Diaz Oscar E, Zhou Liang, Barrington Christopher, Lindqvist Dennis, Graelmann Frederike, Wincent Emma, Stockinger Brigitta
The Francis Crick Institute, London NW1 1AT, UK.
University of Florida, College of Veterinary Medicine, Department of Infectious Diseases and Immunology, Gainesville, FL, USA, 32608.
bioRxiv. 2025 Jun 1:2025.05.28.656570. doi: 10.1101/2025.05.28.656570.
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 . Genetically driven constitutive AHR activation improved resistance to infection, whereas prolonged AHR activation by the pollutant TCDD resulted in delayed clearance of 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.
配体依赖性转录因子芳烃受体（AHR）是一种环境传感器，其激活对宿主免疫反应可能产生生理上有益或有害的后果，这取决于配体。在此，我们研究了一种假说，即由于配体代谢效率低下或基因操作导致的AHR长期激活可能是有益和有害效应之间差异的基础。我们的数据表明，AHR长期激活会导致肝脏和胸腺出现毒性终点，但本身并不干扰宿主对肠道病原体感染的反应。基因驱动的组成型AHR激活提高了抗感染能力，而污染物2,3,7,8-四氯二苯并对二恶英（TCDD）导致的AHR长期激活则导致清除延迟，并伴有抗体产生受到抑制。单细胞RNA测序和转座酶可及染色质测序（ATAC-seq）联合分析提供的证据表明，TCDD而非基因AHR激活对树突状细胞功能产生负面影响，如激活、成熟和抗原呈递。因此，TCDD等环境污染物对免疫反应的有害影响不能仅仅归因于AHR异常长期激活。
