Iriady, I. | Search bioRxiv

bioRxiv2026

Mathematical Modeling of the Canonical Aryl Hydrocarbon Receptor Pathway

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor involved in xenobiotic sensing, as well as development, immunity, and tissue homeostasis. AhR signaling can proceed through a canonical and non-canonical pathway; the present study focuses on the canonical pathway. While ligand-dependent differences in binding affinities and direct ligand degradation kinetics are well known, and subtle differences in ligand binding can shape downstream signaling, it is still unclear which biochemical reaction steps within the canonical pathway are responsible for distinct ligand-specific transcriptional responses. Here, we developed a mechanistic ordinary differential equation model of the canonical AhR pathway. We calibrated the model to time-resolved qPCR measurements of Cyp1a1 and Ahrr mRNA in mouse bone-marrow-derived macrophages exposed to structurally diverse, environmentally relevant ligands with known immunomodulatory activity (3-methylcholanthrene, indolo[3,2-b]carbazole, and bisphenol A) using global optimization under a heteroskedastic likelihood. To dissect ligand specificity, we evaluated 528 candidate models that allow one or two ligand-involving reaction rate constants to vary. Akaike-based model selection reveals a dominant dynamical regime governed by promoter occupancy and target-gene mRNA synthesis, indicating that ligand-specific transcriptional responses are primarily encoded at the level of transcriptional regulation rather than upstream signaling events. The resulting model is made available in SBML and PEtab formats for reproducibility, and to enable further research into whether ligand-specific effects are conserved or rewired across cell types.

systems biology↗

bioRxiv2024

Differential cell type-specific function of the aryl hydrocarbon receptor and its repressor in diet-induced obesity and fibrosis

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor regulating xenobiotic responses as well as physiological metabolism. Dietary AhR ligands activate the AhR signaling axis in the intestine and throughout the organism, whereas AhR activation is negatively regulated by the AhR repressor (AhRR). While AhR-deficient mice are known to be resistant to diet-induced obesity (DIO), we here demonstrate that AhRR deficiency also leads to a robust, but not as profound protection from DIO and hepatosteatosis. Under conditions of DIO, AhRR-/- mice did not accumulate TCA cycle intermediates in the circulation in contrast to wild-type (WT) mice, indicating protection from metabolic dysfunction. This effect could be mimicked by dietary supplementation of AhR ligands in WT mice. Because of the predominant expression of the AhRR in myeloid cells, AhRR-deficient macrophages were analyzed for changes in metabolism and showed major metabolic alterations regarding oxidative phosphorylation and mitochondrial activity as well as increased expression of genes involved in de novo lipogenesis and mitochondrial biogenesis. Mice with a genetic deficiency of the AhRR in myeloid cells did not show alterations in weight gain after high fat diet (HFD) but demonstrated ameliorated liver damage compared to control mice. Further, deficiency of the AhR in myeloid cells also did not affect weight gain but led to enhanced liver damage and adipose tissue fibrosis compared to controls. Although conditional ablation of either the AhR or AhRR in myeloid cells did not recapitulate the phenotype of the global knockout, our findings suggest that enhanced AhR signaling in myeloid cells deficient for AhRR protects from diet-induced liver damage and fibrosis, whereas myeloid cell-specific AhR deficiency is detrimental.

immunology↗