Beneficial and detrimental consequences of AHR stimulation in intestinal infection

The ligand dependent transcription factor aryl hydrocarbon receptor (AHR) is an environmental sensor whose activation can have physiologically beneficial or detrimental consequences for host immune responses depending on the ligand. Here we investigated the hypothesis that prolonged AHR activation either due to inefficient ligand metabolism or due to genetic manipulation may underlie the distinction between beneficial and detrimental effects. Our data indicate that prolonged AHR activation caused toxic endpoints for liver and thymus but was not per se interfering with the host response to infection with the intestinal pathogen C.rodentium. Genetically driven constitutive AHR activation improved resistance to infection, whereas prolonged AHR activation by the pollutant TCDD resulted in delayed clearance of C.rodentium. This was associated to a suppression in antibody production. Combined single cell RNAseq and ATAC-seq analysis provided evidence that TCDD, but not genetic AHR overactivation, affected dendritic cell functions such as activation, maturation and antigen presentation. Thus, the detrimental impact of environmental pollutants such as TCDD on immune responses cannot solely be attributed to aberrantly prolonged activation of AHR. Overall design: Single nuclei were extracted on day 5 after infection with Citrobacter rodentium. Mice were treated with Vehicle or TCDD 6 days before infection. Joint snRNA-seq and scATAC-seq libraries were prepared using the 10x Genomics platform