A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells

Giada Mondanelli, Roberta Bianchi, Maria Teresa Pallotta, Ciriana Orabona, Elisa Albini, Alberta Iacono, Maria Laura Belladonna, Carmine Vacca, Francesca Fallarino, Antonio Macchiarulo, Stefano Ugel, Vincenzo Bronte, Federica Gevi, Lello Zolla, Auke Verhaar, Maikel Peppelenbosch, Emilia Maria Cristina Mazza, Silvio Bicciato, Yasmina Laouar, Laura SantambrogioPaolo Puccetti, Claudia Volpi, Ursula Grohmann

Research output: Contribution to journalArticle

84 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)233-244
Number of pages12
JournalImmunity
Volume46
Issue number2
DOIs
StatePublished - Feb 21 2017

Keywords

  • Arg1
  • IDO1
  • TGF-β
  • amino acid metabolism
  • dendritic cell
  • immune regulation
  • ornithine
  • polyamine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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  • Cite this

    Mondanelli, G., Bianchi, R., Pallotta, M. T., Orabona, C., Albini, E., Iacono, A., Belladonna, M. L., Vacca, C., Fallarino, F., Macchiarulo, A., Ugel, S., Bronte, V., Gevi, F., Zolla, L., Verhaar, A., Peppelenbosch, M., Mazza, E. M. C., Bicciato, S., Laouar, Y., ... Grohmann, U. (2017). A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells. Immunity, 46(2), 233-244. https://doi.org/10.1016/j.immuni.2017.01.005