Targeting AhR as a Novel Therapeutic Modality against Inflammatory Diseases

Abstract

For decades, activation of Aryl Hydrocarbon Receptor (AhR) was excluded from consideration as a therapeutic approach due to the potential toxic effects of AhR ligands and the induction of the cytochrome P450 enzyme, Cyp1a1, following AhR activation. However, it is now understood that AhR activation not only serves as an environmental sensor that regulates the effects of environmental toxins, but also as a key immunomodulator where ligands induce a variety of cellular and epigenetic mechanisms to attenuate inflammation. Thus, the emergence of further in-depth research into diverse groups of compounds capable of activating this receptor has prompted reconsideration of its use therapeutically. The aim of this review is to summarize the body of research surrounding AhR and its role in regulating inflammation. Specifically, evidence supporting the potential of targeting this receptor to modulate the immune response in inflammatory and autoimmune diseases will be highlighted. Additionally, the opportunities and challenges of developing AhR-based therapies to suppress inflammation will be discussed.

Keywords: TCDD; aryl hydrocarbon receptor; atopic dermatitis; epigenetic; inflammation; inflammatory bowel diseases; inflammatory disease; multiple sclerosis.

Figure 1

Canonical and Non-Canonical AhR Pathways. In the Canonical pathway, AhR activation by ligand leads to regulation of genes with XREs such as CYP enzymes among others. AhR also leads to transcription of genes without XREs, such as estrogen-responsive DNA elements, NK-κβ, and STAT proteins. (Created with BioRender.com on 17 November 2021).

Figure 2

Mechanisms of Action of AhR Ligands to Suppress Inflammation (Created with BioRender.com on 17 November 2021).