Microbiome-dependent tryptophan metabolism suppresses inflammatory immunity in the pancreatic tumor microenvironment by activation of the aryl hydrocarbon receptor [RNA-seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171601 | GEO | 2022/03/31
REPOSITORIES: GEO
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Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which despite large research efforts remains poorly understood. Many studies provide evidence that the aryl hydrocarbon receptor (AHR) plays a critical role in the pathogenesis of several cancers and represents new anti-cancer therapeutic target. The role of AHR in PDAC is, however, unclear since AHR has been reported to exhibit both pro- and anti-tumor activities. In this study we evaluated the role of AHR in murine PDAC cells in vitro and in vivo. Loss of AHR did not affect cell proliferation compared with wildtype (WT). Consistent with these findings, no differences in tumor development between WT and AhrKO cells were observed in immunocompromised mice. However, tumors from AhrKO cells grew more slowly than tumors from WT cells in immune competent mice. RNA sequencing of the tumors resulted in 1009 genes upregulated and 477 genes downregulated in AhrKO tumors compared with WT tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, interleukin signaling and PD1 signaling among the top upregulated pathways. Increased infiltration of CD45+ cells and higher numbers of CD8+ T-cells and F4/80+ cells were observed in AhrKO tumors. Analysis of the F4/80+ cell populations revealed a lower percentage of anti-inflammatory (M2) macrophages in AhrKO tumors. Ahr deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of WT cells compared with WT C57BL/6 mice. AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with AhrKO tumors in WT mice. These findings show that tumors derived from AhrKO pancreatic cancer cells exhibit a proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth. They also suggesting that loss of AHR in lymphocytes together Ahr loss in cancer cells further reduces tumor growth.
2025-01-03 | GSE279893 | GEO
Project description:Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease which remains poorly understood. Increasing evidence suggests that the aryl hydrocarbon receptor (AHR) plays a role in the pathogenesis of several cancers; however, its role in PDAC is unclear because AHR exhibits both pro- and anti-tumor activities. Here we evaluated the role of AHR in CR705 and K8484 murine PDAC cells in vitro and CR705 cells in vivo. Loss of Ahr did not affect cell proliferation compared with Cas9 control cells and no differences in tumor development between CR705Cas9 and CR705AhrKO cells were observed in immunocompromised mice. Conversely, tumors from CR705AhrKO cells grew more slowly than tumors from CR705Cas9 cells in immune competent mice. RNA sequencing identified 1279 genes upregulated and 586 genes downregulated in CR705AhrKO tumors compared with CR705Cas9 tumors. Pathway analysis identified immunoregulatory interactions, interferon signaling, and chemokine signaling among the top upregulated pathways. Increased infiltration of CD45+ cells and higher numbers of CD8+ T cells and F4/80+ cells were observed in CR705AhrKO tumors. Ahr deficiency in macrophages (LysMCre) or lymphocytes (RorcCre) did not alter tumor development of CR705Cas9 cells compared with WT C57BL/6 mice. CR705AhrKO tumors in RorcCre mice, but not in LysMCre mice had significantly lower tumor weights normalized to body weights compared with CR705AhrKO tumors in WT mice. These findings show that Ahr loss in CR705 pancreatic cancer cells is sufficient to induce proinflammatory gene responses that contribute to increased immune cell infiltration and reduced tumor growth.
2025-01-03 | GSE284188 | GEO
Project description:Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions. We investigated AhR expression, agonist response, ligand production, and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T.cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation, and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable 34 AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.
2023-10-09 | GSE244478 | GEO
Project description:To analyze transcriptome changes in the tumor microenvironment caused by loss of macrophage AhR we performed scRNA sequencing analysis.
2022-03-31 | GSE171602 | GEO
Project description:To investigate the function of the AhR in lipid mediator production in macrophages we differentiated BMDMs from AhR-KO and wildtype mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of macrophages with and without LPS-stimulation.
2023-02-09 | GSE221144 | GEO
Project description:To investigate the function of the AhR in lipid mediator production in macrophages we differentiated BMDMs from AhR-KO and wildtype mice. We then performed gene expression profiling analysis using data obtained from RNA-seq of macrophages with and without LPS-stimulation.
