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.

Keywords: autoimmunity; dioxin receptor; immune regulation; indoleamine 2,3-dioxygenase; transcription factor.

Figure 1

TLR ligands trigger transcriptional activation of STAT-1 and NF-κB, and then induce IDO mRNA. Although AHR forms complex with STAT-1 and NF-κB in macrophages under pro-inflammatory cytokines production, whether this complex is appeared in DC or required for IDO expression is not known. Induced IDO mRNA may be controlled by miR-203 (not investigated), and the activity or amount of IDO protein is regulated at post-translational modification such as nitration of Tyr and ubiquitin ligation. Kynurenine catalyzed by IDO induces tolerance via regulating the balance of TH1, TH17, Tr1, and Treg. Kynurenine may activate the AHR for IDO induction with autocrine manner, and form AHR/Kynurenine positive-feedback loop.