Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells
| Autor: | Mario Calvitti, Claudia Volpi, Sonia-Maria Poli, Madeleine Heroux, Giada Mondanelli, Maria Laura Belladonna, Silvio Bicciato, Francesca Fallarino, Alberta Iacono, Aldo Solari, Isabelle Royer-Urios, Marco Gargaro, Cinzia Antognelli, Carmine Vacca, Céline Mordant, Mathias Cacquevel, Maria Teresa Pallotta, Paolo Puccetti, Sylvain Celanire, Ursula Grohmann, Roberta Bianchi, Ciriana Orabona, Pierre-Alain Vitte, Manfred Schneider, Elisa Albini, Laurent Galibert |
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| Přispěvatelé: | Volpi, C, Mondanelli, G, Pallotta, M, Vacca, C, Iacono, A, Gargaro, M, Albini, E, Bianchi, R, Belladonna, M, Celanire, S, Mordant, C, Heroux, M, Royer Urios, I, Schneider, M, Vitte, P, Cacquevel, M, Galibert, L, Poli, S, Solari, A, Bicciato, S, Calvitti, M, Antognelli, C, Puccetti, P, Orabona, C, Fallarino, F, Grohmann, U |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Autoimmunity Receptors Metabotropic Glutamate PI3K phosphatidylinositol-3-kinase Dendritic cells PI3K Immune regulation Indoleamine 2 3-dioxygenase 1 mGluR4 Neuroinflammation Noncanonical GPCR signaling Src kinase Tryptophan metabolism Cellular and Molecular Neuroscience Pharmacology Mice Phosphatidylinositol 3-Kinases RNA Small Interfering Metabotropic glutamate receptor 4 Experimental autoimmune encephalomyelitis DC Dendritic cell 3. Good health Cell biology PAM positive allosteric modulator Treg T regulatory IDO1 indoleamine 2 3-dioxygenase 1 Female Signal transduction Dendritic cell Signal Transduction Allosteric modulator Allosteric regulation Indoleamine 2 3-dioxygenase 1 Biology Pertussis toxin Article 03 medical and health sciences Allosteric Regulation RR-EAE relapsing-remitting experimental autoimmune encephalomyelitis mGluR metabotropic glutamate receptor medicine Animals Indoleamine-Pyrrole 2 3 -Dioxygenase PI3K/AKT/mTOR pathway ITIM immunoreceptor tyrosine-based inhibitory motif medicine.disease Thiazoles 3-dioxygenase 1 Pyrimidines 030104 developmental biology Immunology Cytokine secretion Indoleamine 2 |
| Zdroj: | Neuropharmacology |
| Popis: | 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. Highlights • ADX88178, a selective mGluR4 PAM, exerts long-term therapeutic effects in RR-EAE. • ADX88178 activates a noncanonical mGluR4 signaling in DCs. • ADX88178 induces a tolerogenic functional phenotype in DCs via immunoregulatory IDO1. • Highly selective mGluR4 PAMs may represent novel drugs in chronic neuroinflammation. |
| Databáze: | OpenAIRE |
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