2023-02-09 | GSE221093 | GEO
Project description:VAF347 is a low molecular weight compound which inhibits allergic lung inflammation in vivo. This effect is likely due to a block of dendritic cell (DC) function to generate pro-inflammatory T-helper (Th) cells since VAF347 inhibits IL-6, CD86 and HLA-DR expression by human monocyte derived DC, three relevant molecules for Th-cell generation. Here we demonstrate that VAF347 interacts with the aryl hydrocarbon receptor (AhR) protein resulting in activation of the AhR signaling pathway. Functional AhR is responsible for the biological activity of VAF347 since, i) other AhR agonists display an identical activity profile in vitro, ii) gene silencing of wild type AhR expression or forced over-expression of a trans-dominant negative AhR ablates VAF347 activity to inhibit cytokine induced IL-6 expression in a human monocytic cell line and iii) AhR deficient mice are resistant to the compound’s ability to block allergic lung inflammation in vivo. These data identify the AhR protein as key molecular target of VAF347 and its essential role for mediating the anti-inflammatory effects of the compound in vitro and in vivo. Keywords: effect of compound
2008-02-12 | GSE10463 | GEO
Project description:<p>Chagas disease causes a cardiac illness characterized by immunoinflammatory reactions leading to myocardial fibrosis and remodeling. The development of Chronic Chagas Cardiomyopathy (CCC) in some patients while others remain asymptomatic is not fully understood, but dysregulated inflammatory responses are implicated. The Aryl hydrocarbon receptor (AhR) plays a crucial role in regulating inflammation. Certain tryptophan (Trp) metabolites have been identified as AhR ligands with regulatory functions. </p><p><br></p><p>We investigated AhR expression, agonist response, ligand production and AhR-dependent responses, such as IDO activation and regulatory T (Treg) cells induction, in two T. cruzi-infected mouse strains (B6 and Balb/c) showing different polymorphisms in AhR. Furthermore, we assessed the metabolic profile of Trp catabolites and AhR agonistic activity levels in plasma samples from patients with chronic Chagas disease (CCD) and healthy donors (HD) using a luciferase reporter assay and liquid chromatography-mass spectrophotometry (LC-MS) analysis. T. cruzi-infected B6 mice showed impaired AhR-dependent responses compared to Balb/c mice, including reduced IDO activity, kynurenine levels, Treg cell induction, CYP1A1 up-regulation and AhR expression following agonist activation. Additionally, B6 mice exhibited no detectable AhR agonist activity in plasma and displayed lower CYP1A1 up-regulation and AhR expression upon agonist activation. Similarly, CCC patients had decreased AhR agonistic activity in plasma compared to HD patients and exhibited dysregulation in Trp metabolic pathways, resulting in altered plasma metabolite profiles. Notably, patients with severe CCC specifically showed increased N-acetylserotonin levels in their plasma. The methods and findings presented here contribute to a better understanding of CCC development mechanisms and may identify potential specific biomarkers for T. cruzi infection and the severity of associated heart disease. These insights could be valuable in designing new therapeutic strategies. Ultimately, this research aims to establish the AhR agonistic activity and Trp metabolic profile in plasma as an innovative, non-invasive predictor of prognosis for chronic Chagas disease.</p>
2024-01-11 | MTBLS8390 | MetaboLights
Project description:The aryl hydrocarbon receptor (AhR), a transcription factor known for mediating xenobiotic toxicity, is expressed in B cells, which are known targets for environmental pollutants. However, it is unclear what the physiological functions of AhR in B cells are. We show here that expression of Ahr in B cells is up-regulated upon B cell receptor (BCR) engagement and IL-4 treatment. Addition of a natural ligand of AhR, FICZ, induces AhR translocation to the nucleus and transcription of the AhR target gene Cyp1a1, showing that the AhR pathway is functional in B cells. AhR-deficient (Ahr-/-) B cells proliferate less than AhR-sufficient (Ahr+/+) cells following in vitro BCR stimulation and in vivo adoptive transfer models confirmed that Ahr-/- B cells are outcompeted by Ahr+/+ cells. Transcriptome comparison of AhR-deficient and sufficient B cells identified cyclin O (Ccno), a direct target of AhR, as a top candidate affected by AhR deficiency.
2016-11-16 | GSE86521 | GEO
Project description:Understanding the mechanisms of host macrophage responses to M. tuberculosis (M.tb.) is essential for uncovering potential avenues of intervention to boost host resistance to infection. Macrophage transcriptome profiling revealed M.tb. infection strongly induced expression of several enzymes controlling tryptophan (Trp) catabolism. This included indole 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO2), which catalyze the rate-limiting step in the kynurenine pathway, producing ligands for the aryl hydrocarbon receptor (AHR). The AHR and heterodimeric partners AHR nuclear translocator (ARNT) and RELB are robustly expressed, and AHR and RELB levels further increased during infection. Infection enhanced AHR/ARNT and AHR/RELB DNA binding, and stimulated expression of AHR target genes, including that encoding the inflammatory cytokine IL1beta. AHR target gene expression was further enhanced by exogenous kynurenine, and exogenous Trp, kynurenine or synthetic agonist indirubin reduced mycobacterial viability. Comparative expression profiling revealed that AHR ablation diminished expression of numerous genes implicated in innate immune responses, including several cytokines. Notably, AHR depletion reduced expression of IL23A and IL12B transcripts, which encode subunits of interleukin 23 (IL23), a macrophage cytokine that stimulates production of IL22 by innate lymphoid cells. The AHR directly induced IL23A transcription in human and mouse macrophages through near-upstream enhancer regions. Taken together, these findings show that AHR signaling is strongly engaged in Mtb-infected macrophages, and has widespread effects on innate immune responses. Moreover, they reveal a cascade of AHR-driven innate immune signaling, as IL1B (IL-1β) and IL23 stimulate T cell subsets producing IL22, another direct target of AHR transactivation. Gene expression profiling of Mtb-infected THP-1 monocytic cells following siRNA-mediated Aryl hydrocarbon receptor (AHR) knockdown.
2015-07-14 | E-GEOD-70200 | biostudies-arrayexpress