Immune regulation through tryptophan metabolism

Abstract

Amino acids are fundamental units of molecular components that are essential for sustaining life; however, their metabolism is closely interconnected to the control systems of cell function. Tryptophan (Trp) is an essential amino acid catabolized by complex metabolic pathways. Several of the resulting Trp metabolites are bioactive and play central roles in physiology and pathophysiology. Additionally, various physiological functions of Trp metabolites are mutually regulated by the gut microbiota and intestine to coordinately maintain intestinal homeostasis and symbiosis under steady state conditions and during the immune response to pathogens and xenotoxins. Cancer and inflammatory diseases are associated with dysbiosis- and host-related aberrant Trp metabolism and inactivation of the aryl hydrocarbon receptor (AHR), which is a receptor of several Trp metabolites. In this review, we focus on the mechanisms through which Trp metabolism converges to AHR activation for the modulation of immune function and restoration of tissue homeostasis and how these processes can be targeted using therapeutic approaches for cancer and inflammatory and autoimmune diseases.

Fig. 1. Trp catabolism in mammals.

The three main catabolic pathways of Trp are shown with the enzyme metabolizing the corresponding catabolites. Dotted lines indicate that multiple steps are involved. IDO indoleamine-2,3-dioxygenase, TDO tryptophan-2,3-dioxygenase, AFM arylformamidase, L-Kyn kynurenine, KAT kynurenine amino transferase, KynA kynurenic acid, KMO kynurenine 3-monooxygenase, 3-HK 3-hydroxykynurenine, AA anthranilic acid, KYNU kynurenine, 3-HAA 3-hydroxyanthranilic acid, PA picolinic acid, 3HAO 3-hydroxyanthranilate oxidase, Quin quinolinic acid, IL4I1 interleukin-4-induced-1, I3P indole-3-pyruvate, TPH tryptophan hydroxylase, 5-HIAA 5-hydroxyindole-3-acetic acid.

Fig. 2. The role of the Kyn pathway in immune regulation.

a The IDO1-AHR axis in the induction of infectious tolerance. b Suppression of IL6 expression by the IDO1-AHR axis in lung epithelial cells (ECs). c Cooperation of TGF-β1 and AHR in the transdifferentiation of Th17 cells into IL-10-producing Tr1 and Foxp3⁺ Treg cells. d The KynA-GPR35 axis in anti-inflammation and energy metabolism.

Fig. 3. The I3P pathway in cancer and barrier function.

a The IL4I1-AHR axis in tumor growth. b Microbiota-derived indole in intestinal barrier function through AHR.

Fig. 4. The role of the serotonin pathway in cancer and inflammation.

a The TPH1-5-HTP-AHR axis in CD8⁺ T-cell exhaustion. b The 5-HIAA-GPR35 axis in neutrophil recruitment to sites of inflammation.