title: Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells.
abstract: Metabotropic glutamate receptor 4 (mGluR4) possesses immune modulatory properties in vivo, such that a positive allosteric modulator (PAM) of the receptor confers protection on mice with relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE). ADX88178 is a newly-developed, one such mGluR4 modulator with high selectivity, potency, and optimized pharmacokinetics. Here we found that application of ADX88178 in the RR-EAE model system converted disease into a form of mild-yet chronic-neuroinflammation that remained stable for over two months after discontinuing drug treatment. In vitro, ADX88178 modulated the cytokine secretion profile of dendritic cells (DCs), increasing production of tolerogenic IL-10 and TGF-β. The in vitro effects required activation of a Gi-independent, alternative signaling pathway that involved phosphatidylinositol-3-kinase (PI3K), Src kinase, and the signaling activity of indoleamine 2,3-dioxygenase 1 (IDO1). A PI3K inhibitor as well as small interfering RNA targeting Ido1-but not pertussis toxin, which affects Gi protein-dependent responses-abrogated the tolerogenic effects of ADX88178-conditioned DCs in vivo. Thus our data indicate that, in DCs, highly selective and potent mGluR4 PAMs such as ADX88178 may activate a Gi-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis.
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Giada
authors.initials: G
authors.lastname: Mondanelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Maria T
authors.initials: MT
authors.lastname: Pallotta
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Alberta
authors.initials: A
authors.lastname: Iacono
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Albini
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Bianchi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Belladonna
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Celanire
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Céline
authors.initials: C
authors.lastname: Mordant
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Heroux
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Royer-Urios
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Manfred
authors.initials: M
authors.lastname: Schneider
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Pierre-Alain
authors.initials: PA
authors.lastname: Vitte
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Mathias
authors.initials: M
authors.lastname: Cacquevel
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Laurent
authors.initials: L
authors.lastname: Galibert
authors.affiliation: Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.
authors.forename: Sonia-Maria
authors.initials: SM
authors.lastname: Poli
authors.affiliation: Department of Economics, Management, and Statistics, University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milano, Italy.
authors.forename: Aldo
authors.initials: A
authors.lastname: Solari
authors.affiliation: Department of Life Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41100 Modena, Italy.
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Calvitti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Ciriana
authors.initials: C
authors.lastname: Orabona
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.affiliation: Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy. Electronic address: ugrohmann@tin.it.
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
mesh_terms: D000494:Allosteric Regulation / Q000502:physiology; D000818:Animals; D003713:Dendritic Cells / Q000187:drug effects* / Q000378:metabolism; D005260:Female; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013844:Thiazoles / Q000494:pharmacology
chemical_list: C000591920:5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine; C583637:IDO1 protein, mouse; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011743:Pyrimidines; D034741:RNA, Small Interfering; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; D019869:Phosphatidylinositol 3-Kinases; C108823:metabotropic glutamate receptor 4
keywords: Autoimmunity; Dendritic cells; Immune regulation; Indoleamine 2,3-dioxygenase 1; Neuroinflammation; Noncanonical GPCR signaling; PI3K; Src kinase; Tryptophan metabolism; mGluR4