Journal Article

Engagement of Nuclear Coactivator 7 by 3-Hydroxyanthranilic Acid Enhances Activation of Aryl Hydrocarbon Receptor in Immunoregulatory Dendritic Cells

Manni, Giorgia, Pallotta, Maria T., Iamandii, Ioana Maria, Gargaro, Marco, Bianchi, Roberta, Puccetti, Paolo, Mazza, Emilia M. C., Volpi, Claudia, Mondanelli, Giada, Bicciato, Silvio, Belladonna, Maria L., Cecchetti, Violetta, Massari, Serena, Proietti, Elisa, Fallarino, Francesca, Grohmann, Ursula, Vacca, Carmine, Scalisi, Giulia, Panfili, Eleonora, Tabarrini, Oriana, Matino, Davide, Orabona, Ciriana, Iacono, Alberta

2019

Overview

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first step in the kynurenine pathway of tryptophan (Trp) degradation that produces several biologically active Trp metabolites. L-kynurenine (Kyn), the first byproduct by IDO1, promotes immunoregulatory effects via activation of the Aryl hydrocarbon Receptor (AhR) in dendritic cells (DCs) and T lymphocytes. We here identified the nuclear coactivator 7 (NCOA7) as a molecular target of 3-hydroxyanthranilic acid (3-HAA), a Trp metabolite produced downstream of Kyn along the kynurenine pathway. In cells overexpressing NCOA7 and AhR, the presence of 3-HAA increased the association of the two molecules and enhanced Kyn-driven, AhR-dependent gene transcription. Physiologically, conventional (cDCs) but not plasmacytoid DCs or other immune cells expressed high levels of NCOA7. In cocultures of CD4 T cells with cDCs, the co-addition of Kyn and 3-HAA significantly increased the induction of Foxp3 regulatory T cells and the production of immunosuppressive transforming growth factor β in an NCOA7-dependent fashion. Thus, the co-presence of NCOA7 and the Trp metabolite 3-HAA can selectively enhance the activation of ubiquitary AhR in cDCs and consequent immunoregulatory effects. Because NCOA7 is often overexpressed and/or mutated in tumor microenvironments, our current data may provide evidence for a new immune check-point mechanism based on Trp metabolism and AhR.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Acids / Apoptosis / aryl hydrocarbon (Ah) receptor / Biological activity / Bone marrow / CD4 antigen / Chromatography / dendritic cell / Dendritic cells / Foxp3 protein / Homeostasis / Hydrocarbons / immune regulation / Immunology / Immunoregulation / Kinases / Ligands / Lymphocytes / Lymphocytes T / Metabolites / NMR / nuclear coactivator 7 (NCOA7) / Nuclear magnetic resonance / Transforming growth factor-b / Tryptophan / Tryptophan 2,3-dioxygenase / tryptophan metabolism / Tumor microenvironment