Indoleamine 2,3‐dioxygenase 1 (IDO1): an up‐to‐date overview of an eclectic immunoregulatory enzyme

Abstract

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the initial rate-limiting step in the degradation of the essential amino acid tryptophan along the kynurenine pathway. When discovered more than 50 years ago, IDO1 was thought to be an effector molecule capable of mediating a survival strategy based on the deprivation of bacteria and tumor cells of the essential amino acid tryptophan. Since 1998, when tryptophan catabolism was discovered to be crucially involved in the maintenance of maternal T cell tolerance, IDO1 has become the focus of several laboratories around the world. Indeed, IDO1 is now considered as an authentic immune regulator not only in pregnancy, but also in autoimmune diseases, chronic inflammation, and tumor immunity. However, in the last years, a bulk of new information − including structural, biologic, and functional evidence − on IDO1 has come to light. For instance, we now know that IDO1 has a peculiar conformational plasticity and, in addition to a complex and highly regulated catalytic activity, is capable of performing a nonenzymic function that reprograms the expression profile of immune cells towards a highly immunoregulatory phenotype. With this State-of-the-Art review, we aimed at gathering the most recent information obtained for this eclectic protein as well as at highlighting the major unresolved questions.

The Function of the Kynurenine Pathway in the Placenta: A Novel Pharmacotherapeutic Target?

“…These effects may all have contributed to the observed pregnancy complications in animal studies with this inhibitor. Remarkably, IDO1 not only has an enzymatic role, but it can also function as a signaling molecule, as recently discussed by Pallotta et al [ 79 ]. In that role, IDO1 shifts from the cytosol to early endosomes and functions in transforming growth factor (TGF)-β induced noncanonical signaling to establish a long-term immunoregulatory phenotype in dendritic cells [ 80 , 81 ].…”

A Complex Metabolic Network Confers Immunosuppressive Functions to Myeloid-Derived Suppressor Cells (MDSCs) within the Tumour Microenvironment

“…The majority of L-Trp is converted into kyn by indoleamine 2,3-dioxygenase 1-2 (IDO1 and IDO2) and tryptophan-2,3-dioxygenase (TDO). Alterations in the levels of L-Trp and its metabolites are associated with several diseases, including neurological disorders, autoimmunity, and cancer [138]. Recently, 3-hydroxy-L-kynurenamine (3-HKA), a biogenic amine that is produced via a lateral branch of the IDO1 pathway in both DCs and endothelial cells during inflammatory conditions as well as by cancer cells, has been identified as a crucial player in inhibiting CD8 + T lymphocyte proliferation and naïve-to-effector T cell maturation by blocking the STAT1/NF-κB pathway [139].…”

“…Recently, 3-hydroxy-L-kynurenamine (3-HKA), a biogenic amine that is produced via a lateral branch of the IDO1 pathway in both DCs and endothelial cells during inflammatory conditions as well as by cancer cells, has been identified as a crucial player in inhibiting CD8 + T lymphocyte proliferation and naïve-to-effector T cell maturation by blocking the STAT1/NF-κB pathway [139]. Among the L-Trp-converting enzymes, IDO1 plays a central role in orchestrating immune responses [138,140,141]. Indeed, its expression and activity have been described in several cancer types in response to IFNγ, and both have been correlated with poor prognosis [142].…”

Dysregulated tumor-associated macrophages in carcinogenesis, progression and targeted therapy of gynecological and breast cancers

“…Indoleamine-2,3-dioxygenase (IDO1) is a key enzyme to degrade amino acid tryptophan through the kynurenine pathway [ 142 ], which can regulate macrophages and inhibit the immune function of T cells in a variety of diseases and cancers [ 142 – 145 ]. In cervical cancer, existing studies have shown that IFN-γ activated autophagy of cervical cancer cells and macrophage phagocytosis reactivation through IDO1 overexpression and kynurenine metabolism [ 146 , 147 ]. In addition to cervical cancer, Feng et al confirmed that high expression of IDO1 showed better survival prognosis in breast and ovarian cancer [ 148 ].…”