Role of the Kynurenine Pathway in Immune-Mediated Inflammation

Abstract

Indoleamine 2,3-dioxygenase (IDO) plays a key role in immune homeostasis via depletion of tryptophan and accumulation of kynurenines and is recognized as an important factor contributing to suppression of antitumor immune responses. However, the possibility of harnessing the IDO pathway for the therapy of autoimmune disease represents an intriguing possibility, and in this review, we highlight recent research on the involvement of IDO in immune-mediated inflammatory diseases, with a focus on rheumatoid arthritis. Inhibition of IDO was shown to exacerbate experimental arthritis and increase numbers of pathogenic Th1 and Th17 cells in the joints and draining lymph nodes. Analysis of the kinetics of expression of kynurenine pathway enzymes in animal models also pointed to a potential role for tryptophan metabolites in disease resolution and administration of l-kynurenine or [3,4-dimethoxycinnamonyl]-anthranilic acid (a synthetic derivative of 3-hydroxyanthranilic acid) reduced the severity of disease. A more recent study has identified an association between defective regulatory T cells in rheumatoid arthritis with reduced capacity to activate the kynurenine pathway. These findings suggest that strategies to activate IDO in a targeted manner may be effective in the therapy of autoimmune disease.