학술논문
Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells.
Document Type
Academic Journal
Author
Volpi C; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Mondanelli G; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Pallotta MT; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Vacca C; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Iacono A; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Gargaro M; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Albini E; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Bianchi R; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Belladonna ML; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Celanire S; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Mordant C; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Heroux M; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Royer-Urios I; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Schneider M; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Vitte PA; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Cacquevel M; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Galibert L; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Poli SM; Addex Therapeutics, Chemin des Aulx 14, 1228, Plans les Ouates, Geneva, Switzerland.; Solari A; Department of Economics, Management, and Statistics, University of Milano-Bicocca, Piazza dell'Ateneo Nuovo 1, 20126 Milano, Italy.; Bicciato S; Department of Life Sciences, Via G. Campi 287, University of Modena and Reggio Emilia, 41100 Modena, Italy.; Calvitti M; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Antognelli C; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Puccetti P; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Orabona C; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Fallarino F; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy.; Grohmann U; Department of Experimental Medicine, University of Perugia, Piazzale Gambuli 1, 06132 Perugia, Italy. Electronic address: ugrohmann@tin.it.
Source
Publisher: Pergamon Press Country of Publication: England NLM ID: 0236217 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7064 (Electronic) Linking ISSN: 00283908 NLM ISO Abbreviation: Neuropharmacology Subsets: MEDLINE
Subject
Language
English
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.
(Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)
(Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.)