Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Liu, Hong-biao; Loo, Kyi Kyi; Palaszynski, Karen M.; Ashouri, Judith F.; Lubahn, Dennis B.; Voskuhl, Rhonda R.

doi:10.4049/jimmunol.171.12.6936

Cited by 142 publications

(138 citation statements)

References 43 publications

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“…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.…”

Section: Discussionsupporting

confidence: 76%

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Elloso¹,

Phiel²,

Henderson³

et al. 2005

Journal of Endocrinology

100

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Estrogens have been shown to modulate disease activity in experimental autoimmune encephalomyelitis (EAE), the mouse model for multiple sclerosis. Consistent with these findings, the severity of disease is reduced in pregnant women with multiple sclerosis when levels of estrogens are high. Estrogens bind to two known estrogen receptors (ER), ER and ER . The relative contribution of these receptors to estrogen-mediated suppression of EAE was explored using ER-selective ligands. The ER antagonist ICI 182 780 reversed the suppressive effects of 17 -estradiol (E2), demonstrating that the protective effects of E2 on disease are dependent upon ER signaling. Treatment of SJL mice with the ER -selective agonist proteolipid protein (PPT) prior to the induction of disease resulted in suppression of clinical symptoms of disease, whereas treatment with an ER -selective agonist (WAY-202041) had no effect. Treatment of mice with PLP peptide 139-151 (PPT) was also associated with decreased immune responses associated with disease. Consistent with its lack of effect on disease, the ER agonist had minimal effects on immune responses. The use of selective estrogen receptor modulators (SERMs) in this model was also explored, and we show that raloxifene and WAY-138923 were also effective in suppressing disease. These results demonstrate the beneficial effects of estrogen receptor ligands, in particular ER -selective ligands, and may have implications in the development of therapeutic strategies for multiple sclerosis.

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Section: Discussionsupporting

confidence: 76%

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Elloso¹,

Phiel²,

Henderson³

et al. 2005

Journal of Endocrinology

100

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“…(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].…”

supporting

confidence: 63%

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

et al. 2010

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Sex hormones influence immune responses and the development of autoimmune diseases including MS and its animal model, EAE. Although it has been previously reported that ovariectomy could worsen EAE, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been addressed. In this report, we now show that endogenous estrogens limit EAE development and CNS inflammation in adult female mice through estrogen receptor a expression in the host non-hematopoietic tissues. We provide evidence that the enhancing effect of gonadectomy on EAE development was due to quantitative rather than qualitative changes in effector Th1 or Th17 cell recruitment into the CNS. Consistent with this observation, adoptive transfer of myelin oligodendrocyte glycoprotein-specific encephalitogenic CD41 T lymphocytes induced more severe EAE in ovariectomized mice as compared to normal female mice. Finally, we show that gonadectomy accelerated the early recruitment of inflammatory cells into the CNS upon adoptive transfer of encephalitogenic CD4 1 T cells. Altogether, these data show that endogenous estrogens, through estrogen receptor a, exert a protective effect on EAE by limiting the recruitment of blood-derived inflammatory cells into the CNS.Key words: EAE/MS . Estrogen . Estrogen receptor . Inflammation . Th1/Th17 cells Supporting Information available onlineIntroduction MS and its prototypic animal model, EAE, are autoimmune demyelinating diseases of the CNS. In MS and EAE, the inflammatory process is mediated by T lymphocytes reactive to CNS and brain autoantigens. It is well documented that sex hormones could influence immune responses and the development of autoimmune diseases including MS and EAE [1]. Indeed, protective effects of exogenous estrogens have been extensively reported in animal models of EAE [2][3][4]. The actions of estrogens are mediated primarily through nuclear estrogen receptor (ER) a and ERb [5]. Analysis of the effect of exogenous 17b-estradiol 3489(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]. Indeed, a clinical trial in women with MS has documented a beneficial effect of exogenous estriol administration [10]. Thus, although it has been shown that exogenous estrogens down modulate EAE through ERa, it is still unclear whether physiological levels of endogenous estrogens can significantly influence CNS autoimmunity [11,12]. In female mice, sex steroid hormones, such as estrogens, are mainly produced by the ovaries, and previous studies have reported that ovariectomy could worsen EAE [2,13,14]. However, the mechanisms implicated in the protective action of endogenous ovarian hormones have not been previously examined. For instance, it is still unknown whether these effects were due to ovarian-derived estrogens or other gonadal hormones, and whether classical ER...

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“…Both ER␣ and ER␤ are expressed in lymphoid organs. Although there are some reports of differential ER␣ and ER␤ expression by immune cells, the relative roles of ER␣ and ER␤ in myeloid cell regulation remain poorly understood (12)(13)(14)(15)(16).…”

Section: Angerhans Cells (Lc)mentioning

confidence: 99%

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

Mao¹,

Paharkova-Vatchkova²,

Hardy

et al. 2005

The Journal of Immunology

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The steroid hormone estrogen regulates the differentiation, survival, or function of diverse immune cells. Previously, we found that physiological amounts of 17β-estradiol act via estrogen receptors (ER) to promote the GM-CSF-mediated differentiation of dendritic cells (DC) from murine bone marrow progenitors in ex vivo cultures. Of the two major subsets of CD11c+ DC that develop in these cultures, estrogen is preferentially required for the differentiation of a CD11bintLy6C− population, although it also promotes increased numbers of a CD11bhighLy6C+ population. Although both DC subsets express ERα, only the CD11bhighLy6C+ DC express ERβ, perhaps providing a foundation for the differential regulation of these two DC types by estrogen. The two DC populations exhibit distinct phenotypes in terms of capacity for costimulatory molecule and MHC expression, and Ag internalization, which predict functional differences. The CD11bintLy6C− population shows the greatest increase in MHC and CD86 expression after LPS activation. Most notably, the estrogen-dependent CD11bintLy6C− DC express langerin (CD207) and contain Birbeck granules characteristic of Langerhans cells. These data show that estrogen promotes a DC population with the unique features of epidermal Langerhans cells and suggest that differentiation of Langerhans cells in vivo will be dependent upon local estrogen levels and ER-mediated signaling events in skin.

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Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Cited by 142 publications

References 43 publications

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

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

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

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Estrogen Receptor α Mediates Estrogen’s Immune Protection in Autoimmune Disease

Cited by 142 publications

References 43 publications

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

Suppression of experimental autoimmune encephalomyelitis using estrogen receptor-selective ligands

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

Estrogen Selectively Promotes the Differentiation of Dendritic Cells with Characteristics of Langerhans Cells

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