Differential Effects of Exogenous and Endogenous Aryl Hydrocarbon Receptor Ligands on Dendritic Cell Phenotype and Function: Insights into Immune Regulation
SADEGHI SHERMEH A. 1, ROYZMAN D. 1, KUHNT C. 1, DRAßNER C. 1, STICH L. 1, STEINKASSERER A. 1, KNIPPERTZ I. 1, WILD A. 1
1 Universitätsklinikum Erlangen, Immune Modulation department, Erlangen, Germany
The regulatory effects of the aryl hydrocarbon receptor (AhR) as a ligand-activated transcription factor are influenced by the structure of its ligands, their affinity to the AhR and their metabolic rate. The most common classification for AhR ligands divides them into exogenous (natural and synthetic) and endogenous (host and microbiota-derived) agonists. AhR activation following ligand binding controls the expression of multiple genes via canonical and non-canonical pathways. Dendritic cells (DCs), bridging the innate and adaptive immune response, are constantly exposed to AhR agonists due to their localization in the body and their antigen presenting role. Investigating phenotypic and functional changes in human monocyte-derived DCs (hMoDCs) following AhR exposure to exogenous and endogenous ligands helps us to understand the role of this receptor/transcription factor in the fine-tuning of the immune system. Therefore, experiments were performed to investigate the effects of three AhR agonists including benzo(a)pyrene (BP), 6-formylindolo[3,2-b]carbazole (FICZ) and indoxyl-3-sulfate (I3S) on DC phenotype and function using flow cytometry, qPCR and bromdesoxyuridine (BrdU) assay. Our results showed that BP exposure significantly induced a tolerogenic phenotype in lipopolysaccharide (LPS)-matured DCs at both phenotypic and functional levels, whereas this effect was only present at a lower level and only at the phenotypic level when FICZ or I3S were used. Although all three types of ligand activate AhR-dependent pathways, BP in particular induces the expression of immune regulators that suppress immune responses and greatly reduce the ability of DCs to stimulate T cells. Using the CRISPR/Cas9 technique, we also confirmed that the regulatory effect of BP is strongly AhR dependent. These findings suggest that AhR ligands may have different contributions to DC responses, highlighting the need for further research to uncover the specific mechanisms and molecules involved in AhR activation.