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
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank the patients and subjects who participated in this study as well as nurses and staff of the Neurology Clinic of S. Maria della Misericordia Hospital, Perugia, Italy. We also thank Dr. Giovanni Ricci for histologies. This work was supported by the European Research Council (338954-DIDO and 780807-DIDO-MS; both to U.G. and A.M.) and the Italian Ministry of Education, University, and Research (PRIN 20155C2PP7 to C. Volpi). A. Carvalho, C.C., and P.M. were supported by the Northern Portugal Regional Operational Programme (NORTE 2020), under the Portugal 2020 Partnership Agreement, through the European Regional Development Fund (FEDER) (NORTE-01-0145-FEDER-000013), and the Fundação para a Ciência e Tecnologia (CEECIND/04601/2017 to C.C.; CEECIND/03628/ 2017 to A. Carvalho).
Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/2/18
Y1 - 2020/2/18
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
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U2 - 10.1073/pnas.1918215117
DO - 10.1073/pnas.1918215117
M3 - Article
C2 - 32024760
AN - SCOPUS:85079512937
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
SN - 0027-8424
IS - 7
ER -