Regulation of the Immune Response by the Aryl Hydrocarbon Receptor

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism, and pollutants. AhR is expressed by a number of immune cells, and thus AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response. Studies have shown that AhR signaling plays important roles in the immune system in health and disease. As its activity is regulated by small molecules, AhR also constitutes a potential target for therapeutic immunomodulation. In this review we discuss the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.

FIGURE 1. AhR signaling pathway

Inactive AhR is localized in the cytosol complexed to HSP90, AIP, p23 and c-SRC. Upon interaction with an agonist, conformational changes result in the translocation of the complex to the nucleus and the interaction of AhR with ARNT after the dissociation of the cytoplasmic complex. The AhR-ARNT heterodimer controls the transcription of DRE containing genes. AhR signaling also includes non-genomic pathways, for example AhR functions as an E3 ubiquitin ligase, while the release of the c-SRC kinase results in the phosphorylation of multiple targets. AhR activation is limited by regulatory mechanisms, some of which are actually triggered by AhR activation. AhR drives the expression of CYP enzymes, which degrade AhR ligands. AhR also induces the expression of its repressor AhRR, which inhibits the formation of AhR/ARNT complex required for AhR signaling.

FIGURE 2. AhR physiological ligands

A. Indole-derived AhR agonists provided by the diet. B. Tryptophan-derived AhR agonists. Both the host and the microbiota are implicated in the generation of these agonists.

FIGURE 3. Effects of AhR signaling in Th17 and Tr1 cells

In Tr1 cells, AhR cooperates with c-Maf to induce the expression of IL-10 and IL-21 and with STAT 3 to drive CD39 expression; AhR also drives its own expression. AhR mediates the metabolic reprogramming of Tr1 cells by controlling the expression of enzymes ivolved in glucose metabolism. In Th17 cells, AhR induces IL-22 expression in cooperation with RORγt. AhR also inhibits STAT1 and STAT5 activation, as well as IL-2 expression by inducing the epigenetic modifier Aiolos in cooperation with STAT3. AhR has been implicated in the plasticity of Th17 by driving their trans-differentiation into Tr1 cells.