Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERα)

Gold, Stefan M.; Sasidhar, Manda V.; Morales, Laurie Beth J.; Du, Sienmi; Sicotte, Nancy L.; Tiwari‐Woodruff, Seema K.; Voskuhl, Rhonda R.

doi:10.1038/labinvest.2009.79

Cited by 73 publications

(53 citation statements)

References 48 publications

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“…Estriol and estradiol, both DHEA metabolites (39,40), have been reported to exert anti-inflammatory and neuroprotective effects in EAE (41)(42)(43). However, these molecules activate ERa and if used therapeutically could promote estrogenic side effects, posing a great risk for women to develop breast or uterine cancer (44).…”

Section: Discussionmentioning

confidence: 99%

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

Aggelakopoulou

Kourepini

Paschalidis

et al. 2016

The Journal of Immunology

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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 β by CD4+ T cells was necessary for DHEA-mediated EAE amelioration, as well as for direct downregulation of Th17 responses. TGF-β1 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.

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Section: Discussionmentioning

confidence: 99%

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

Aggelakopoulou

Kourepini

Paschalidis

et al. 2016

The Journal of Immunology

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“…Peripheral blood mononuclear cells had signifi cantly increased expression of interleukin 5 and interleukin 10 and decreased concentrations of tumour necrosis factor (TNF) α and matrix metalloproteinase 9. 8,9 When estriol treatment was discontinued for 6 months, both enhancing lesions and immune responses returned to pre-treatment levels. Furthermore, when estriol was administered again for 4 additional months, combined with a progestin for uterine protection, 10 the reduction in enhancing lesions and immunomodulation returned.…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, when estriol was administered again for 4 additional months, combined with a progestin for uterine protection, 10 the reduction in enhancing lesions and immunomodulation returned. [7][8][9] Estriol has been used for several decades throughout Europe and Asia for treating menopausal symptoms. [11][12][13] A Women's Health Initiative study 14 done in 2002 to assess whether premarin (a complex mix of conjugated oestrogens) protects against coronary heart disease in menopausal women aged 50-79 years was stopped prematurely because of an increased risk for cardiovascular disease and breast cancer, whereas the number of colorectal cancers and hip fractures decreased.…”

Section: Introductionmentioning

confidence: 99%

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

Voskuhl

Wang

et al. 2016

The Lancet Neurology

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166

143

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SummaryBackground Relapses of multiple sclerosis decrease during pregnancy, when the hormone estriol is increased. Estriol treatment is anti-infl ammatory and neuroprotective in preclinical studies. In a small single-arm study of people with multiple sclerosis estriol reduced gadolinium-enhancing lesions and was favourably immunomodulatory. We assessed whether estriol treatment reduces multiple sclerosis relapses in women.

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“…There remain differences of opinion among laboratories as to whether ERα or ERβ is responsible for the anti-inflammatory effects of estrogen on microglia (16). Saijo et al (17) demonstrated that at the mRNA level, ERβ was much more abundant than ERα.…”

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confidence: 99%

Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis

Tan

Dai

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

131

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A therapeutic goal in the treatment of certain CNS diseases, including multiple sclerosis, amyotrophic lateral sclerosis, and Parkinson disease, is to down-regulate inflammatory pathways. Inflammatory molecules produced by microglia are responsible for removal of damaged neurons, but can cause collateral damage to normal neurons located close to defective neurons. Although estrogen can inactivate microglia and inhibit the recruitment of T cells and macrophages into the CNS, there is controversy regarding which of the two estrogen receptors (ERs), ERα or ERβ, mediates the beneficial effects in microglia. In this study, we found that ERβ, but not ERα, is expressed in microglia. Using the experimental autoimmune encephalomyelitis (EAE) model in SJL/J mice, we evaluated the benefit of an ERβ agonist as a modulator of neuroinflammation. Treatment of EAE mice with LY3201, a selective ERβ agonist provided by Eli Lilly, resulted in marked reduction of activated microglia in the spinal cord. LY3201 down-regulated the nuclear transcription factor NF - κB, as well as the NF-κB–induced gene inducible nitric oxide synthase in microglia and CD3 + T cells. In addition, LY3201 inhibited T-cell reactivity through regulation of indoleamine-2,3-dioxygenase. In the EAE model, treatment with LY3201 decreased mortality in the first 2 wk after disease onset, and also reduced the severity of symptoms in mice surviving for 4 wk. Our data show that ERβ-selective agonists, by modulating the immune system in both microglia and T cells, offer promise as a useful class of drugs for treating degenerative diseases of the CNS.

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Estrogen treatment decreases matrix metalloproteinase (MMP)-9 in autoimmune demyelinating disease through estrogen receptor alpha (ERα)

Cited by 73 publications

References 48 publications

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

ERβ-Dependent Direct Suppression of Human and Murine Th17 Cells and Treatment of Established Central Nervous System Autoimmunity by a Neurosteroid

Estriol combined with glatiramer acetate for women with relapsing-remitting multiple sclerosis: a randomised, placebo-controlled, phase 2 trial

Targeting estrogen receptor β in microglia and T cells to treat experimental autoimmune encephalomyelitis

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