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

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

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Abstract

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.

Original languageEnglish
Pages (from-to)1973
JournalFrontiers in Immunology
Volume10
DOIs
Publication statusPublished - 2019

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Gargaro, M., Vacca, C., Massari, S., Scalisi, G., Manni, G., Mondanelli, G., Mazza, E. M. C., Bicciato, S., Pallotta, M. T., Orabona, C., Belladonna, M. L., Volpi, C., Bianchi, R., Matino, D., Iacono, A., Panfili, E., Proietti, E., Iamandii, I. M., Cecchetti, V., ... Grohmann, U. (2019). Engagement of Nuclear Coactivator 7 by 3-Hydroxyanthranilic Acid Enhances Activation of Aryl Hydrocarbon Receptor in Immunoregulatory Dendritic Cells. Frontiers in Immunology, 10, 1973. https://doi.org/10.3389/fimmu.2019.01973