title: A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells.
abstract: Arginase 1 (Arg1) and indoleamine 2,3-dioxygenase 1 (IDO1) are immunoregulatory enzymes catalyzing the degradation of l-arginine and l-tryptophan, respectively, resulting in local amino acid deprivation. In addition, unlike Arg1, IDO1 is also endowed with non-enzymatic signaling activity in dendritic cells (DCs). Despite considerable knowledge of their individual biology, no integrated functions of Arg1 and IDO1 have been reported yet. We found that IDO1 phosphorylation and consequent activation of IDO1 signaling in DCs was strictly dependent on prior expression of Arg1 and Arg1-dependent production of polyamines. Polyamines, either produced by DCs or released by bystander Arg1+myeloid-derived suppressor cells, conditioned DCs toward an IDO1-dependent, immunosuppressive phenotype via activation of the Src kinase, which has IDO1-phosphorylating activity. Thus our data indicate that Arg1 and IDO1 are linked by an entwined pathway in immunometabolism and that their joint modulation could represent an important target for effective immunotherapy in several disease settings.
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Mondanelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Albini
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Iacono
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Belladonna
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, 06132 Perugia, Italy.
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.affiliation: Department of Medicine, Verona University Hospital, 37134 Verona, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Ugel
authors.affiliation: Department of Medicine, Verona University Hospital, 37134 Verona, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Bronte
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, 01100 Viterbo, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Gevi
authors.affiliation: Department of Ecological and Biological Sciences, University of Tuscia, 01100 Viterbo, Italy.
authors.forename: Lello
authors.initials: L
authors.lastname: Zolla
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre Rotterdam, 3015 CE Rotterdam, the Netherlands.
authors.forename: Auke
authors.initials: A
authors.lastname: Verhaar
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Centre Rotterdam, 3015 CE Rotterdam, the Netherlands.
authors.forename: Maikel
authors.initials: M
authors.lastname: Peppelenbosch
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Emilia Maria Cristina
authors.initials: EMC
authors.lastname: Mazza
authors.affiliation: Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Department of Microbiology & Immunology, University of Michigan School of Medicine, Ann Arbor, MI 48109-5620, US.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Laouar
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, New York, NY 10461, US.
authors.forename: Laura
authors.initials: L
authors.lastname: Santambrogio
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. Electronic address: claudia.volpi@unipg.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.affiliation: Department of Experimental Medicine, University of Perugia, 06132 Perugia, Italy. Electronic address: ursula.grohmann@unipg.it.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
mesh_terms: D000818:Animals; D001119:Arginase / Q000276:immunology* / Q000378:metabolism; D001120:Arginine / Q000276:immunology / Q000378:metabolism; D015153:Blotting, Western; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D007108:Immune Tolerance / Q000502:physiology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology*; D059467:Transcriptome; D014364:Tryptophan / Q000276:immunology / Q000378:metabolism
chemical_list: C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D014364:Tryptophan; D001120:Arginine; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: Arg1; IDO1; TGF-β; amino acid metabolism; dendritic cell; immune regulation; ornithine; polyamine