LRH-1/NR5A2 for the treatment of autoimmune diseases
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ABSTRACT:
PROVIDER: PRJNA412364 | ENA |
REPOSITORIES: ENA
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Project description:The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimental cross talk between immune cells and insulin producing b-cells leading to their destruction has stumped the development of effective disease modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can revert hyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmune attack coupled to b-cell survival/regeneration, prompt us to investigate whether LRH-1/NR5A2-mediated immune tolerization could be achieved in individuals with T1DM and improve islet survival and function subsequent to xenotransplantation. We found that LRH-1/NR5A2 activation using the agonist BL001 blunted the pro-inflammatory genetic signature and cytokine secretome of both monocyte-derived macrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM. Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammation propagation while mitochondria turnover was increased in mDCs assisting transit towards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cells within the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted into hyperglycemic immunocompetent mice was enhanced by BL001 treatment leading to improved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizing phenotype empowering them to repress cytotoxic T-cell proliferation and facilitates islet engraftment and function after transplantation. Our finding demonstrate the feasibility of re-establishing human immune tolerance within a pro-inflammatory environment, rather than suppression, opening an unprecedent pharmacological therapeutic venue for T1DM
2025-04-09 | PXD053517 | Pride
Project description:The intricate aetiology of type 1 diabetes mellitus (T1DM) implicating a detrimental cross talk between immune cells and insulin producing -cells leading to their destruction has stumped the development of effective disease modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can revert hyperglycemia in pre-clinical mouse models of T1DM by attenuating the autoimmune attack coupled to -cell survival/regeneration, prompt us to investigate whether LRH-1/NR5A2-mediated immune tolerization could be achieved in individuals with T1DM and improve islet survival and function subsequent to xenotransplantation. We found that LRH-1/NR5A2 activation using the agonist BL001 blunted the pro-inflammatory genetic signature and cytokine secretome of both monocyte-derived macrophages (MDM1) and mature dendritic cells (mDCs) from individuals with T1DM. Mechanistically, mitohormesis was induced in MDM1 restricting pro-inflammation propagation while mitochondria turnover was increased in mDCs assisting transit towards a tolerogenic phenotype. BL001 treatment also increased T-regulatory cells within the T-cell subpopulation. BL001-treated MDM1, mDCs or T-cells impeded T-effector cell expansion. Engraftment and function of human islets transplanted into hyperglycemic immunocompetent mice was enhanced by BL001 treatment leading to improved glycemia. Collectively, LRH-1/NR5A2 agonism fosters a coordinated re-programming of T1DM immune cells from a pro- to an anti-inflammatory/tolerizing phenotype empowering them to repress cytotoxic T-cell proliferation and facilitates islet engraftment and function after transplantation. Our finding demonstrate the feasibility of re-establishing human immune tolerance within a pro-inflammatory environment, rather than suppression, opening an unprecedent pharmacological therapeutic venue for T1DM.
2025-04-09 | PXD045222 | Pride
Project description:The ovarian reserve of follicles comprises all oocytes for lifetime fertility and is depleted by progressive activation. The orphan nuclear receptor liver receptor homolog 1 (LRH-1; Nr5a2) is essential for ovulation, but its role in the early stages of follicular development is not known. We therefore developed a model of conditional depletion of LRH-1 from early postnatal ovaries (postnatal day 4) and performed RNAsequencing to identify LRH-1 regulated genes during the earliest stages of follicular activation.
2022-10-24 | GSE216392 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-05-01 | GSE104328 | GEO
Project description:We report the gene expression changes in murine small intestinal organoids following deletion of LRH-1 (NR5A2) and humanization by expression of human LRH-1 in mouse LRH-1 knockout organoids.
2018-07-04 | GSE116563 | GEO
Project description:LRH-1/NR5A2 induces M1 to M2 macrophage phenotypic switch
| PRJNA412367 | ENA
Project description:Tumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. Patients with estrogen receptor a(ERa)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). We further characterized these LRH-1 binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1 binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1 depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies.
2014-02-27 | GSE47027 | GEO
Project description:Tumor characteristics are decisive in the determination of treatment strategy for breast cancer patients. Patients with estrogen receptor a(ERa)-positive breast cancer can benefit from long-term hormonal treatment. Nonetheless, the majority of patients will develop resistance to these therapies. Here, we investigated the role of the nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) in anti-estrogen (AE) sensitive and resistant breast cancer cells. We identified genome-wide LRH-1 binding sites using ChIP-seq, uncovering preferential binding to regions distal to transcriptional start sites (TSS). We further characterized these LRH-1 binding sites by integrating overlapping layers of specific chromatin marks, revealing that many LRH-1 binding sites are active and could be involved in long-range enhancer-promoter looping. Combined with transcriptome analysis of LRH-1 depleted cells, these results show that LRH-1 regulates specific subsets of genes involved in cell proliferation in AE-sensitive and AE-resistant breast cancer cells. Furthermore, the LRH-1 transcriptional program is highly associated with a signature of poor outcome and high-grade breast cancer tumors in vivo. Herein we report the genome-wide location and molecular function of LRH-1 in breast cancer cells and reveal its therapeutic potential for the treatment of breast cancers, notably for tumors resistant to treatments currently used in therapies. ChIP-seq examination of LRH-1 binding sites with specific chromatin marks in MCF7 breast cancer cells.
2014-02-27 | E-GEOD-47027 | biostudies-arrayexpress
Project description:Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress. 24 total samples. One sample represents one mouse. Three samples were analyzed from the following groups: Lrh-1 f/f (control littermates) treated with vehicle, Lrh-1 f/f treated with tunicamycin (TM; 1mg/kg BW for 24h), Lrh-1 f/f treated with tunicamycin and DLPC (100mg/kg BW 4x), Lrh-1 f/f treated with tunicamycin and vehicle for DLPC, Lrh-1 liver-specific KO mice (LKO) treated with vehicle, Lrh-1 LKO treated with tunicamycin, and Lrh-1 LKO treated with tunicamycin and DLPC, Lrh-1 LKO treated with tunicamycin and vehicle for DLPC
2015-05-12 | E-GEOD-68718 | biostudies-arrayexpress
Project description:Chronic endoplasmic reticulum (ER) stress results in toxicity that contributes to multiple human disorders. We report a stress resolution pathway initiated by the nuclear receptor LRH-1 that is independent of known unfolded protein response (UPR) pathways. Like mice lacking primary UPR components, hepatic Lrh-1-null mice cannot resolve ER stress, despite a functional UPR. In response to ER stress, LRH-1 induces expression of the kinase Plk3, which phosphorylates and activates the transcription factor ATF2. Plk3-null mice also cannot resolve ER stress, and restoring Plk3 expression in Lrh-1-null cells rescues ER stress resolution. Reduced or heightened ATF2 activity also sensitizes or desensitizes cells to ER stress, respectively. LRH-1 agonist treatment increases ER stress resistance and decreases cell death. We conclude that LRH-1 initiates a novel pathway of ER stress resolution that is independent of the UPR, yet equivalently required. Targeting LRH-1 may be beneficial in human disorders associated with chronic ER stress.
2015-05-12 | GSE68718 | GEO