title: ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid.
abstract: Multiple sclerosis (MS), an autoimmune disease of the CNS, is mediated by autoreactive Th cells. A previous study showed that the neurosteroid dehydroepiandrosterone (DHEA), when administered preclinically, could suppress progression of relapsing-remitting experimental autoimmune encephalomyelitis (EAE). However, the effects of DHEA on human or murine pathogenic immune cells, such as Th17, were unknown. In addition, effects of this neurosteroid on symptomatic disease, as well as the receptors involved, had not been investigated. In this study, we show that DHEA suppressed peripheral responses from patients with MS and reversed established paralysis and CNS inflammation in four different EAE models, including the 2D2 TCR-transgenic mouse model. DHEA directly inhibited human and murine Th17 cells, inducing IL-10-producing regulatory T cells. Administration of DHEA in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in an IL-10-dependent manner. Expression of the estrogen receptor β by CD4(+) T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-β1 as well as aryl hydrocarbon receptor activation was necessary for the expansion of IL-10-producing T cells by DHEA. Thus, our studies demonstrate that compounds that inhibit pathogenic Th17 responses and expand functional regulatory cells could serve as therapeutic agents for autoimmune diseases, such as MS.
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece;
authors.forename: Maria
authors.initials: M
authors.lastname: Aggelakopoulou
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece;
authors.forename: Evangelia
authors.identifier: 0000-0002-2299-1007
authors.initials: E
authors.lastname: Kourepini
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece;
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Paschalidis
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece;
authors.forename: Davina C M
authors.identifier: 0000-0002-7262-1784
authors.initials: DC
authors.lastname: Simoes
authors.affiliation: Division of Hematology, Department of Internal Medicine, University of Patras Medical School, Rion 265 00, Greece; and.
authors.forename: Dimitra
authors.identifier: 0000-0002-1853-9368
authors.initials: D
authors.lastname: Kalavrizioti
authors.affiliation: Department of Neurology, Patras University Hospital, Patras 265 00, Greece.
authors.forename: Nikolaos
authors.identifier: 0000-0003-1765-3211
authors.initials: N
authors.lastname: Dimisianos
authors.affiliation: Department of Neurology, Patras University Hospital, Patras 265 00, Greece.
authors.forename: Panagiotis
authors.identifier: 0000-0002-6893-7735
authors.initials: P
authors.lastname: Papathanasopoulos
authors.affiliation: Division of Hematology, Department of Internal Medicine, University of Patras Medical School, Rion 265 00, Greece; and.
authors.forename: Athanasia
authors.identifier: 0000-0001-5548-7002
authors.initials: A
authors.lastname: Mouzaki
authors.affiliation: Cellular Immunology Laboratory, Center for Basic Research, Biomedical Research Foundation of the Academy of Athens, Athens 115 27, Greece; vpan@bioacademy.gr.
authors.forename: Vily
authors.identifier: 0000-0002-1569-1508
authors.initials: V
authors.lastname: Panoutsakopoulou
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology; D003687:Dehydroepiandrosterone / Q000008:administration & dosage / Q000494:pharmacology*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018377:Neurotransmitter Agents / Q000008:administration & dosage / Q000494:pharmacology*; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology
chemical_list: D047629:Estrogen Receptor beta; D018377:Neurotransmitter Agents; D003687:Dehydroepiandrosterone