Estrogen Receptor α Signaling in Inflammatory Leukocytes Is Dispensable for 17β-Estradiol-Mediated Inhibition of Experimental Autoimmune Encephalomyelitis

Abstract

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 17β-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 α (ERα) has been unambiguously inactivated, we found that ERα was responsible for the E2-mediated inhibition of EAE. We next generated irradiation bone marrow chimeras in which ERα 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 ERα signaling in inflammatory T cells. Likewise, EAE development was not prevented by E2 treatment in chimeric mice that selectively expressed ERα in the systemic immune compartment. In conclusion, our data demonstrate that the beneficial effect of E2 on this autoimmune disease does not involve ERα signaling in blood-derived inflammatory cells, and indicate that ERα expressed in other tissues, such as CNS-resident microglia or endothelial cells, mediates this effect.

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

“…These results are consistent with the findings that pregnancy as well as estrogen treatment during EAE induces a population of CD45 dim VLA-4 + regulatory cells that appear to be non-T cells but confer protection from EAE (Matejuk et al 2004). Additional studies using bone marrow chimeras further support these observations and provide evidence that E2 may act on nonhematopoietic cells such as endothelial cells, or on resident cells of the CNS (for example, microglia) to prevent disease (Garidou et al 2004). Modulation of cells such as these by E2 may in turn suppress the activation and/or function of T cells.…”

Endogenous estrogens, through estrogen receptor α, constrain autoimmune inflammation in female mice by limiting CD4+ T‐cell homing into the CNS

“…(E2) on EAE induction in ER-mutant mice clearly showed that this protective effect of E2 was mediated through ERa but not ERb [6][7][8]. Altogether, these studies support a protective role of estrogens on EAE that could explain the protective effect of pregnancy on MS [9].…”

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Estrogens are able to shift the T-cell population towards a Th2 phenotype, an activity also confirmed in pilot clinical studies ( [47,83,211,214]) and to influence a subpopulation of Th cells, named T-regulatory cells ( [184,226]). On the other hand, microglia and endothelial cells have probably a more significant role in estrogen action; using irradiation bone marrow chimeras it has been recently shown that the effect of estradiol on clinical EAE and CNS inflammation was not dependent on ERa expression in the peripheral immune system but was conferred by ERa expression on CNS resident cells, namely endothelial and microglial cells ( [80,185]). It is thus important to fill the gap in the characterization of estrogen signalling in these resident brain cells and in assessing its relevance in estrogen-mediated neuroprotective activity in EAE.…”

“…Through the use of the estrogen receptor antagonist ICI 182780 we and others initially ascribed hormone action in microglia to the activation of endogenous ERs, since this molecule was able to block the effect of estradiol ( [24,25,141,241]). Using ER-null mice several reports described the selective involvement of ERa in the anti-inflammatory and neuroprotective activity of estradiol against neuroinflammatory and vascular pathologies of the brain ( [62,80,185,242]). Despite the fact that ERb has been shown to be expressed widely in the CNS in adult mice ( [161,167]), it appears that this receptor isoform is not involved in mediating the protective effect of estrogens in neuroinflammatory diseases.…”