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.
journal_name
Proc Natl Acad Sci U S Aauthors
Mondanelli G,Coletti A,Greco FA,Pallotta MT,Orabona C,Iacono A,Belladonna ML,Albini E,Panfili E,Fallarino F,Gargaro M,Manni G,Matino D,Carvalho A,Cunha C,Maciel P,Di Filippo M,Gaetani L,Bianchi R,Vacca C,Iamandiidoi
10.1073/pnas.1918215117subject
Has Abstractpub_date
2020-02-18 00:00:00pages
3848-3857issue
7eissn
0027-8424issn
1091-6490pii
1918215117journal_volume
117pub_type
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