ERb-Dependent Direct Suppression of Human and MurineTh17 Cells and Treatment of Established Central NervousSystem Autoimmunity by a Neurosteroid

Evangelina Kourepini, Maria Aggelakopoulou, Nikolaos Paschalidis, Davina Camargo Madeira Simoes, Dimitra Kalavrizioti, Nikolaos Dimisianos, Panagiotis Papathanasopoulos, Athanasia Mouzaki, Vily Panoutsakopoulou

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)

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 b by CD4+ T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-b1 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.
Original languageEnglish
Pages (from-to)2598-2609
Number of pages20
JournalThe Journal of Immunology
Volume197
Issue number7
DOIs
Publication statusPublished - 1 Oct 2016
Externally publishedYes

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