title: Cinnabarinic acid, an endogenous agonist of type-4 metabotropic glutamate receptor, suppresses experimental autoimmune encephalomyelitis in mice.
abstract: Cinnabarinic acid (CA) is an endogenous metabolite of the kynurenine pathway which acts as an orthosteric agonist of type-4 metabotropic glutamate receptor (mGlu4). We now report that systemic administration of CA (0.1-10 mg/kg, i.p.) was highly protective against experimental autoimmune encephalomyelitis (EAE) induced by the myelin oligodendrocyte glycoprotein (MOG35-55) peptide, which models multiple sclerosis in mice. Full protection against EAE required daily injections of CA since the time of immunization, similarly to what reported for the mGlu4 enhancer N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1acarboxamide (PHCCC). CA treatment boosted an immune response dominated by regulatory T (Treg) cells at the expenses of Th17 cells. In addition, exogenous CA enhanced endogenous CA formation in lymphocytes, suggesting the occurrence of a positive feedback loop sustaining immune tolerance. To examine whether activation of mGlu4 could account for the protective activity of CA against EAE, we used mGlu4 knockout mice. As expected, these mice displayed a more severe form of EAE in response to immunization. CA was still protective against EAE in mGlu4-deficient mice, although its action was significantly reduced both at high and low CA doses. This suggests that the action of CA against neuroinflammation involves multiple mechanisms including the activation of mGlu4. These data further suggest that CA is one possible bridge between activation of the kynurenine pathway and immune tolerance aimed at restraining neuroinflammation.
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Parco Tecnologico, Località Camerelle, Via dell'Elettronica, 86077 Pozzilli, IS, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazio
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Parco Tecnologico, Località Camerelle, Via dell'Elettronica, 86077 Pozzilli, IS, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Zappulla
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Parco Tecnologico, Località Camerelle, Via dell'Elettronica, 86077 Pozzilli, IS, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Notartomaso
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Parco Tecnologico, Località Camerelle, Via dell'Elettronica, 86077 Pozzilli, IS, Italy.
authors.forename: Carla
authors.initials: C
authors.lastname: Busceti
authors.affiliation: ImmuSmol, 15 Rue Am. Prouhet, 33600 Pessac, France.
authors.forename: Alban
authors.initials: A
authors.lastname: Bessede
authors.affiliation: I.R.C.C.S. Neuromed, Pozzilli, Parco Tecnologico, Località Camerelle, Via dell'Elettronica, 86077 Pozzilli, IS, Italy.
authors.forename: Pamela
authors.initials: P
authors.lastname: Scarselli
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Vacca
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Gargaro
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Volpi
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Allegrucci
authors.affiliation: NESMOS Department, Advanced Molecular Diagnostic Unit, Sant'Andrea Hospital, University of Rome 'Sapienza', Via di Grotta Rossa 1035-39, 00189 Rome, Italy.
authors.forename: Luana
authors.initials: L
authors.lastname: Lionetto
authors.affiliation: NESMOS Department, Advanced Molecular Diagnostic Unit, Sant'Andrea Hospital, University of Rome 'Sapienza', Via di Grotta Rossa 1035-39, 00189 Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Simmaco
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy.
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Belladonna
authors.affiliation: Department of Human Physiology and Pharmacology, University of Rome 'Sapienza', Piazzale Aldo Moro 5, 00185 Rome, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Nicoletti
authors.affiliation: Department of Experimental Medicine, University of Perugia, Polo Didattico Sant'Andrea delle Fratte, Piazzale Gambuli, 06132 Perugia, Italy. Electronic address: fllfnc@tin.it.
authors.forename: Francesca
authors.initials: F
authors.lastname: Fallarino
mesh_terms: D000818:Animals; D001578:Benzopyrans / Q000627:therapeutic use; D002490:Central Nervous System / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D024462:Myosin Type II / Q000378:metabolism; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D010078:Oxazines / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000633:toxicity; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D001578:Benzopyrans; D016207:Cytokines; D018690:Excitatory Amino Acid Agonists; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; C442478:N-phenyl-7-(hydroxyimino)cyclopropa(b)chromen-1a-carboxamide; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D010078:Oxazines; D010446:Peptide Fragments; D018094:Receptors, Metabotropic Glutamate; C539901:Rorc protein, mouse; C097348:T-Box Domain Protein 2; D020825:T-Box Domain Proteins; D014157:Transcription Factors; C445081:myelin oligodendrocyte glycoprotein (35-55); C000483:cinnabarinic acid; D024462:Myosin Type II; C108823:metabotropic glutamate receptor 4
keywords: Cinnabarinic acid; Experimental autoimmune encephalomyelitis; Metabotropic glutamate receptor 4; Tolerance