TY - JOUR
T1 - Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation
AU - Mondanelli, Giada
AU - Coletti, Alice
AU - Greco, Francesco Antonio
AU - Pallotta, Maria Teresa
AU - Orabona, Ciriana
AU - Iacono, Alberta
AU - Belladonna, Maria Laura
AU - Albini, Elisa
AU - Panfili, Eleonora
AU - Fallarino, Francesca
AU - Gargaro, Marco
AU - Manni, Giorgia
AU - Matino, Davide
AU - Carvalho, Agostinho
AU - Cunha, Cristina
AU - Maciel, Patricia
AU - Filippo, Massimiliano Di
AU - Gaetani, Lorenzo
AU - Bianchi, Roberta
AU - Vacca, Carmine
AU - Iamandii, Ioana Maria
AU - Proietti, Elisa
AU - Boscia, Francesca
AU - Annunziato, Lucio
AU - Peppelenbosch, Maikel
AU - Puccetti, Paolo
AU - Calabresi, Paolo
AU - Macchiarulo, Antonio
AU - Santambrogio, Laura
AU - Volpi, Claudia
AU - Grohmann, Ursula
PY - 2020
Y1 - 2020
N2 - 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.
AB - 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.
KW - Aryl hydrocarbon receptor (AhR)
KW - Dendritic cells
KW - Indoleamine 2,3-dioxygenase 1 (IDO1)
KW - N-acetylserotonin (NAS)
KW - Neuroinflammation
KW - Aryl hydrocarbon receptor (AhR)
KW - Dendritic cells
KW - Indoleamine 2,3-dioxygenase 1 (IDO1)
KW - N-acetylserotonin (NAS)
KW - Neuroinflammation
UR - http://hdl.handle.net/10807/150405
U2 - 10.1073/pnas.1918215117
DO - 10.1073/pnas.1918215117
M3 - Article
SN - 0027-8424
VL - 117
SP - 3848
EP - 3857
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
ER -