title: Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation.
abstract: 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 (T(H)17) cells. In dendritic cells (DCs) from those mice, defective mGluR4 signaling-which would normally decrease intracellular cAMP formation-biased T(H) cell commitment to the T(H)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 (T(reg)) 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.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazio
authors.forename: Serena
authors.initials: S
authors.lastname: Notartomaso
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.forename: Carla
authors.initials: C
authors.lastname: Busceti
authors.forename: Silvio
authors.initials: S
authors.lastname: Bicciato
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Battaglia
authors.forename: Valeria
authors.initials: V
authors.lastname: Bruno
authors.forename: Paolo
authors.initials: P
authors.lastname: Puccetti
authors.forename: Maria C
authors.initials: MC
authors.lastname: Fioretti
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.forename: Ursula
authors.initials: U
authors.lastname: Grohmann
authors.forename: Roberto
authors.initials: R
authors.lastname: Di Marco
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism / Q000502:physiology; D004660:Encephalitis / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology; D018698:Glutamic Acid / Q000378:metabolism / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009410:Nerve Degeneration / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015213:Neuroimmunomodulation / Q000235:genetics / Q000502:physiology; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D006377:T-Lymphocytes, Helper-Inducer / Q000502:physiology
chemical_list: D016207:Cytokines; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; C108823:metabotropic glutamate receptor 4