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.

Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells / Volpi, Claudia; Mondanelli, Giada; Pallotta, Maria T.; Vacca, Carmine; Iacono, Alberta; Gargaro, Marco; Albini, Elisa; Bianchi, Roberta; Belladonna, Maria L.; Celanire, Sylvain; Mordant, Céline; 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. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - ELETTRONICO. - 102:(2016), pp. 59-71. [10.1016/j.neuropharm.2015.10.036]

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

BICCIATO, Silvio;
2016

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.
30-ott-2015
102
59
71
Allosteric modulation of metabotropic glutamate receptor 4 activates IDO1-dependent, immunoregulatory signaling in dendritic cells / Volpi, Claudia; Mondanelli, Giada; Pallotta, Maria T.; Vacca, Carmine; Iacono, Alberta; Gargaro, Marco; Albini, Elisa; Bianchi, Roberta; Belladonna, Maria L.; Celanire, Sylvain; Mordant, Céline; 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. - In: NEUROPHARMACOLOGY. - ISSN 0028-3908. - ELETTRONICO. - 102:(2016), pp. 59-71. [10.1016/j.neuropharm.2015.10.036]
Volpi, Claudia; Mondanelli, Giada; Pallotta, Maria T.; Vacca, Carmine; Iacono, Alberta; Gargaro, Marco; Albini, Elisa; Bianchi, Roberta; Belladonna, Maria L.; Celanire, Sylvain; Mordant, Céline; 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
File in questo prodotto:
File Dimensione Formato  
Volpi_et_al_Neuropharmacology_2015.pdf

non disponibili

Tipologia: Pre-print dell'autore (bozza pre referaggio)
Dimensione 1.58 MB
Formato Adobe PDF
1.58 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
1-s2.0-S0028390815301593-main.pdf

accesso aperto

Tipologia: Versione dell'editore (versione pubblicata)
Dimensione 1.8 MB
Formato Adobe PDF
1.8 MB Adobe PDF Visualizza/Apri
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

Licenza Creative Commons
I metadati presenti in IRIS UNIMORE sono rilasciati con licenza Creative Commons CC0 1.0 Universal, mentre i file delle pubblicazioni sono rilasciati con licenza Attribuzione 4.0 Internazionale (CC BY 4.0), salvo diversa indicazione.
In caso di violazione di copyright, contattare Supporto Iris

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1074865
Citazioni
  • ???jsp.display-item.citation.pmc??? 10
  • Scopus 21
  • ???jsp.display-item.citation.isi??? 21
social impact