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

Giada Mondanelli, Alice Coletti, Francesco Antonio Greco, Maria Teresa Pallotta, Ciriana Orabona, Alberta Iacono, Maria Laura Belladonna, Elisa Albini, Eleonora Panfili, Francesca Fallarino, Marco Gargaro, Giorgia Manni, Davide Matino, Agostinho Carvalho, Cristina Cunha, Patricia Maciel, Massimiliano Di Filippo, Lorenzo Gaetani, Roberta Bianchi, Carmine VaccaIoana Maria Iamandii, Elisa Proietti, Francesca Boscia, Lucio Annunziato, Maikel Peppelenbosch, Paolo Puccetti, Paolo Calabresi, Antonio Macchiarulo, Laura Santambrogio, Claudia Volpi, Ursula Grohmann

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3848-3857
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number7
DOIs
Publication statusPublished - Feb 18 2020

Keywords

  • Aryl hydrocarbon receptor (AhR)
  • Dendritic cells
  • Indoleamine 2,3-dioxygenase 1 (IDO1)
  • N-acetylserotonin (NAS)
  • Neuroinflammation

ASJC Scopus subject areas

  • General

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