Pharmacological activation of LRH-1/NR5A2 triggers an anti-inflammatory phenotypic switch in immune cells from individuals with type 1 diabetes and improves human islet engraftment/function
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PROVIDER: PRJEB65863 | 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 -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 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 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:LRH-1/NR5A2 for the treatment of autoimmune diseases
| PRJNA412364 | ENA
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:Nr5a2 (also known as liver receptor homolog-1, Lrh-1) has been shown to bind both the proximal enhancer and proximal promoter regions of Pou5f1 and regulate Pou5f1 in the epiblast stage of mouse embryonic development (Gu et al., 2005). Nr5a2-null embryos display a loss of Oct4 expression in the epiblasts (Gu et al., 2005) and die between E6.5 and E7.5 (Gu et al., 2005; Pare et al., 2004). To identify the targets of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2 for ChIP-seq analysis. Keywords: Transcription factor binding sites To identify the binding sites of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2.
2010-01-22 | E-GEOD-19019 | biostudies-arrayexpress
Project description:The intricate etiology of type 1 diabetes mellitus (T1D), characterized by harmful interactions between the immune system and insulin-producing beta cells, has hindered the development of effective therapies including human islet transplantation, which requires strong immunosuppressants that impair beta cell survival and function. As such alternative immunomodulating therapies are required for successful transplantation. The discovery that pharmacological activation of the nuclear receptor LRH-1/NR5A2 can reverse hyperglycemia in mouse models of T1D by altering, and not suppressing the autoimmune attack, prompted us to investigate whether LRH-1/NR5A2 activation could improve human islet function/survival after xenotransplantation in immunocompetent mice. Human islets were transplanted under the kidney capsule of streptozotocin (STZ)-induced diabetic mice, and treatment with BL001 (LRH-1/NR5A2 agonist) or vehicle was administered one week post-transplant. Our study, encompassing 3 independent experiments with 3 different islet donors, revealed that mice treated for 8 weeks with BL001 exhibited lower blood glucose levels correlating with improved mouse survival rates as compared to vehicle-treated controls. Human C-peptide was detectable in BL001-treated mice at both 4 and 8 weeks indicating functional islet beta cells. Accordingly, in mice treated with BL001 for 8 weeks, the beta cell mass was preserved, while a significant decrease in alpha cells was observed compared to mice treated with BL001 for only 4 weeks. In contrast, vehicle-treated mice exhibited a reduction in insulin-expressing cells at 8 weeks compared to those at 4 weeks. These results suggest that BL001 significantly enhances the survival, engraftment, and functionality of human islets in a STZ-induced diabetic mouse model.
| S-EPMC11466778 | biostudies-literature
Project description:Nr5a2 (also known as liver receptor homolog-1, Lrh-1) has been shown to bind both the proximal enhancer and proximal promoter regions of Pou5f1 and regulate Pou5f1 in the epiblast stage of mouse embryonic development (Gu et al., 2005). Nr5a2-null embryos display a loss of Oct4 expression in the epiblasts (Gu et al., 2005) and die between E6.5 and E7.5 (Gu et al., 2005; Pare et al., 2004). To identify the targets of Nr5a2, we generated a stable ES cell-line that expresses HA-tagged Nr5a2. Anti-HA antibody was used to immunoprecipitate HA-Nr5a2 for ChIP-seq analysis. Keywords: Transcription factor binding sites
2010-01-22 | GSE19019 | GEO
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