The Protective Effect of 17β-Estradiol on Experimental Autoimmune Encephalomyelitis Is Mediated through Estrogen Receptor-α

Abstract

Low-dose estrogen (E2) treatment significantly inhibits the clinical signs and histopathological lesions of experimental autoimmune encephalomyelitis (EAE), and is being used in clinical trials to treat multiple sclerosis. To assess the role of intracytoplasmic estrogen receptors in mediating suppression of EAE, we studied mice with disrupted estrogen receptor-alpha (Esr1) and -beta (Esr2) genes. We demonstrate that the protective effect of E2 is abrogated in B6.129-Esr1(tm1Unc) mice (Esr1-/-) but not in B6.129-Esr2(tm1Unc) mice (Esr2-/-). The loss of E2-mediated protection from EAE in Esr1-/- mice immunized with the encephalitogenic MOG-35-55 peptide was manifested phenotypically by the development of severe acute clinical signs and histopathological lesions even in the presence of moderately high serum E2 levels. This is in contrast to C57BL/6 wild-type (WT) mice and Esr2-/- mice in which E2 treatment resulted in comparable serum levels and markedly suppressed clinical signs of EAE and abolished inflammatory lesions in the CNS. This pattern showing a lack of E2-dependent inhibition of EAE in Esr1-/- mice was mirrored by an enhanced rather than a reduced secretion of TNF-alpha, IFN-gamma, and interleukin (IL)-6 in MOG-specific splenocytes and a lack of inhibition of message for inflammatory cytokines, chemokines and chemokine receptors in CNS tissue. These results indicate that the immunomodulatory effects of E2 in EAE are dependent on Esr1 and not Esr2 signaling.

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

“…In contrast, an ER -selective agonist had little to no effect on disease. This suggests that the effects of estrogens on disease in the EAE model are mediated primarily through ER and are consistent with the recently reported findings that the immunosuppressive effects of E2 and estriol are dependent upon ER (Liu et al 2003, Polanczyk et al 2003. Further, we show that SERMs, which are non-steroidal ER ligands that have tissue-selective mixed agonist/antagonist activity, also suppressed EAE.…”

T Lymphocytes Do Not Directly Mediate the Protective Effect of Estrogen on Experimental Autoimmune Encephalomyelitis

“…Radioimmunoassay measurement of E2 serum levels in mice implanted with 15-mg pellets showed the mean level ranged between 4000 to 5000 pg/ml, which was significantly higher than in placebotreated mice (Table 1). Taken together, these results are consistent with previous findings 19 regarding the requirement for E2 signaling through Esr1 and confirm that E2 protection in EAE does not require direct E2 signaling to pathogenic T cells expressing the estrogen receptor-␣.…”

“…18 We have shown recently that estrogen receptor-␣ (Esr1) is crucial for the beneficial therapeutic effect of 17␤-estradiol (E2) in murine experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. 19 The expression of estrogen receptors among various immune cells (eg, T and B lymphocytes, antigenpresenting cells) suggests that the therapeutic effect of E2 is likely mediated directly through specific receptor binding. However, the target immune cell populations responsive to E2 treatment have not been identified.…”

Functional modification of CD11c+ liver dendritic cells during liver regeneration after partial hepatectomy in mice

“…21 One interpretation of these results is that estrogen may drive Th2 and suppress Th1 responses, and that this is achieved by multiple interactions with cells of the immune system. 21,23,41 Our data demonstrate a significant increase in ER expression by DC isolated from livers 6 hours after PH (both in PBS-and Flt3L-treated animals), associated with concomitant increases in serum estrogen. These events occur together with the increased numbers of immature LDC, and with upregulation of IL-10 and downregulation of IFN-␥ gene expression by these cells.…”