Higher mammals possess two closely linked and homologous genes encoding indoleamine 2,3-dioxygenase (IDO1, IDO2), which catabolizes compounds containing indole rings, including tryptophan (Trp) and the neurotransmitter serotonin, aka 5-hydroxytryptamine (5HT). IDO1 gene expression is responsive to interferons (IFNs), explaining why IDO activity is elevated in many inflammatory settings, including infectious, allergic and autoimmune (AI) diseases, tumorigenesis, and pregnancy. In this brief review, we highlight key aspects of IDO1 immunobiology and summarize prospects for exploiting this pathway to protect tissues from immune-mediated damage in patients with AI syndromes and transplanted tissues. The concise format of this review precludes a comprehensive overview and readers are directed elsewhere for detailed discussions of the current state of this highly active field. The ability of cells expressing IDO1 genes to suppress immune responses was first described almost 20 years ago (1). Since then, research on IDO has blossomed and IDO inhibitors are promising immune checkpoint inhibitor drugs to enhance cancer immunotherapy (2, 3).

Interferons released at sites of inflammation stimulate hundreds of downstream genes, known collectively as IFN-stimulated genes (ISGs). Historically, ISGs that activate immune cells to incite immunity to infections have been the major focus of research. However, some ISGs activate immune regulatory cells to promote tolerogenic, rather than immunogenic processes. The local balance of immunogenic and tolerogenic responses to IFNs is a key factor driving the effects of local inflammation on immune responses and tissue functions.

IDO1 is an example of a tolerogenic ISG because IDO suppresses immune responses and the IDO1 gene is responsive to both IFN type I (IFN-I) and type II (IFN-II). IFN response elements called ISRE and GAS sequences, which confer responsiveness to IFN-I and IFN-II signaling, respectively, are located in mammalian IDO1 gene promoters. Though most cell types express IFN receptors, IFNs induce IDO only in select cell types because IFN signaling is regulated in some cells. For example, discrete subsets of dendritic cells (DCs) from humans and mice are competent to express IDO when exposed to IFNs (4). Importantly, IDO1 gene transcription may not enhance IDO enzyme activity due to posttranslational controls, such as limited access to hemin, an IDO enzyme co-factor, local redox status, and nitric oxide, which inhibits heme/O₂ conjugation needed to break indole structures (5, 6). IDO can also promote tolerance via non-catalytic signaling to induce TGFβ release by some DCs (7). Thus, whether IDO activity manifests in inflamed tissues depends on many factors, linked to the complexity of biochemical pathways and cell interactions driving responses to IFNs in tissues. Thus, it is important to study responses to IFNs in physiologic settings, where multiple effects are integrated to generate particular responses to inflammatory insults. Though much can be learned by studying how cultured or physiologic cells and isolated tissues respond to IFNs, these approaches cannot predict physiologic outcomes accurately in the absence of the full panoply of biochemical processes and cellular interactions that exist in inflamed tissues.

IDO catalyzes the initial, rate-limiting step in oxidative catabolism of compounds containing indole rings (Figure 1), including Trp and 5HT. Cells expressing IDO1 genes deplete Trp and generate bioactive catabolites, known as kynurenines, after the catabolite kynurenine (Kyn). Enzymes downstream of IDO further degrade Kyn to generate kynurenic acid (KA), 3-hydroxy-anthranilic acid (HAA), quinolinic acid (QA), niacin, and other catabolites. Some immune cells can sense Trp depletion or catabolites to suppress innate and adaptive immunity and promote tolerogenic responses. Limiting access to Trp activates the ribosomal kinase GCN2, which senses binding of uncharged tRNA to ribosomes. Activated GCN2 triggers the integrated stress response (ISR) to amino acid withdrawal, which induces CHOP gene expression but shuts down most gene transcription to promote cell autophagy. The ISR blocks cell cycle entry by TCR-activated T cells and activates resting Foxp3-lineage regulatory CD4 T cells (Tregs) to promote tolerogenic responses to inflammatory signals from immune adjuvants and tumor vaccines (8). Some catabolites in the Kyn pathway bind to receptors expressed by immune cells to promote tolerogenic responses. For example, HAA, Kyn, and KA suppress T cell responses by binding to PDK1 or aryl hydrocarbon receptors (AhR) in T cells, APCs, or other immune cells. As well as influencing inflammatory and immunologic processes, the Kyn pathway also drives neurologic comorbidities such as pain, depression, and fatigue, commonly associated with chronic inflammatory disease. By consuming Trp, the substrate for 5HT and melatonin synthesis, IDO impacts mood and promotes depression. Moreover, receptors such as NMDA, α7AChR, and Gpr35 expressed by neuronal cells can sense neuroactive catabolites such as KA and QA. An intriguing link between physical exercise and reduced depression was reported due to increased uptake of circulating Kyn by PGC1a1 receptors expressed by active skeletal muscles (9). Niacin, another product of the kynurenine pathway that binds to the Gpr109a receptor, also suppresses colonic inflammation and carcinogenesis to promote gut homeostasis and health (10). Collectively, these points reveal pivotal roles for the Kyn pathway as a critical modifier of immunologic and neurologic responses to inflammation via the biochemical effects of catabolizing indole compounds such as Trp and 5HT.

