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Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice

ABSTRACT: Estrogen is a disease-modifying factor in multiple sclerosis (MS), and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNβ), a first-line MS treatment. Estrogen synthesized by extra-gonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNβ components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT- lymphotoxin beta receptor (LTβR) signaling. LTβR antagonist abolished EAE disease symptoms in the DC-specific ERα deficient mice. These findings indicate that estrogen derived from extra-gonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.

SUBMITTER: Ms. Yee Ming Khaw

PROVIDER: S-SCDT-10_15252-EMBR_202154228 | biostudies-other |

REPOSITORIES: biostudies-other

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Estrogen receptor alpha signaling in dendritic cells modulates autoimmune disease phenotype in mice.

Project description:Estrogen is a disease-modifying factor in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) via estrogen receptor alpha (ERα). However, the mechanisms by which ERα signaling contributes to changes in disease pathogenesis have not been completely elucidated. Here, we demonstrate that ERα deletion in dendritic cells (DCs) of mice induces severe neurodegeneration in the central nervous system in a mouse EAE model and resistance to interferon beta (IFNβ), a first-line MS treatment. Estrogen synthesized by extragonadal sources is crucial for controlling disease phenotypes. Mechanistically, activated ERα directly interacts with TRAF3, a TLR4 downstream signaling molecule, to degrade TRAF3 via ubiquitination, resulting in reduced IRF3 nuclear translocation and transcription of membrane lymphotoxin (mLT) and IFNβ components. Diminished ERα signaling in DCs generates neurotoxic effector CD4+ T cells via mLT-lymphotoxin beta receptor (LTβR) signaling. Lymphotoxin beta receptor antagonist abolished EAE disease symptoms in the DC-specific ERα-deficient mice. These findings indicate that estrogen derived from extragonadal sources, such as lymph nodes, controls TRAF3-mediated cytokine production in DCs to modulate the EAE disease phenotype.

| S-EPMC9986829 | biostudies-literature

Estrogen receptor-? ligand treatment modulates dendritic cells in the target organ during autoimmune demyelinating disease.

Project description:Estrogens act upon nuclear estrogen receptors (ER) to ameliorate cell-mediated autoimmune disease. As most immunomodulatory effects of estrogens in EAE have been attributed to the function of ER-?, we previously demonstrated that ER-? ligand treatment reduced disease severity without affecting peripheral cytokine production or levels of CNS inflammation, suggesting a direct neuroprotective effect; however, the effect of ER-? treatment on the function of immune cells within the target organ remained unknown. Here, we used adoptive transfer studies to show that ER-? ligand treatment was protective in the effector, but not the induction phase of EAE, as shown by decreased clinical disease severity with the preservation of axons and myelin in spinal cords. The analysis of the immune cell infiltrates in the CNS revealed that while ER-? ligand treatment did not reduce overall levels of CNS inflammation, there was a decrease in the DC percentage, and these CNS DC had decreased TNF-? production. Finally, experiments using DC deficient in ER-? revealed that the expression of ER-? on DC was essential for protective effects of ER-? ligand treatment in EAE. Our results demonstrate for the first time an effect of ER-? ligand treatment in vivo on DC in the target organ of a prototypic cell-mediated autoimmune disease.

| S-EPMC3042725 | biostudies-literature

Effect of estrogen receptor alpha (ERα) signaling in dendritic cells in modulating autoimmune disease phenotype in animal model of Multiple Sclerosis

Project description:ERα has been shown to have a protective effect.We found that ERα deficiency in dendritic cells (DCs) of mice induced a phenotype “switch” in EAE, defined by severe neurodegeneration and resistance to interferon beta. Diminished ERα signaling in DCs generate neurotoxic effector CD4+ T cells.

2023-02-21 | GSE215238 | GEO

Effect of estrogen receptor alpha (ERα) signaling in dendritic cells in modulating autoimmune disease phenotype in animal model of Multiple Sclerosis

Project description:Effect of estrogen receptor alpha (ERα) signaling in dendritic cells in modulating autoimmune disease phenotype in animal model of Multiple Sclerosis

| PRJNA889404 | ENA

Estrogen Receptor ? Deficiency Modulates TLR Ligand-Mediated PDC-TREM Expression in Plasmacytoid Dendritic Cells in Lupus-Prone Mice.

