Aryl Hydrocarbon Receptor and Kynurenine: Recent Advances in Autoimmune Disease Research

Abstract

Aryl hydrocarbon receptor (AHR) is thought to be a crucial factor in the regulation of immune responses. Many AHR-mediated immunoregulatory mechanisms have been discovered, and this knowledge may enhance our understanding of the molecular pathogenesis of autoimmune inflammatory syndromes such as collagen-induced arthritis, experimental autoimmune encephalomyelitis, and experimental colitis. Recent findings have elucidated the critical link between AHR and indoleamine 2,3-dioxygenase (IDO) in the development of regulatory T cells and Th17 cells, which are key factors in a variety of human autoimmune diseases. Induction of IDO and IDO-mediated tryptophan catabolism, together with its downstream products such as kynurenine, is an important immunoregulatory mechanism underlying immunosuppression, tolerance, and immunity. Recent studies revealed that induction of IDO depends on AHR expression. This review summarizes the most current findings regarding the functions of AHR and IDO in immune cells as they relate to the pathogenesis of autoimmune diseases in response to various stimuli. We also discuss the potential link between AHR and IDO/tryptophan metabolites, and the involvement of several novel related factors (such as microRNA) in the development of autoimmune diseases. These novel factors represent potential therapeutic targets for the treatment of autoimmune disorders.

Laquinimod arrests experimental autoimmune encephalomyelitis by activating the aryl hydrocarbon receptor

“…Laquinimod, like other AhR activators, can induce the differentiation of APCs with a tolerogenic phenotype. The mechanisms responsible for this tolerogenic phenotype may result from the upregulation of indoleamine 2,3-dioxygenase expression, resulting in increased synthesis of immunosuppressive kynurenines (21,22). Indeed, our transcriptome data showed up-regulation of both Ido1 and Ido2 (Fig.…”

“…2B), indicating that activation of AhR was inherent to drug and independent of disease state. However, many other AhR-associated genes, including Cyp1b1 (20), Tiparp (19), Ido1 and Ido2 (21,22), Spint1, and Serpins (23) were induced by laquinimod in both naive and EAE mice. Laquinimod-induced activation of the AhR pathway was confirmed by assessing gene expression levels of the AhR biomarker, Cyp1a1 in mouse liver.…”

Tryptophan Catabolites and Migraine

“…AHR is a nuclear transcription factor regulating the expression of genes of xenobiotic metabolizing enzymes, such as cytochrome P450 protein and glutathione transferase. This receptor possesses important functions in immune regulation, and T-cell development [26] .…”

The Coevolution of IDO1 and AhR in the Emergence of Regulatory T Cells in Mammals

“…Microorganisms such as E. coli and HIV are known to highjack the immunosuppressive effects of IDO1, though. Intriguingly, Kishimoto et al discussed the possibility that microRNAs (miRNAs) may regulate the transcriptional expression of IDO-encoding genes, mainly in autoimmunity (24). Because miRNAs have been suggested to be instrumental in the evolution of organismal complexity (25) and AhR has been shown to induce the expression of several miRNAs (26), these observations further underline the critical interdependence of AhR and IDO enzymes in coping with mammalian challenges.…”