Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation
Giada Mondanelli, Alice Coletti, Francesco 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, Patrı́cia Maciel, Massimiliano Di Filippo, Lorenzo Gaetani, Roberta Bianchi, Carmine Vacca, Ioana Maria Iamandii, Elisa Proietti, Francesca Boscia, Lucio Annunziato, Maikel P. Peppelenbosch, Paolo Puccetti, Paolo Calabresi, Antonio Macchiarulo, Laura Santambrogio, Claudia Volpi, Ursula Grohmann
Abstract
-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.