Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation

Francesca Fallarino, Claudia Volpi, Francesco Fazio, Serena Notartomaso, Carmine Vacca, Carla Busceti, Silvio Bicciato, Giuseppe Battaglia, Valeria Bruno, Paolo Puccetti, Maria C. Fioretti, Ferdinando Nicoletti, Ursula Grohmann, Roberto Di Marco

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


High amounts of glutamate are found in the brains of people with multiple sclerosis, an inflammatory disease marked by progressive demyelination. Glutamate might affect neuroinflammation via effects on immune cells. Knockout mice lacking metabotropic glutamate receptor-4 (mGluR4) were markedly vulnerable to experimental autoimmune encephalomyelitis (EAE, a mouse model of multiple sclerosis) and developed responses dominated by interleukin-17-producing T helper (TH17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased TH cell commitment to the TH 17 phenotype. In wild-type mice, mGluR4 was constitutively expressed in all peripheral DCs, and this expression increased after cell activation. Treatment of wild-type mice with a selective mGluR4 enhancer increased EAE resistance via regulatory T (Treg) cells. The high amounts of glutamate in neuroinflammation might reflect a counterregulatory mechanism that is protective in nature and might be harnessed therapeutically for restricting immunopathology in multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)897-902
Number of pages6
JournalNature Medicine
Issue number8
StatePublished - Aug 2010
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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