Elevated IDO activity manifests in many chronic inflammatory syndromes, including cancer, infections, AI and allergic diseases, transplant rejection, and pregnancy (11). A link between IDO and immune regulation was first described in pregnancy. IDO inhibitors applied to pregnant mice induced allogeneic fetal rejection by maternal T cells, while sparing syngeneic fetus’ from the same fate (1), indicating that IDO stops maternal T cells from attacking fetal allografts during pregnancy. Further studies revealed that complement activation drove fetal allograft rejection when IDO was inhibited, indicating that IDO blocks complement activation by maternal T cells responsive to fetal alloantigens (12).

The tolerogenic effects of cells expressing IDO have prompted efforts to boost IDO activity, particularly in DCs, as novel strategies to alleviate AI disease and prolong transplant survival. A number of strategies can be envisaged to exploit these properties for clinical benefit, as described below.

As stated above, the Kyn pathway has profound effects on neurologic, as well as inflammatory and immunologic, processes. The KA:QA balance is a major factor in neuro-inflammatory syndromes, as high QA levels correlate with neuro-toxicities and dementia, while KA ameliorates these damaging effects. Heightened and sustained IDO activity during chronic inflammatory diseases may contribute to enhanced pain sensitivity, depression, and fatigue, which are common comorbidities associated with many of these syndromes. These effects complicate efforts to exploit the Kyn pathway because beneficial therapeutic effects that suppress hyper-immunity and promote tolerance may come at the cost of increased pain, depression and fatigue, as consequences of therapy. Nevertheless, using IDO inducers to reduce disease-associated inflammation and hyper-immunity in the short term may attenuate innate IDO activity that promotes debilitating neurologic comorbidities. For example, in the EAE model of MS in mice, IDO activity was elevated in CNS tissues during EAE induction but STING agonists treatments to induce IDO in peripheral lymphoid tissues and suppress autoimmunity abolished IDO1 expression in the CNS (30). Thus, overall beneficial effects in attenuating disease progression and reducing comorbidities may accrue from the diametric effects of IDO activity in distinct neuronal and lymphoid tissues. Furthermore, it may be possible to use drugs that modify the Kyn pathway to enhance production of immune suppressive Trp catabolites and reduce production of neurotoxic Trp catabolites. Thus, using HAAO inhibitors to block neurotoxic QA production and KATII inhibitors to promote immune suppressive HAA production may enhance therapeutic responses and reduce neurologic comorbidities, especially if combined with reagents that stimulate the Kyn pathway.

Elevated IDO activity manifests in many settings of high clinical significance, driving substantial interest in manipulating IDO and the Kyn pathway for clinical benefit. Extensive research on mouse models of chronic inflammatory syndromes supports the hypothesis that IDO activity suppresses innate and adaptive immunity by depleting Trp and generating bioactive Trp catabolites. Though IDO-mediated tolerogenic responses to sustained inflammation are particularly prominent, elevated IDO activity may also manifest rapidly to overcome co-induced immunogenic responses. It remains to be seen how many observations from mouse models of clinical syndromes can be translated into clinical practice. Promising initial results from recently completed or ongoing experimental clinical trials on cancer patients using several different IDO inhibitors will be the first potential clinical application to be tested fully. If outcomes support the use of IDO inhibitors in cancer, future research will focus on identifying optimal drug combinations to halt tumor growth and disrupt immune checkpoints in the widest range of patients, without stimulating autoimmunity or other toxic responses. Since immune checkpoints may also promote pathogen persistence and many infections induce IDO activity, there may also be opportunities to use IDO inhibitors to reduce pathogen burdens and promote pathogen clearance in patients with chronic infections. However, more research is needed to understand the balance between anti-microbial and (host) tolerogenic effects of IDO, as the risk of inducing undesirable toxic effects is high until the role of IDO in specific chronic infections is elucidated fully. On the flip side, enhancing IDO activity as novel strategies to prevent or alleviate hyper-immune syndromes are supported by many proof-of-concept studies in mouse models of transplantation and AI syndromes. Translating these outcomes into clinical application will take some time, in part due to potential for many IDO inducing drugs to elicit tissue-damaging immunogenic responses as well as co-inducing tissue-protective tolerogenic responses. Thus, it may not be straightforward to satisfy ethical and corporate requirements for specific molecular targets driving unequivocal outcomes, unless more precise ways are found to manipulate the immune balance for clinical benefit. Finally, the combined immunologic and neurologic effects of bioactive Trp catabolites emphasizes the key roles of IDO and the Kyn pathway as drivers or regulators of many chronic conditions and common comorbidities, including pain depression and fatigue. Clearly, while more research is needed to understand the complex roles of IDO and the Kyn pathway in chronic diseases, the prospects are good for major novel insights and advances leading to clinical practice.

AM wrote the review. HL and LH read and critiqued the review.

The author (AM) is a consultant for NewLink Genetics Inc. and receives income from this source. All other authors have no competing interests to disclose.