Beneficial and detrimental consequences of AHR activation in intestinal infection

Abstract 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 associated with a suppression in antibody production. Combined single cell RNAseq and ATAC-seq analysis provided evidence that TCDD, but not genetic AHR activation, negatively 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. Footnotes ↵* joint corresponding authors