Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis

Lanz, Tobias V.; Williams, Sarah K.; Stojic, Aleksandar; Iwantscheff, Simeon; Sonner, Jana K.; Grabitz, Carl; Becker, Simon; Böhler, Laura Inés; Mohapatra, Soumya R.; Sahm, Felix; Küblbeck, Günter; Nakamura, Toshikazu; Funakoshi, Hiroshi; Opitz, Christiane A.; Wick, Wolfgang; Diem, Ricarda; Platten, Michael

doi:10.1038/srep41271

Cited by 48 publications

(44 citation statements)

References 58 publications

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“…Kynurenine aminotransferase (KAT1) converts kynurenine into kynurenic acid, an inhibitor of NMDA glutamate receptors [ 95 , 96 , 97 , 98 ] and α7-nicotinic (neuronal) acetylcholine receptors [ 96 , 97 , 99 ]. I3AA inhibits human KAT1, thereby blocking formation of kynurenic acid [ 100 ].…”

Section: Resultsmentioning

confidence: 99%

Organic and Peptidyl Constituents of Snake Venoms: The Picture Is Vastly More Complex Than We Imagined

Villar‐Briones

Aird

2018

Toxins

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Small metabolites and peptides in 17 snake venoms (Elapidae, Viperinae, and Crotalinae), were quantified using liquid chromatography-mass spectrometry. Each venom contains >900 metabolites and peptides. Many small organic compounds are present at levels that are probably significant in prey envenomation, given that their known pharmacologies are consistent with snake envenomation strategies. Metabolites included purine nucleosides and their bases, neurotransmitters, neuromodulators, guanidino compounds, carboxylic acids, amines, mono- and disaccharides, and amino acids. Peptides of 2–15 amino acids are also present in significant quantities, particularly in crotaline and viperine venoms. Some constituents are specific to individual taxa, while others are broadly distributed. Some of the latter appear to support high anabolic activity in the gland, rather than having toxic functions. Overall, the most abundant organic metabolite was citric acid, owing to its predominance in viperine and crotaline venoms, where it chelates divalent cations to prevent venom degradation by venom metalloproteases and damage to glandular tissue by phospholipases. However, in terms of their concentrations in individual venoms, adenosine, adenine, were most abundant, owing to their high titers in Dendroaspis polylepis venom, although hypoxanthine, guanosine, inosine, and guanine all numbered among the 50 most abundant organic constituents. A purine not previously reported in venoms, ethyl adenosine carboxylate, was discovered in D. polylepis venom, where it probably contributes to the profound hypotension caused by this venom. Acetylcholine was present in significant quantities only in this highly excitotoxic venom, while 4-guanidinobutyric acid and 5-guanidino-2-oxopentanoic acid were present in all venoms.

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Section: Resultsmentioning

confidence: 99%

Organic and Peptidyl Constituents of Snake Venoms: The Picture Is Vastly More Complex Than We Imagined

Villar‐Briones

Aird

2018

Toxins

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“…patients and healthy subjects (19). Interestingly, whereas several pieces of evidence would indicate IDO1 as a protective player in RRMS (55,56), lack of TDO expression will protect mice with EAE from neuronal loss in the spinal cord (57). Because of the protective effects of NAS in WT mice with EAE, we investigated whether the Trp metabolite could modulate IDO1 activity in PBMCs from RRMS patients.…”

Section: Nas Confers Immunosuppressive Effects On Dcs Via Increased Cmentioning

confidence: 99%

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

Mondanelli

Coletti

Greco

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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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.

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“…Murine models of the disease have also implicated Trp metabolism. Tdo2 deficiency (the gene encoding hepatic TDO) is protective in EAE (128). However, DC-targeted type 1 IFN treatment decreased EAE severity by upregulating Ido1 expression and inducing a tolerogenic DC phenotype (129).…”

Section: Tryptophan Metabolites In Autoimmunitymentioning

confidence: 99%

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

2020

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The development of autoimmunity involves complex interactions between genetics and environmental triggers. The gut microbiota is an important environmental constituent that can heavily influence both local and systemic immune reactivity through distinct mechanisms. It is therefore a relevant environmental trigger or amplifier to consider in autoimmunity. This review will examine recent evidence for an association between intestinal dysbiosis and autoimmune diseases, and the mechanisms by which the gut microbiota may contribute to autoimmune activation. We will specifically focus on recent studies connecting tryptophan metabolism to autoimmune disease pathogenesis and discuss evidence for a microbial origin. This will be discussed in the context of our current understanding of how tryptophan metabolites regulate immune responses, and how it may, or may not, be applicable to autoimmunity.

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Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis

Cited by 48 publications

References 58 publications

Organic and Peptidyl Constituents of Snake Venoms: The Picture Is Vastly More Complex Than We Imagined

Organic and Peptidyl Constituents of Snake Venoms: The Picture Is Vastly More Complex Than We Imagined

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

Intestinal Dysbiosis and Tryptophan Metabolism in Autoimmunity

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