IDO and Kynurenine Metabolites in Peripheral and CNS Disorders

Abstract

The importance of the kynurenine pathway in normal immune system function has led to an appreciation of its possible contribution to autoimmune disorders such as rheumatoid arthritis. Indoleamine-2,3-dioxygenase (IDO) activity exerts a protective function, limiting the severity of experimental arthritis, whereas deletion or inhibition exacerbates the symptoms. Other chronic disorder with an inflammatory component, such as atherosclerosis, are also suppressed by IDO activity. It is suggested that this overall anti-inflammatory activity is mediated by a change in the relative production or activity of Th17 and regulatory T cell populations. Kynurenines may play an anti-inflammatory role also in CNS disorders such as Huntington's disease, Alzheimer's disease and multiple sclerosis, in which signs of inflammation and neurodegeneration are involved. The possibility is discussed that in Huntington's disease kynurenines interact with other anti-inflammatory molecules such as Human Lymphocyte Antigen-G which may be relevant in other disorders. Kynurenine involvement may account for the protection afforded to animals with cerebral malaria and trypanosomiasis when they are treated with an inhibitor of kynurenine-3-monoxygenase (KMO). There is some evidence that changes in IL-10 may contribute to this protection and the relationship between kynurenines and IL-10 in arthritis and other inflammatory conditions should be explored. In addition, metabolites of kynurenine downstream of KMO, such as anthranilic acid and 3-hydroxy-anthranilic acid can influence inflammation, and the ratio of these compounds is a valuable biomarker of inflammatory status although the underlying molecular mechanisms of the changes require clarification. Hence it is essential that more effort be expended to identify their sites of action as potential targets for drug development. Finally, we discuss increasing awareness of the epigenetic regulation of IDO, for example by DNA methylation, a phenomenon which may explain differences between individuals in their susceptibility to arthritis and other inflammatory disorders.

The Role of the Kynurenine Signaling Pathway in Different Chronic Pain Conditions and Potential Use of Therapeutic Agents

“…This is synchronous with the binding of IFN-γ-regulated factor-1 (IRF-1) to one or both of the IFN-sensitive response elements (ISREs) [ 6 ]. The second, IFN-independent, mechanism of IDO-1 enzyme activation stems from an interaction between B7 complex found on DCs and cytotoxic T-lymphocyte antigen-4 (CTLA-4) on regulatory T-cells (Treg), and is maintained via transforming growth factor-β (TGF-β) and the non-canonical nuclear factor-κB (NFκB) signaling pathway [ 10 ]. More than a decade ago, Metz et al demonstrated the existence of the indoleamine 2,3-dioxygenase 2 (IDO-2) enzyme, and found its tissue pattern expression similar to that of IDO-1 [ 11 ].…”

The Role of Tryptophan Metabolites in Musculoskeletal Stem Cell Aging

“…They found that this ratio was significantly reversed in patients with osteoporosis, as patients showed not only lower baseline levels for 3HAA, but also higher levels of AA compared to control [41]. Some studies suggest that a possible explanation is an inhibition of the enzymatic conversion of AA to 3HAA, thus resulting in lower levels of 3HAA [42]. Another project from the Hordaland Health Study examined the relationship between different Kyn pathway metabolites and BMD.…”

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

“…Additionally, hepatocytes express all enzymes within the Kyn pathway and represent a significant source for downstream kynurenines. Some kynurenines, such as quinolinic acid and kynurenic acid exhibit neuromodulatory properties and have thus been implicated in numerous peripheral and CNS diseases (80,81). De novo synthesis of NAD, an essential co-factor in energy metabolism, represents the last step of the Kyn pathway in some cells, such as hepatocytes and macrophages (50,82).…”

“…However, IDO expression was decreased in PBMCs of patients with stable disease compared to HCs, and was more drastically reduced along with the serum Kyn/Trp ratio in response to treatment (127). Moreover, a higher Kyn/Trp ratio was observed in patients with depression (46), likely due to decreased serotonin synthesis, and/or neuromodulatory effects of downstream kyurenines (80,81), which are also perturbed in MS patients (47). Murine models of the disease have also implicated Trp metabolism.…”