Project description:Female lupus-prone NZM2410 estrogen receptor ? (ER?)-deficient mice are protected from renal disease and have prolonged survival compared with wild-type littermates; however, the mechanism of protection is unknown. Plasmacytoid dendritic cells (pDCs) and type I IFN drive lupus pathogenesis. Estrogen acting via ER? enhances both pDC development and IFN production. The objectives for this study were to determine if ER? modulates pDC function and IFN activity in predisease NZM2410 mice as a possible protective mechanism of ER? deficiency in lupus-prone mice. We measured the effect of ER? deficiency on spleen pDC frequency, number, maturation, and activation state. ER? deficiency reduced type I IFN activity and the frequency of MHC class II(+) pDCs in the spleen without altering overall pDC frequency, number, or maturation state. Additionally, ER?-deficient NZM2410 mice had a significantly decreased frequency of pDCs expressing PDC-TREM, a modulator of TLR-mediated IFN production. After in vitro TLR9 stimulation, ER? deficiency significantly reduced the expression of PDC-TREM on pDCs from both NZM2410 and C57BL/6 mice. Thus, we have identified a significant effect of ER? deficiency on pDCs in predisease NZM2410 mice, which may represent a mechanism by which ER? deficiency protects NZM2410 mice from lupuslike disease.

| S-EPMC4790076 | biostudies-literature

Estrogen/estrogen receptor alpha signaling in mouse posterofrontal cranial suture fusion.

Project description:BackgroundWhile premature suture fusion, or craniosynostosis, is a relatively common condition, the cause is often unknown. Estrogens are associated with growth plate fusion of endochondral bones. In the following study, we explore the previously unknown significance of estrogen/estrogen receptor signaling in cranial suture biology.Methodology/principal findingsFirstly, estrogen receptor (ER) expression was examined in physiologically fusing (posterofrontal) and patent (sagittal) mouse cranial sutures by quantitative RT-PCR. Next, the cranial suture phenotype of ER alpha and ER beta knockout (alphaERKO, betaERKO) mice was studied. Subsequently, mouse suture-derived mesenchymal cells (SMCs) were isolated; the effects of 17-beta estradiol or the estrogen antagonist Fulvestrant on gene expression, osteogenic and chondrogenic differentiation were examined in vitro. Finally, in vivo experiments were performed in which Fulvestrant was administered subcutaneously to the mouse calvaria. Results showed that increased ERalpha but not ERbeta transcript abundance temporally coincided with posterofrontal suture fusion. The alphaERKO but not betaERKO mouse exhibited delayed posterofrontal suture fusion. In vitro, addition of 17-beta estradiol enhanced both osteogenic and chondrogenic differentiation in suture-derived mesenchymal cells, effects reversible by Fulvestrant. Finally, in vivo application of Fulvestrant significantly diminished calvarial osteogenesis, inhibiting suture fusion.Conclusions/significanceEstrogen signaling through ERalpha but not ERbeta is associated with and necessary for normal mouse posterofrontal suture fusion. In vitro studies suggest that estrogens may play a role in osteoblast and/or chondrocyte differentiation within the cranial suture complex.

| S-EPMC2743190 | biostudies-literature

Estrogen receptor ß activity modulates synaptic signaling and structure.

Project description:Brain-synthesized estrogen has been shown to influence synaptic structure, function, and cognitive processes. However, the molecular mechanisms underlying the rapid effects of estrogen on the dendritic spines of cortical neurons are not clear. Estrogen receptor ? (ER?) is expressed in cortical neurons, and ER? knock-out mice display impaired performance in cortically mediated processes, suggesting that signaling via this receptor has profound effects on cortical neuron function. However, the effect of rapid signaling via ER? on dendritic spines and the signaling pathways initiated by this receptor in cortical neurons are unknown. Here, we show that activation of ER? with the specific agonist WAY-200070 results in increased spine density and PSD-95 (postsynaptic density-95) accumulation in membrane regions. Activation of ER? by WAY-200070 also resulted in the phosphorylation of p21-activated kinase (PAK) and extracellular signal-regulated kinase 1/2 (ERK1/2) in cultured cortical neurons, suggesting a mechanism for the regulation of the actin cytoskeleton. Moreover, we found that aromatase, an enzyme critical for estrogen production, is present at presynaptic termini, supporting a role for brain-synthesized estrogen as a neuromodulator in the cortex. These results implicate ER? signaling in controlling dendritic spine morphology, in part via a PAK/ERK1/2-dependent pathway, and provide mechanistic insight into the rapid cellular effects of estrogen on brain function.

