Metabotropic glutamate receptor-4 modulates adaptive immunity and restrains neuroinflammation.
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.
Fallarino
Francesca
F
Department of Experimental Medicine and Biochemical Sciences, University of Perugia, Perugia, Italy.
Volpi
Claudia
C
Fazio
Francesco
F
Notartomaso
Serena
S
Vacca
Carmine
C
Busceti
Carla
C
Bicciato
Silvio
S
Battaglia
Giuseppe
G
Bruno
Valeria
V
Puccetti
Paolo
P
Fioretti
Maria C
MC
Nicoletti
Ferdinando
F
Grohmann
Ursula
U
Di Marco
Roberto
R
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
D016207:Cytokines; D018094:Receptors, Metabotropic Glutamate; D018698:Glutamic Acid; C108823:metabotropic glutamate receptor 4