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

Neuropharmacology. 2016 Mar:102:59-71. doi: 10.1016/j.neuropharm.2015.10.036. Epub 2015 Oct 30.

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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / physiology
  • Animals
  • Dendritic Cells / drug effects*
  • Dendritic Cells / metabolism
  • Female
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Mice
  • Phosphatidylinositol 3-Kinases / metabolism
  • Pyrimidines / pharmacology
  • RNA, Small Interfering
  • Receptors, Metabotropic Glutamate / metabolism*
  • Signal Transduction / drug effects*
  • Thiazoles / pharmacology

Substances

  • 5-methyl-N-(4-methylpyrimidin-2-yl)-4-(1H-pyrazol-4-yl)thiazol-2-amine
  • IDO1 protein, mouse
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Pyrimidines
  • RNA, Small Interfering
  • Receptors, Metabotropic Glutamate
  • Thiazoles
  • Phosphatidylinositol 3-Kinases
  • metabotropic glutamate receptor 4