title: Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance.
abstract: Experimental autoimmune encephalomyelitis (EAE), the experimental model for multiple sclerosis (MS), is triggered by myelin-specific Th1 and Th17 cells. The immunomodulatory activities of melatonin have been shown to be beneficial under several conditions in which the immune system is exacerbated. Here, we sought to elucidate the basis of the melatonin protective effect on EAE by characterizing the T effector/regulatory responses, particularly those of the memory cell subsets. Melatonin was tested for its effect on Th1, Th17 and T regulatory (Treg) cells in the lymph nodes and CNS of immunodominant peptide of myelin oligodendrocyte glycoprotein (pMOG)-immunized and EAE mice, respectively. The capacity of melatonin to ameliorate EAE as well as modifying both T cell response and effector/regulatory balance was surveyed. T cell memory subsets and CD44, a key activation marker involved in the EAE pathogenesis, were also examined. Melatonin protected from EAE by decreasing peripheral and central Th1/Th17 responses and enhancing both the Treg frequency and IL-10 synthesis in the CNS. Melatonin reduced the T effector memory population and its pro-inflammatory response and regulated CD44 expression, which was decreased in T effector cells and increased in Tregs. The alterations in the T cell subpopulations were associated with a reduced mononuclear infiltration (CD4 and CD11b cells) of the melatonin-treated mice CNS. For the first time, we report that melatonin protects against EAE by controlling peripheral and central T effector/regulatory responses, effects that might be partially mediated by CD44. This immunomodulatory effect on EAE suggests that melatonin may represent an effective treatment option for MS.
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Álvarez-Sánchez
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Spain.
authors.forename: Ivan
authors.initials: I
authors.lastname: Cruz-Chamorro
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Neurosurgery, Virgen Macarena & Virgen del Rocío University Hospitals, Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: López-González
authors.affiliation: Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Spain.
authors.forename: José C
authors.initials: JC
authors.lastname: Utrilla
authors.affiliation: Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Spain.
authors.forename: José M
authors.initials: JM
authors.lastname: Fernández-Santos
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Spain.
authors.forename: Alicia
authors.initials: A
authors.lastname: Martínez-López
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Spain.
authors.forename: Patricia J
authors.initials: PJ
authors.lastname: Lardone
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Spain; Department of Clinical Biochemistry, Virgen del Rocío University Hospital, Seville, Spain.
authors.forename: Juan M
authors.initials: JM
authors.lastname: Guerrero
authors.affiliation: Institute of Biomedicine of Seville (IBiS), Virgen del Rocío University Hospital/CSIC/University of Seville, Spain; Department of Medical Biochemistry, Molecular Biology and Immunology, School of Medicine, University of Seville, Spain. Electronic address: vico@us.es.
authors.forename: Antonio
authors.initials: A
authors.lastname: Carrillo-Vico
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008550:Melatonin / Q000008:administration & dosage* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines; D008550:Melatonin
keywords: CD44; EAE/MS; IL-10; Melatonin; T effector memory cells; T regulatory cells; Th1; Th17