TY - JOUR
T1 - A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells
AU - Mondanelli, Giada
AU - Bianchi, Roberta
AU - Pallotta, Maria Teresa
AU - Orabona, Ciriana
AU - Albini, Elisa
AU - Iacono, Alberta
AU - Belladonna, Maria Laura
AU - Vacca, Carmine
AU - Fallarino, Francesca
AU - Macchiarulo, Antonio
AU - Ugel, Stefano
AU - Bronte, Vincenzo
AU - Gevi, Federica
AU - Zolla, Lello
AU - Verhaar, Auke
AU - Peppelenbosch, Maikel
AU - Mazza, Emilia Maria Cristina
AU - Bicciato, Silvio
AU - Laouar, Yasmina
AU - Santambrogio, Laura
AU - Puccetti, Paolo
AU - Volpi, Claudia
AU - Grohmann, Ursula
N1 - Publisher Copyright:
© 2017 The Author(s)
PY - 2017/2/21
Y1 - 2017/2/21
N2 - 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.
AB - 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.
KW - Arg1
KW - IDO1
KW - TGF-β
KW - amino acid metabolism
KW - dendritic cell
KW - immune regulation
KW - ornithine
KW - polyamine
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U2 - 10.1016/j.immuni.2017.01.005
DO - 10.1016/j.immuni.2017.01.005
M3 - Article
C2 - 28214225
AN - SCOPUS:85012926948
SN - 1074-7613
VL - 46
SP - 233
EP - 244
JO - Immunity
JF - Immunity
IS - 2
ER -