Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation

Abstract

l-tryptophan (Trp), an essential amino acid for mammals, is the precursor of a wide array of immunomodulatory metabolites produced by the kynurenine and serotonin pathways. The kynurenine pathway is a paramount source of several immunoregulatory metabolites, including l-kynurenine (Kyn), the main product of indoleamine 2,3-dioxygenase 1 (IDO1) that catalyzes the rate-limiting step of the pathway. In the serotonin pathway, the metabolite N-acetylserotonin (NAS) has been shown to possess antioxidant, antiinflammatory, and neuroprotective properties in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). However, little is known about the exact mode of action of the serotonin metabolite and the possible interplay between the 2 Trp metabolic pathways. Prompted by the discovery that NAS neuroprotective effects in EAE are abrogated in mice lacking IDO1 expression, we investigated the NAS mode of action in neuroinflammation. We found that NAS directly binds IDO1 and acts as a positive allosteric modulator (PAM) of the IDO1 enzyme in vitro and in vivo. As a result, increased Kyn will activate the ligand-activated transcription factor aryl hydrocarbon receptor and, consequently, antiinflammatory and immunoregulatory effects. Because NAS also increased IDO1 activity in peripheral blood mononuclear cells of a significant proportion of MS patients, our data may set the basis for the development of IDO1 PAMs as first-in-class drugs in autoimmune/neuroinflammatory diseases.

Genetic variant rs7820258 regulates the expression of indoleamine 2,3-dioxygenase 1 in brain regions

“…Interestingly, restoration of IDO1 activity could be obtained by tocilizumab, an anti-IL-6 receptor antibody, in one-third of T1D patients mostly characterized by the CT genotype. Very recently, a significant and differential allele and genotype distribution was detected for the same IDO1 SNP in patients with relapsing-remitting multiple sclerosis (RRMS) compared to control subjects (2).…”

Kynurenines in the Pathogenesis of Multiple Sclerosis: Therapeutic Perspectives

“…NAS was able to ameliorate the inflammation in EAE in mice with functioning IDO-1 and AHR genes. This effect was lost, however in IDO-1 −/− and/or AHR −/− knockout mice [97]. NAS conferred an immunosuppressive effect on dendritic cells via positive allosteric modulation of the IDO1 enzyme.…”

“…In fact, NAS has been shown to easily cross the BBB, where it elicited virtually no toxicity. Even though there is an increasing amount of evidence for the presence of the enzyme-producing NAS in organs with function related to the immune system (spleen, bone marrow, and thymus), the exact source of NAS on the periphery remains yet to be pinpointed [97,98].…”

“…After binding to an allosteric site on the AHR increased IDO-1's catalytic activity, but no changes in gene or protein expression levels were seen. This resulted in increased AHR activation and immunosuppression via the aforementioned feedback loop [97,100].…”

New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures

“…A third cleft (cleft C) has been identified through crystallographic studies of substrate‐bound IDO1 . Cleft C is located below the heme plane, accounting for the inhibition by substrate phenomenon and the binding of a positive allosteric modulator of the enzyme (Figure ; residues Phe270, Asp274 and Arg343) . Noteworthy, a heme‐free form (holo‐) of IDO1 has been also characterized, wherein the three clefts shape a unique and larger ligand binding pocket in which potent suicide inhibitors bind to the enzyme .…”