Effect of estrogen receptor alpha (ERα) signaling in dendritic cells in modulating autoimmune disease phenotype in animal model of Multiple Sclerosis
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE215238 | GEO | 2023/02/21
REPOSITORIES: GEO
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Project description:Innate immune cells are integral to the pathogenesis of several diseases of the central nervous system (CNS), including multiple sclerosis (MS). Dendritic cells (DCs) are potent CD11c+ antigen presenting cells which function as critical regulators of adaptive immune responses, particularly in autoimmune diseases such as MS. The regulation of DC function in both the periphery and CNS compartment has not been fully elucidated. One limitation to studying the role of CD11c+ DCs in the CNS is that microglia have been shown to upregulate CD11c during inflammation, making it challenging to distinguish hematopoietically-derived DCs from microglia. Selective expression of microRNAs (miRNAs) has been shown to distinguish populations of innate cells within the CNS during neuro-inflammation and is proposed as a mechanism for the regulation of innate cell function. Using the experimental autoimmune encephalomyelitis (EAE) murine model of MS, we characterized the expression of miRNAs in CD11c+ cells using a non-biased murine array. Several miRNAs, including miR-31, were enriched in CD11c+ cells within the CNS during EAE, but not LysM+ microglia. Moreover, to distinguish CD11c+ DCs from microglia that upregulate CD11c, we generated bone marrow chimeras and found that miR-31 expression was specific to bone marrow-derived DCs (BMDCs). Interestingly, miR-31 binding sites were enriched in mRNAs downregulated BMDCs that migrated into the CNS. Finally, miR-31 was enriched in DCs that migrated through an in vitro blood-brain barrier. Our findings suggest that miRNAs, including miR-31, may participate in the regulation of DCs entry into the CNS during EAE and could potentially represent therapeutic targets for CNS autoimmune diseases such as MS.
2019-01-31 | GSE111256 | GEO
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
Project description:We have performed transcriptomic analysis in the spinal cord of experimental autoimmune encephalomyelitis (EAE) mice compared to naive mice at different time intervals in order to observe the gene expression changes within the CNS compartment
2017-09-30 | E-MTAB-5225 | biostudies-arrayexpress
Project description:Estrogen and estrogen receptor alpha (ERα) have been implicated in systemic lupus erythematosus (SLE) pathogenesis. ERα signaling influences B cell and dendritic cell (DC) development and function, as well as inflammation and downstream immune responses. We previously reported that ERα modulates TLR-stimulated inflammatory pathways in conventional and plasmacytoid DCs in lupus-prone mice. CD11chiMHCII+ cell numbers are reduced in mice with global ERα deficiency or when expressing a short variant of ERα. RNA-seq analysis in CD11chi cells from bone marrow of NZM2410 mice expressing WT ERα vs. an ERα short (AF-1 mutant) vs. ERα null, revealed differentially expressed complement genes, interferon-related genes and cytokine signaling (e.g., IL-17 and Th17 pathways). Cytokine levels varied among different genotypes, demonstrating the complex nature of ERα regulation. To better understand the role of ERα in CD11c+ cells, lupus prone NZM2410 mice with selective deletion of the Esr1 gene in CD11c+ cells were generated. Phenotype and survival of these mice were similar with the exception of Cre positive (CrePos) female mice. CrePos females, but not males, all died prior to 35 weeks. Surprisingly, DC populations were not significantly different between groups. Since ERα is necessary for optimal development of most DC subsets, this result suggests that DC fate was determined prior to CD11c expression and subsequent ERα deletion (i.e. proximally in DC ontogeny). Overall, findings point to a clear functional role for ERα in regulating cytokine signaling and inflammation, suggesting that further study into ERα-mediated regulatory mechanisms in DCs is warranted.
