Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells

作者：Volpi Claudia; Mondanelli Giada; Pallotta Maria T; Vacca Carmine; Iacono Alberta; Gargaro Marco; Albini Elisa; Bianchi Roberta; Belladonna Maria L; Celanire Sylvain; Mordant Celine; Heroux Madeleine; Royer Urios Isabelle; Schneider Manfred; Vitte Pierre Alain; Cacquevel Mathias; Galibert Laurent; Poli Sonia Maria; Solari Aldo; Bicciato Silvio; Calvitti Mario; Antognelli Cinzia; Puccetti Paolo; Orabona Ciriana; Fallarino Francesca; Grohmann Ursula^*

来源：Neuropharmacology, 2016, 102: 59-71.

DOI：10.1016/j.neuropharm.2015.10.036

• Neuroinflammation
• Autoimmunity
• mGluR4
• Noncanonical GPCR signaling
• PI3K
• Src kinase
• Tryptophan metabolism
• Indoleamine 2,3-dioxygenase 1
• Dendritic cells
• Immune regulation

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-beta. The in vitro effects required activation of a G(i)-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 Idol but not pertussis toxin, which affects G(i) 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 G(i)-independent, long-lived regulatory pathway that could be therapeutically exploited in chronic autoimmune diseases such as multiple sclerosis.

• 出版日期2016-3