Under normal circumstances, AhR is involved with the metabolism of foreign substances and reduction of inflammatory responses

The aryl hydrocarbon receptor (AhR) is a ligand activated transcription factor, normally present in epithelial cells and immune cells. Under normal circumstances AhR activity is low in most tissues. However, AhR can be activated by exogenous agents and by endogenous ligands like kynurenine. AhR activation causes the expression of many genes that are related to reducing inflammatory responses to exogenous agents and to their metabolic degradation. 

However, AhR is hijacked by tumors and by viruses to support their growth and replication

In tumor tissue, AhR is hijacked to act as direct mediator of tumor progression and a powerful inhibitor of tumor-specific immune responses. In the tumor microenvironment AhR seems to be mostly activated by tryptophan catabolites like kynurenine.

Abnormally high levels of AhR are produced in many solid tumors, where AhR is constantly activated causing suppression of anti-tumor immune responses. Many cells involved in immunity express AhR. Examples are macrophages, dendritic cells and T cells. Activation of AhR in these immune cells causes reduced anti-tumor immunity. 

During viral infections AhR is activated by viral agents, causing the suppression of natural mechanisms that block viral replication. It was found that AhR activation by Zika-virus, limits the production of type I interferons (IFN-I) involved in antiviral immunity. Moreover, AHR activation suppressed intrinsic anti-viral immunity driven by the promyelocytic leukemia (PML) protein, resulting in increased viral replication. AHR inhibition not only suppressed replication of Zika-virus, but also of Dengue, a related flavivirus. A similar mechanism may apply to the replication of Covid-19 and other corona viruses.




Studies showing reduced viral replication by Hercules' AhR inhibitors were recently published in Nature Neuroscience: