title: ERβ in CD4+ T Cells Is Crucial for Ligand-Mediated Suppression of Central Nervous System Autoimmunity.
abstract: The development of therapies for multiple sclerosis targeting pathogenic T cell responses remains imperative. Previous studies have shown that estrogen receptor (ER) β ligands could inhibit experimental autoimmune encephalomyelitis. However, the effects of ERβ-specific ligands on human or murine pathogenic immune cells, such as Th17, were not investigated. In this article, we show that the synthetic ERβ-specific ligand 4-(2-phenyl-5,7-bis[trifluoromethyl]pyrazolo[1,5-a]pyrimidin-3-yl)phenol (PHTPP) reversed established paralysis and CNS inflammation, characterized by a dramatic suppression of pathogenic Th responses as well as induction of IL-10-producing regulatory CD4(+) T cell subsets in vivo. Moreover, administration of PHTPP in symptomatic mice induced regulatory CD4(+) T cells that were suppressive in vivo. PHTPP-mediated experimental autoimmune encephalomyelitis amelioration was canceled in mice with ERβ-deficient CD4(+) T cells only, indicating that expression of ERβ by these cells is crucial for the observed therapeutic effect. Importantly, synthetic ERβ-specific ligands acting directly on CD4(+) T cells suppressed human and mouse Th17 cells, downregulating Th17 cell signature gene expression and expanding IL-10-producing T cells among them. TGF-β1 and aryl hydrocarbon receptor activation enhanced the ERβ ligand-mediated expansion of IL-10-producing T cells among Th17 cells. In addition, these ERβ-specific ligands promoted the induction and maintenance of Foxp3(+) T regulatory cells, as well as their in vitro suppressive function. Thus, ERβ-specific ligands targeting pathogenic Th17 cells and inducing functional regulatory cells represent a promising subset of therapeutic agents for multiple sclerosis.
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 vpan@bioacademy.gr.
authors.forename: Vily
authors.identifier: 0000-0002-1569-1508
authors.initials: V
authors.lastname: Panoutsakopoulou
mesh_terms: D000818:Animals; D015551:Autoimmunity; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology*; D047629:Estrogen Receptor beta / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis / Q000276:immunology; D008024:Ligands; D051379:Mice; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology; D010243:Paralysis / Q000188:drug therapy; D011720:Pyrazoles / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis / Q000627:therapeutic use*; D018336:Receptors, Aryl Hydrocarbon / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology; D053773:Transforming Growth Factor beta1 / Q000276:immunology
chemical_list: C556295:4-(2-phenyl-5,7-bis(trifluoromethyl)pyrazolo(1,5-a)pyrimidin-3-yl)phenol; D047629:Estrogen Receptor beta; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D018336:Receptors, Aryl Hydrocarbon; D053773:Transforming Growth Factor beta1; D016753:Interleukin-10