ERb-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

Kourepini, Evangelina, Aggelakopoulou, Maria, Paschalidis, Nikolaos, Camargo Madeira Simoes, Davina, Kalavrizioti, Dimitra, Dimisianos, Nikolaos, Papathanasopoulos, Panagiotis, Mouzaki, Athanasia and Panoutsakopoulou, Vily (2016) ERb-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid. The Journal of Immunology, 197 (7). pp. 2598-2609. ISSN 0022-1767

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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.

Item Type:	Article
Subjects:	C900 Others in Biological Sciences
Department:	Faculties > Health and Life Sciences > Sport, Exercise and Rehabilitation
Depositing User:	Dr Davina Camargo Madeira Simoes
Date Deposited:	19 Jun 2017 09:55
Last Modified:	12 Oct 2019 12:01
URI:	http://nrl.northumbria.ac.uk/id/eprint/31125

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