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Signaling in Inflammatory Leukocytes Is Dispensable for 17
-Estradiol-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis1
* Institut National de la Santé et de la Recherche Médicale Unité 563, Centre de Physiopathologie de Toulouse Purpan, Institut Claude de Préval, Hôpital Purpan, Toulouse, France; and
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Centre National de la Recherche Scientifique-Institut National de la Santé et de la Recherche Médicale-Université Louis Pasteur-Collège de France, Illkirch, France
Estrogen treatment has been shown to exert a protective effect on experimental autoimmune encephalomyelitis (EAE), and is under clinical trial for multiple sclerosis. Although it is commonly assumed that estrogens exert their effect by modulating immune functions, we show in this study that 17
-estradiol (E2) treatment can inhibit mouse EAE without affecting autoantigen-specific T cell responsiveness and type 1 cytokine production. Using mutant mice in which estrogen receptor 
(ER) has been unambiguously inactivated, we found that ER was responsible for the E2-mediated inhibition of EAE. We next generated irradiation bone marrow chimeras in which ER expression was selectively impaired in inflammatory T lymphocytes or was limited to the radiosensitive hemopoietic compartment. Our data show that the protective effect of E2 on clinical EAE and CNS inflammation was not dependent on ER signaling in inflammatory T cells. Likewise, EAE development was not prevented by E2 treatment in chimeric mice that selectively expressed ER in the systemic immune compartment. In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ER signaling in blood-derived inflammatory cells, and indicate that ER expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect.
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