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

Autor:	Mondanelli G; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Coletti A; Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy., Greco FA; Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy., Pallotta MT; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Orabona C; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Iacono A; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Belladonna ML; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Albini E; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy.; Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy., Panfili E; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Fallarino F; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Gargaro M; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Manni G; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Matino D; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Carvalho A; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.; ICVS/3B's-PT Government Associate Laboratory, 4704-553 Braga/Guimarães, Portugal., Cunha C; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.; ICVS/3B's-PT Government Associate Laboratory, 4704-553 Braga/Guimarães, Portugal., Maciel P; Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, 4710-057 Braga, Portugal.; ICVS/3B's-PT Government Associate Laboratory, 4704-553 Braga/Guimarães, Portugal., Di Filippo M; Department of Medicine, University of Perugia, 06100 Perugia, Italy., Gaetani L; Department of Medicine, University of Perugia, 06100 Perugia, Italy., Bianchi R; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Vacca C; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Iamandii IM; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Proietti E; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Boscia F; Department of Neuroscience, University of Naples Federico II, 80131 Naples, Italy., Annunziato L; Department of Neuroscience, University of Naples Federico II, 80131 Naples, Italy., Peppelenbosch M; Department of Gastroenterology and Hepatology, Erasmus Medical Centre-University Medical Centre Rotterdam, 3015 GD Rotterdam, The Netherlands., Puccetti P; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy., Calabresi P; Department of Medicine, University of Perugia, 06100 Perugia, Italy., Macchiarulo A; Department of Pharmaceutical Sciences, University of Perugia, 06100 Perugia, Italy., Santambrogio L; Englander Institute of Precision Medicine, Weill Cornell Medicine, New York, NY 10065.; Department of Radiation Oncology, Weill Cornell Medicine, New York, NY 10065.; Department of Physiology and Biophysics, Weill Cornell Medicine, New York, NY 10065., Volpi C; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy; claudia.volpi@unipg.it ursula.grohmann@unipg.it., Grohmann U; Department of Experimental Medicine, University of Perugia, 06100 Perugia, Italy; claudia.volpi@unipg.it ursula.grohmann@unipg.it.; Department of Pathology, Albert Einstein College of Medicine, New York, NY 10461.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2020 Feb 18; Vol. 117 (7), pp. 3848-3857. Date of Electronic Publication: 2020 Feb 05.
DOI:	10.1073/pnas.1918215117
Abstrakt:	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. Competing Interests: The authors declare no competing interest.
Databáze:	MEDLINE
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