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

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

doi:10.3389/fimmu.2019.01973

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.

Highlights

Immune regulation is a highly evolved form of biologic response that controls immunity and dampens exaggerated inflammation [1,2,3,4]
No effect could be detected for Biot3, incubation of mesenteric lymph node (MLN) cells with Biot1 and, more so, Biot2 determined a functional profile very similar to that induced by 3-hydroxyanthranilic acid (3-HAA) (Figures 1B–E)
Because Aryl hydrocarbon Receptor (AhR) can be activated by endogenous ligands [24], including Kyn, and because our current data indicated the occurrence of nuclear coactivator 7 (NCOA7) binding by a Trp metabolite, we investigated whether 3-HAA could favor recruitment of NCOA7 by AhR and modulate the transactivating ability of the receptor

Summary

Introduction

Immune regulation is a highly evolved form of biologic response that controls immunity and dampens exaggerated inflammation [1,2,3,4]. Indoleamine 2,3-dioxygenase 1 (IDO1) and the Aryl hydrocarbon Receptor (AhR) represent two ancient metabolic molecules that may have functionally co-evolved to integrate their immunoregulatory potential [5, 6]. Dendritic cells (DCs) express the highest levels of IDO1, in response to the cytokine interferon γ (IFN-γ) [9,10,11]. Trp starvation and the production of kynurenines by DCs induce the conversion of naïve CD4+ T cells into Foxp3+ regulatory T (Treg) cells [12, 13]. The high levels of Kyn produced by DCs under inflammatory conditions—as well as by tumors—can exert immunoregulatory effects on T cells via AhR activation in the absence of Trp starvation [5, 14]

Methods

Results

Conclusion