Year: 2025
Type: article
Abstract: Description Interferon gamma (IFNg) signaling is often intensified in chronic inflammatory and autoimmune conditions. This generally results in the activation of compensatory mechanisms such as indoleamine-2,3-dioxygenase 1 (IDO1)-mediated tryptophan catabolism, which generates the anti-inflammatory biogenic amine 3-hydroxy-kynurenamine (3HKA). Herein, we report that 3HKA functions as a low affinity ligand for the aryl hydrocarbon receptor (AHR) by docking in a PAS-B sub-pocket which overlaps with binding sites for the AHR antagonists, pyrene and GNF351. Upon binding, 3HKA induces inositol 1,4,5-trisphosphate receptor type 3 (IP3R3)-mediated Ca2+ release from intracellular stores, culminating with cyclic AMP (cAMP)-dependent protein kinase A (PKA) activation and consequent inhibition of ERK1/2 MAP kinase. In dendritic cells, PKA activation reduces interferon gamma receptor 1 (IFNGR1) phosphorylation, resulting in (1) IFNGR1 internalization coupled with proteasomal degradation, (2) decreased signaling through JAK-STAT1/2, and (3) reduced secretion of pro-inflammatory cytokines including interleukin 1 beta (IL1B), IL6, IL12 and tumor necrosis factor (TNF). Pharmacophore-based drug discovery approaches were used to identify a series of 3HKA analogs that, to different degrees, phenocopied and outperformed the 3HKA induced restrain of IFNg-mediated inflammation. Altogether, our data mechanistically delineate the pathways involved in 3HKA-dependent anti-inflammatory responses. Funding Sources NIH-RO1AI169723 Topic Categories Immune Response Regulation: Molecular Mechanisms (IRM)
Source: The Journal of Immunology
Authors: Cristina C. Clement, Laura Santambrogio
Institution: Weill Cornell Medicine
Language: English
Subfield: Biological Psychiatry
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W4416448933
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