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

Paolo Calabresi, 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 BianchiCarmine Vacca, Ioana Maria Iamandii, Elisa Proietti, Francesca Boscia, Lucio Annunziato, Maikel Peppelenbosch, Paolo Puccetti, Antonio Macchiarulo, Laura Santambrogio, Claudia Volpi, Ursula Grohmann

Risultato della ricerca: Contributo in rivistaArticolo in rivista

16 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)3848-3857
Numero di pagine10
RivistaProceedings of the National Academy of Sciences of the United States of America
Volume117
DOI
Stato di pubblicazionePubblicato - 2020

Keywords

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

Fingerprint Entra nei temi di ricerca di 'Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation'. Insieme formano una fingerprint unica.

Cita questo