted in the diabetic mitochondria. Finally, using 31P-magnetic resonance spectroscopy we demonstrated that diabetic hearts lose ATP more rapidly during ischaemia, with a 3-fold higher ATP decay rate compared with control hearts. In conclusion, PCoA plays a role in protecting mitochondrial energetics during ischaemia, by preventing wasteful ATP hydrolysis. However, this beneficial effect is blunted in diabetes, contributing to the impaired energy metabolism during myocardial ischaemia.
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Project description:The Aryl Hydrocarbon Receptor (AHR) regulates the expression of numerous genes in response to activation by agonists including xenobiotics. Although it is well appreciated that environmental signals and cell intrinsic features may modulate this transcriptional response, how it is mechanistically achieved remains poorly understood. We show that Hexokinase 2 (HK2) a metabolic enzyme fuelling cancer cell growth, is a transcriptional target of AHR as well as a modulator of its activity. Expression of HK2 is positively regulated by AHR upon exposure to agonists both in human cells and in mice lung tissues. Conversely, over-expression of HK2 regulates the abundance of many proteins involved in the regulation of AHR signalling and these changes are linked with altered AHR expression levels and transcriptional activity. HK2 expression also shows a negative correlation with AHR promoter methylation in tumours, and these tumours with high HK2 expression and low AHR methylation are associated with a worse overall survival in patients. In sum, our study provides novel insights into how AHR signalling is regulated which may help our understanding of the context-specific effects of this pathway and may have implications in cancer.
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