| S-EPMC2956485 | biostudies-literature

Project description:Metabolic modifications of tumor cells are hallmarks of cancer. They exhibit an altered metabolism that allows them to sustain higher proliferation rates in hostile environment outside the cell. In thyroid tumors, the expression of the estrogen-related receptor ? (ERR?), a major factor of metabolic adaptation, is closely related to the oxidative metabolism and the proliferative status of the cells. To elucidate the role played by ERR? in the glycolytic adaptation of tumor cells, we focused on the regulation of lactate dehydrogenases A and B (LDHA, LDHB) and the LDHA/LDHB ratio. Our study included tissue samples from 10 classical and 10 oncocytic variants of follicular thyroid tumors and 10 normal thyroid tissues, as well as samples from three human thyroid tumor cell lines: FTC-133, XTC.UC1 and RO82W-1. We identified multiple cis-acting promoter elements for ERR?, in both the LDHA and LDHB genes. The interaction between ERR? and LDH promoters was confirmed by chromatin immunoprecipitation assays and in vitro analysis for LDHB. Using knock-in and knock-out cellular models, we found an inverse correlation between ERR? expression and LDH activity. This suggests that thyroid tumor cells may reprogram their metabolic pathways through the up-regulation of ERR? by a process distinct from that proposed by the recently revisited Warburg hypothesis.

| S-EPMC3596295 | biostudies-literature

Developmental phenotype of a membrane only estrogen receptor alpha (MOER) mouse.

Project description:Estrogen receptors (ERs) alpha and beta exist as nuclear, cytoplasmic, and membrane cellular pools in a wide variety of organs. The relative contributions of each ERalpha pool to in vivo phenotypes resulting from estrogen signaling have not been determined. To address this, we generated a transgenic mouse expressing only a functional E domain of ERalpha at the plasma membrane (MOER). Cells isolated from many organs showed membrane only localized E domain of ERalpha and no other receptor pools. Liver cells from MOER and wild type mice responded to 17-beta-estradiol (E2) with comparable activation of ERK and phosphatidylinositol 3-kinase, not seen in cells from ERalphaKO mice. Mating the MOER female mice with proven male wild type breeders produced no pregnancies because the uterus and vagina of the MOER female mice were extremely atrophic. Ovaries of MOER and homozygous Strasbourg ERalphaKO mice showed multiple hemorrhagic cysts and no corpus luteum, and the mammary gland development in both MOER and ERalphaKO mice was rudimentary. Despite elevated serum E2 levels, serum LH was not suppressed, and prolactin levels were low in MOER mice. MOER and Strasbourg female mice showed plentiful abdominal visceral and other depots of fat and increased body weight compared to wild type mice despite comparable food consumption. These results provide strong evidence that the normal development and adult functions of important organs in female mice requires nuclear ERalpha and is not rescued by membrane ERalpha domain expression alone.

| S-EPMC2635032 | biostudies-literature

Spontaneous airway hyperresponsiveness in estrogen receptor-alpha-deficient mice.

Project description:RationaleAirway hyperresponsiveness is a critical feature of asthma. Substantial epidemiologic evidence supports a role for female sex hormones in modulating lung function and airway hyperresponsiveness in humans.ObjectivesTo examine the role of estrogen receptors in modulating lung function and airway responsiveness using estrogen receptor-deficient mice.MethodsLung function was assessed by a combination of whole-body barometric plethysmography, invasive measurement of airway resistance, and isometric force measurements in isolated bronchial rings. M2 muscarinic receptor expression was assessed by Western blotting, and function was assessed by electrical field stimulation of tracheas in the presence/absence of gallamine. Allergic airway disease was examined after ovalbumin sensitization and exposure.Measurements and main resultsEstrogen receptor-alpha knockout mice exhibit a variety of lung function abnormalities and have enhanced airway responsiveness to inhaled methacholine and serotonin under basal conditions. This is associated with reduced M2 muscarinic receptor expression and function in the lungs. Absence of estrogen receptor-alpha also leads to increased airway responsiveness without increased inflammation after allergen sensitization and challenge.ConclusionsThese data suggest that estrogen receptor-alpha is a critical regulator of airway hyperresponsiveness in mice.

| S-EPMC1899278 | biostudies-literature

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