TY - JOUR
T1 - ERb-Dependent Direct Suppression of Human and MurineTh17 Cells and Treatment of Established Central NervousSystem Autoimmunity by a Neurosteroid
AU - Kourepini, Evangelina
AU - Aggelakopoulou, Maria
AU - Paschalidis, Nikolaos
AU - Camargo Madeira Simoes, Davina
AU - Kalavrizioti, Dimitra
AU - Dimisianos, Nikolaos
AU - Papathanasopoulos, Panagiotis
AU - Mouzaki, Athanasia
AU - Panoutsakopoulou, Vily
PY - 2016/10/1
Y1 - 2016/10/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?eid=2-s2.0-84989883044&partnerID=MN8TOARS
U2 - 10.4049/jimmunol.1601038
DO - 10.4049/jimmunol.1601038
M3 - Article
SN - 0022-1767
VL - 197
SP - 2598
EP - 2609
JO - The Journal of Immunology
JF - The Journal of Immunology
IS - 7
ER -