2022-03-28 | GSE199488 | GEO
Project description:Multiple sclerosis (MS) affects the cerebral cortex, inducing cortical atrophy and neuronal and synaptic pathology. Despite the fact that women are more susceptible to getting MS, men with MS have worse disability progression. Here, we address sex differences in neurodegenerative mechanisms focusing on the cerebral cortex using the MS model, chronic experimental autoimmune encephalomyelitis (EAE). RNA sequencing of neurons in cerebral cortex during EAE showed robust differential gene expression in male EAE mice compared to male healthy, age-matched, control mice. In contrast, there were few differences in female EAE mice compared to female controls. The most enriched differential gene expression pathways in male mice during EAE were mitochondrial dysfunction and oxidative phosphorylation. Mitochondrial morphology showed significant abnormalities in the cerebral cortex of EAE males, but not EAE females. Regarding function, synaptosomes isolated from cerebral cortex of male EAE mice demonstrated decreased oxygen consumption rates during respirometry assays. Together, cortical neuronal transcriptomics, mitochondrial morphology, and functional respirometry assays in synaptosomes revealed worse neurodegeneration in male EAE mice. This is consistent with worse neurodegeneration in MS men and reveals a model and a target to develop treatments to prevent cortical neurodegeneration and mitigate disability progression in MS men.
2023-11-13 | GSE239455 | GEO
Project description:The signal transducer and activator of transcription 4 (STAT4) promotes protective immunity and autoimmunity downstream of pro-inflammatory cytokines including IL-12 and IL-23. In experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), Stat4-/- mice are resistant to the development of inflammation and paralysis. Here, we examined cell-type requirements and found that in addition to T cells, STAT4 is required in dendritic cells for development of EAE. Deficiency of STAT4 in CD11c-expressing cells resulted in decreased T cell priming and inflammation in the CNS. EAE susceptibility was recovered following adoptive transfer of wild type bone marrow-derived DC to mice with STAT4-deficient DCs, but not adoptive transfer of STAT4- or IL-23R-deficient DCs. Single cell RNA-seq identified STAT4-dependent genes in DC subsets that paralleled a signature in MS patient DCs. Together, these data define a novel IL-23/DC/STAT4 pathway in DCs that could be a key to novel therapeutic targets in MS.
2024-07-17 | GSE243202 | GEO
Project description:Disease activity of autoimmune disorders such as multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) is temporarily suppressed by pregnancy. However, whether disease amelioration is due to non-specific immunomodulation or mediated by antigen-specific regulation of disease-causing conventional T cells (Tcon) and immuno- suppressive regulatory T cells (Treg), remains elusive. In the present study, we systematically analyzed changes of the T cell receptor (TCR) β repertoire driven by EAE and pregnancy using TCR sequencing. We demonstrate that EAE, but not pregnancy, robustly increased TCR repertoire clonality in both peripheral Tcon and Treg. Notably, pregnancy was required for the expansion of Treg harboring the dominant EAE-associated TRBV chain 13.2 and increased the frequency of EAE-associated clonotypes within the Treg compartment. Our findings indicate that pregnancy supports the expansion of Treg clonotypes that are equipped to recognize EAE- associated antigens. These Treg are thereby particularly suited to control corresponding encephalitogenic Tcon responses and likely contribute to pregnancy-associated protection in autoimmunity.
2019-07-30 | GSE122894 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186645 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186644 | GEO
Project description:Dysregulated estrogen and estrogen receptor (ER)-induced gene transcription is tightly associated with estrogen receptor alpha (ERα)-positive breast carcinogenesis. ERα-occupied enhancers, particularly super enhancers, have been suggested to play a vital role in such transcriptional events. However, the landscape of ERα-occupied super enhancers (ERSEs) as well as key super enhancer-associated genes remain to be fully characterized. Here, we defined the landscape of ERSEs in MCF7, a ERα-positive breast cancer cell line, and demonstrated that bromodomain protein BRD4 is a master regulator of the transcriptional activation of ERSE and cognate ERα-target genes. Furthermore, RET, a member of the tyrosine protein kinase family of proteins, was identified to be a key target gene of BRD4-regulated ERSEs, which is vital for estrogen/ ERα-induced gene transcriptional activation and malignant phenotypes through activating the Ras-Raf-MEK-ERK-p90RSK-ERα phosphorylation cascade. Accordingly, combination therapy with BRD4 and RET inhibitors exhibited synergistic effects on suppressing ERα-positive breast cancer both in vitro and in vivo. Taken together, our data uncovered the critical role of a super enhancer-associated BRD4/ERα-RET-ERα positive feedback loop in ERα-positive breast cancer, and targeting components in this loop will provide new therapeutic avenue for treating ERα-positive breast cancer in the clinic.
2022-10-19 | GSE186643 | GEO