Aryl Hydrocarbon Receptor (AhR) Activation: An Emerging Immunology Target?

Publisher Summary This chapter focuses on the research on the key role played by the aryl hydrocarbon receptor (AhR) in the immune system. The AhR was originally characterized as a nanomolar-affinity receptor for the polychlorinated aromatic species dioxin responsible for the toxic effects—such as thymic involution and tumor promotion—observed in animals following exposure to this industrial pollutant. The AhR is a ligand-activated transcription factor that resides in the cytoplasm in its unactivated state. Extensive rodent studies reporting dioxin-induced, AhR-dependent wasting, immunosuppression, and carcinogenesis have suggested that AhR activation is a path logical event. However, recent evidence that dioxin at nontoxic doses has therapeutic activity in rodent models of autoimmune diseases, with concomitant induction of regulatory T cell (Tregs) and suppression of T H 17 development, has kindled interest in AhR agonism as a therapeutic target. This is supported by key findings that AhR activation-induced cytochrome P450 (CYP) protein induction is not inexorably toxic, that several drug-like compounds have AhR-dependent therapeutic activity in in-vivo animal models of human disease, and that CYP induction can be decoupled from AhR-dependent therapeutic effects.