Use of natural AhR ligands as potential therapeutic modalities against inflammatory disorders

Abstract

The aim of this review is to discuss research involving ligands for the aryl hydrocarbon receptor (AhR) and their role in immunomodulation. While activation of the AhR is well known for its ability to regulate the biochemical and toxic effects of environmental chemicals, more recently an exciting discovery has been made indicating that AhR ligation can also regulate T-cell differentiation, specifically through activation of Foxp3(+) regulatory T cells (Tregs) and downregulation of the proinflammatory Th17 cells. Such findings have opened new avenues of research on the possibility of targeting the AhR to treat inflammatory and autoimmune diseases. Specifically, this review will discuss the current research involving natural and dietary AhR ligands. In addition, evidence indicating the potential use of these ligands in regulating inflammation in various diseases will be highlighted. The importance of the AhR in immunological processes can be illustrated by expression of this receptor on a majority of immune cell types. In addition, AhR signaling pathways have been reported to influence a number of genes responsible for mediating inflammation and other immune responses. As interest in the AhR and its ligands increases, it seems prudent to consolidate current research on the contributions of these ligands to immune regulation during the course of inflammatory diseases.

Figure 1. AhR domain structure

Domains: bHLH, basic helix-loop-helix; PAS, Per/Ahr-ARNT/Sim; glutamine-rich region.

Figure 2. AhR signaling pathway

(a) Ligand passes through plasma membrane into the cellular cytoplasm. (b) Ligand binds the cytosolic AhR complex. (c) The ligand-bound AhR complex is translocated into the nucleus. (d) The ligand-bound AhR complex dissociates from chaperone proteins after dimerization with ARNT. (e) Ligand-bound AhR/ARNT complex binds to DREs/XREs, (f) which leads to transcriptional activation of target genes.

Figure 3. AhR ligand structure and binding affinities

Binding affinities are based on half-maximal effective concentration (EC₅₀) values as determined by induction or inhibition of CYP1A1 expression.