Dataset Information

What role for AHR activation in IL4I1-mediated immunosuppression ?

ABSTRACT: The amino-acid catabolizing enzyme Interleukin-4 induced gene 1 (IL4I1) remains poorly characterized despite it is emerging as a pertinent therapeutic target for cancer. IL4I1 is secreted in the synaptic cleft by antigen-presenting cells. It inhibits TCR signaling, modulates naïve T cell differentiation and limits effector T cell proliferation. IL4I1 expression in tumors shapes the tumor microenvironment and impairs the antitumor cytotoxic T cell response, thereby facilitating cancer immune escape. Several mechanisms participate in these effects. Recent data suggest a role of new IL4I1 metabolites in activation of the aryl-hydrocarbon receptor (AHR). Here, we observe that expression of IL4I1 is poorly correlated with that of validated targets of AHR in human cancers. Moreover, dendritic cells do not upregulate AHR target genes in relation with IL4I1 expression in vivo. Finally, IL4I1 activity toward tryptophan leading to production of AHR-activating products is very low, and should be negligible when tryptophan-degrading enzymes of higher affinity compete for the substrate. We recently showed that IL4I1 expression by dendritic cells directly regulates immune synapse formation and modulates the repertoire and memory differentiation of responding CD8 T cells after viral infection. Thus, IL4I1 may restrain tumor control through regulating the priming of tumor-specific CD8 T cells, independently of AHR activation.

SUBMITTER: Castellano F

PROVIDER: S-EPMC8118450 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BACKGROUND/AIMS:Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter and hormone with important physiological functions in many organs, including the intestine. We have previously shown that 5-HT activates the aryl hydrocarbon receptor (AhR) in intestinal epithelial cells (IECs) via a serotonin transporter (SERT)-dependent mechanism. AhR is a nuclear receptor that binds a variety of molecules including tryptophan (TRP) metabolites to regulate physiological processes in the intestine including xenobiotic detoxification and immune modulation. We hypothesized that 5-HT activates AhR indirectly by interfering with metabolic clearance of AhR ligands by cytochrome P450 1A1 (CYP1A1). METHODS:Inhibition of CYP1A1 activity by 5-HT was assessed in the human intestinal epithelial cell line Caco-2 and recombinant CYP1A1 microsomes using both luciferase and LC-MS/MS. Degradation of 5-HT by recombinant CYP1A1 was measured by LC-MS/MS. For in vitro studies, CYP1A1 and CYP1B1 mRNA expression levels were measured by RT-PCR and CYP1A1 activity was measured by ethoxyresorufin-O-deethylase (EROD) assays. For in vivo studies, AhR ligands were administered to SERT KO mice and WT littermates and intestinal mucosa CYP1A1 mRNA was measured. RESULTS:We show that 5-HT inhibits metabolism of both the pro-luciferin CYP1A1 substrate Luc-CEE as well as the high affinity AhR ligand 6-formylindolo[3,2-b] carbazole (FICZ). Recombinant CYP1A1 assays revealed that 5-HT is metabolized by CYP1A1 in an NADPH dependent manner. Treatment with 5-HT in TRP-free medium, which is devoid of trace AhR ligands, showed that 5-HT requires the presence of AhR ligands to activate AhR. Cotreatment with 5-HT and FICZ confirmed that 5-HT potentiates induction of AhR target genes by AhR ligands. However, this was only true for ligands which are CYP1A1 substrates such as FICZ. Administration of ?-napthoflavone by gavage or indole-3-carbinol via diet to SERT KO mice revealed that lack of SERT impairs intestinal AhR activation. CONCLUSION:Our studies provide novel evidence of crosstalk between serotonergic and AhR signaling where 5-HT can influence the ability of AhR ligands to activate the receptor in the intestine.

Project description:BackgroundA structurally diverse group of chemicals, including dioxins [e.g., 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)] and polycyclic aromatic hydrocarbons (PAHs), can xenobiotically activate the aryl hydrocarbon receptor (AHR) and contribute to adverse health effects in humans and wildlife. In the zebrafish model, repression of sox9b has a causal role in several AHR-mediated toxic responses, including craniofacial cartilage malformations; however, the mechanism of sox9b repression remains unknown. We previously identified a long noncoding RNA, sox9b long intergenic noncoding RNA (slincR), which is increased (in an AHR-dependent manner) by multiple AHR ligands and is required for the AHR-activated repression of sox9b.ObjectiveUsing the zebrafish model, we aimed to enhance our understanding of the signaling events downstream of AHR activation that contribute to toxic responses by identifying: a) whether slincR is enriched on the sox9b locus, b) slincR's functional contributions to TCDD-induced toxicity, c) PAHs that increase slincR expression, and d) mammalian orthologs of slincR.MethodsWe used capture hybridization analysis of RNA targets (CHART), qRT-PCR, RNA sequencing, morphometric analysis of cartilage structures, and hemorrhaging screens.ResultsThe slincR transcript was enriched at the 5' untranslated region (UTR) of the sox9b locus. Transcriptome profiling and human ortholog analyses identified processes related to skeletal and cartilage development unique to TCDD-exposed controls, and angiogenesis and vasculature development unique to TCDD-exposed zebrafish that were injected with a splice-blocking morpholino targeting slincR. In comparison to TCDD exposed control morphants, slincR morphants exposed to TCDD resulted in abnormal cartilage structures and a smaller percentage of animals displaying the hemorrhaging phenotype. In addition, slincR expression was significantly increased in six out of the sixteen PAHs we screened.ConclusionOur study establishes that in zebrafish, slincR is recruited to the sox9b 5' UTR to repress transcription, can regulate cartilage development, has a causal role in the TCDD-induced hemorrhaging phenotype, and is up-regulated by multiple environmentally relevant PAHs. These findings have important implications for understanding the ligand-specific mechanisms of AHR-mediated toxicity. https://doi.org/10.1289/EHP3281.

Dataset Information

What role for AHR activation in IL4I1-mediated immunosuppression ?

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets