Cell-Specific Modulation of the Aryl Hydrocarbon Receptor by Kynurenine in Pulmonary Fibrosis Requires Microenvironmental Crosstalk.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive, chronic lung disease with limited therapeutic options. Tryptophan metabolism is significantly dysregulated during lung fibrogenesis, with the metabolite kynurenine (kyn) accumulating in lung tissue and driving pathology via the aryl hydrocarbon receptor (AHR). This study evaluates the cell-specific contributions of kyn-mediated AHR signaling across different pulmonary cell types to clarify its role in disease progression. Methods: Using a murine model of bleomycin-induced pulmonary fibrosis, lung tryptophan metabolites were profiled via liquid chromatography-mass spectrometry. The functional and transcriptomic impacts of kyn administration and AHR modulation were subsequently characterized across three distinct cellular compartments: CD103+ dendritic cells (DCs), fibroblasts, and alveolar epithelial cells (AECs). Results: Kyn levels were elevated in fibrotic lungs, and exogenous kyn selectively exacerbated collagen deposition during the fibrogenic phase rather than altering acute injury. Conclusions: Pathogenic AHR signaling in pulmonary fibrosis is highly cell-context dependent and driven by complex cell-cell interactions. Reductionist monocultures fail to replicate tissue-level dendritic cell phenotypes, highlighting the necessity of co-culture models and providing a cautionary note for the systemic clinical use of AHR-targeted therapeutics.