Open Access

Proceedings of the National Academy of Sciences of the United States of America, volume 117, issue 7, pages 3848-3857

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

Giada Mondanelli ¹

Alice Coletti ²

Francesco Antonio Greco ²

Maria Teresa Pallotta ¹

Ciriana Orabona ¹

Alberta Iacono ¹

Maria Laura Belladonna ¹

Elisa Albini ^{1, 2}

Eleonora Panfili ¹

Francesca Fallarino ¹

Marco Gargaro ¹

Giorgia Manni ¹

Davide Matino ¹

Agostinho Carvalho ^{3, 4}

Cristina Cunha ^{3, 4}

Patricia Maciel ^{3, 4}

Massimiliano Di Filippo ⁵

Lorenzo Gaetani ⁵

Roberta Bianchi ¹

Carmine Vacca ¹

Ioana Maria Iamandii ¹

Elisa Proietti ¹

Francesca Boscia ⁶

Lucio Annunziato ⁶

Maikel Peppelenbosch ⁷

PAOLO PUCCETTI ¹

Paolo Calabresi ⁵

Antonio Macchiarulo ²

L Santambrogio ^{8, 9, 10}

Claudia Volpi ¹

Ursula Grohmann ^{1, 11}

Show full list: 31 authors

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Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy; |

Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy; |

Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal; |

⁴

ICVS/3B’s–PT Government Associate Laboratory, 4704-553 Braga/Guimarães, Portugal; |

⁵

Department of Medicine, University of Perugia, 06100 Perugia, Italy; |

⁶

Department of Neuroscience, University of Naples Federico II, 80131 Naples, Italy; |

⁷

Department of Gastroenterology and Hepatology, Erasmus Medical Centre–University Medical Centre Rotterdam, 3015 GD Rotterdam, The Netherlands; |

⁸

Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY 10065; |

⁹

Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065; |

¹⁰

Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065; |

¹¹

Department of Pathology, Albert Einstein College of Medicine, New York, NY 10461 |

Publication type: Journal Article

Publication date: 2020-02-05

Proceedings of the National Academy of Sciences (PNAS)

Journal: Proceedings of the National Academy of Sciences of the United States of America

scimago Q1

wos Q1

SJR: 3.737

CiteScore: 19.0

Impact factor: 9.4

ISSN: 00278424, 10916490

DOI: 10.1073/pnas.1918215117

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Multidisciplinary

Abstract

Significance

Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunoregulatory enzyme that transforms tryptophan into kynurenine, an endogenous agonist of the aryl hydrocarbon receptor (AhR) whose activation sustains IDO1 expression and activity over the long term in dendritic cells (DCs). Here we found that N -acetylserotonin (NAS), a tryptophan metabolite produced along the serotonin pathway, acts as a positive allosteric modulator (PAM) of IDO1 and thus increases kynurenine-mediated AhR activation in DCs. NAS effects on IDO1 translated into protection of mice from neuroinflammation and reinstallment of physiologic IDO1 activity in peripheral blood mononuclear cells from patients with relapsing-remitting multiple sclerosis.

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