The biogenic amine 3HKA restrains inflammation via non-canonical AhR signaling 3831

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)