Nadia Cobo-Vuilleumier, Silvia Rodríguez-Fernandez, Livia López-Noriega, Petra I. Lorenzo, Jaime M. Franco, Christian C. Lachaud, Eugenia Martin Vazquez, Raquel Araujo Legido, Akaitz Dorronsoro, Raul López-Férnandez-Sobrino, Beatriz Fernández-Santos, Carmen Espejo Serrano, Daniel Salas-Lloret, Nila van Overbeek, Mireia Ramos-Rodriguez, Carmen Mateo-Rodríguez, Lucia Hidalgo, Sandra Marin-Canas, Rita Nano, Ana I. Arroba, Antonio Campos Caro, Alfred CO Vertegaal, Alejandro Martin Montalvo, Franz Martín, Manuel Aguilar-Diosdado, Lorenzo Piemonti, Lorenzo Pasquali, Roman González Prieto, Maria Isabel García Sánchez, Decio L. Eizirik, Maria Asuncion Martínez-Brocca, Marta Vives-Pi, Benoit R. Gauthier
{"title":"LRH-1/NR5A2靶向线粒体动力学，将1型糖尿病巨噬细胞和树突状细胞重编程为免疫耐受表型。","authors":"Nadia Cobo-Vuilleumier, Silvia Rodríguez-Fernandez, Livia López-Noriega, Petra I. Lorenzo, Jaime M. Franco, Christian C. Lachaud, Eugenia Martin Vazquez, Raquel Araujo Legido, Akaitz Dorronsoro, Raul López-Férnandez-Sobrino, Beatriz Fernández-Santos, Carmen Espejo Serrano, Daniel Salas-Lloret, Nila van Overbeek, Mireia Ramos-Rodriguez, Carmen Mateo-Rodríguez, Lucia Hidalgo, Sandra Marin-Canas, Rita Nano, Ana I. Arroba, Antonio Campos Caro, Alfred CO Vertegaal, Alejandro Martin Montalvo, Franz Martín, Manuel Aguilar-Diosdado, Lorenzo Piemonti, Lorenzo Pasquali, Roman González Prieto, Maria Isabel García Sánchez, Decio L. Eizirik, Maria Asuncion Martínez-Brocca, Marta Vives-Pi, Benoit R. Gauthier","doi":"10.1002/ctm2.70134","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Background</h3>\n \n <p>The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell proliferation. BL001 treatment also increased CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup> regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. Additionally, BL001 alleviated PBMC-induced apoptosis and maintained insulin expression in human iPSC-derived islet organoids.</p>\n </section>\n \n <section>\n \n <h3> Conclusion</h3>\n \n <p>These findings demonstrate the potential of LRH-1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.</p>\n </section>\n \n <section>\n \n <h3> Key Points</h3>\n \n <div>\n <ul>\n \n <li>\n <p>LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release.</p>\n </li>\n \n <li>\n <p>LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages.</p>\n </li>\n \n <li>\n <p>Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover.</p>\n </li>\n \n <li>\n <p>LRH-1/NR5A2 agonistic activation expands a CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup> T-cell subpopulation.</p>\n </li>\n \n <li>\n <p>Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D.</p>\n </li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":10189,"journal":{"name":"Clinical and Translational Medicine","volume":"14 12","pages":""},"PeriodicalIF":7.9000,"publicationDate":"2024-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ctm2.70134","citationCount":"0","resultStr":"{\"title\":\"LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype\",\"authors\":\"Nadia Cobo-Vuilleumier, Silvia Rodríguez-Fernandez, Livia López-Noriega, Petra I. Lorenzo, Jaime M. Franco, Christian C. Lachaud, Eugenia Martin Vazquez, Raquel Araujo Legido, Akaitz Dorronsoro, Raul López-Férnandez-Sobrino, Beatriz Fernández-Santos, Carmen Espejo Serrano, Daniel Salas-Lloret, Nila van Overbeek, Mireia Ramos-Rodriguez, Carmen Mateo-Rodríguez, Lucia Hidalgo, Sandra Marin-Canas, Rita Nano, Ana I. Arroba, Antonio Campos Caro, Alfred CO Vertegaal, Alejandro Martin Montalvo, Franz Martín, Manuel Aguilar-Diosdado, Lorenzo Piemonti, Lorenzo Pasquali, Roman González Prieto, Maria Isabel García Sánchez, Decio L. Eizirik, Maria Asuncion Martínez-Brocca, Marta Vives-Pi, Benoit R. Gauthier\",\"doi\":\"10.1002/ctm2.70134\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Background</h3>\\n \\n <p>The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4<sup>+</sup> and CD8<sup>+</sup> T-cell proliferation. BL001 treatment also increased CD4<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup> regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. 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LRH-1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype
Background
The complex aetiology of type 1 diabetes (T1D), characterised by a detrimental cross-talk between the immune system and insulin-producing beta cells, has hindered the development of effective disease-modifying therapies. The discovery that the pharmacological activation of LRH-1/NR5A2 can reverse hyperglycaemia in mouse models of T1D by attenuating the autoimmune attack coupled to beta cell survival/regeneration prompted us to investigate whether immune tolerisation could be translated to individuals with T1D by LRH-1/NR5A2 activation and improve islet survival.
Methods
Peripheral blood mononuclear cells (PBMCs) were isolated from individuals with and without T1D and derived into various immune cells, including macrophages and dendritic cells. Cell subpopulations were then treated or not with BL001, a pharmacological agonist of LRH-1/NR5A2, and processed for: (1) Cell surface marker profiling, (2) cytokine secretome profiling, (3) autologous T-cell proliferation, (4) RNAseq and (5) proteomic analysis. BL001-target gene expression levels were confirmed by quantitative PCR. Mitochondrial function was evaluated through the measurement of oxygen consumption rate using a Seahorse XF analyser. Co-cultures of PBMCs and iPSCs-derived islet organoids were performed to assess the impact of BL001 on beta cell viability.
Results
LRH-1/NR5A2 activation induced a genetic and immunometabolic reprogramming of T1D immune cells, marked by reduced pro-inflammatory markers and cytokine secretion, along with enhanced mitohormesis in pro-inflammatory M1 macrophages and mitochondrial turnover in mature dendritic cells. These changes induced a shift from a pro-inflammatory to an anti-inflammatory/tolerogenic state, resulting in the inhibition of CD4+ and CD8+ T-cell proliferation. BL001 treatment also increased CD4+/CD25+/FoxP3+ regulatory T-cells and Th2 cells within PBMCs while decreasing CD8+ T-cell proliferation. Additionally, BL001 alleviated PBMC-induced apoptosis and maintained insulin expression in human iPSC-derived islet organoids.
Conclusion
These findings demonstrate the potential of LRH-1/NR5A2 activation to modulate immune responses and support beta cell viability in T1D, suggesting a new therapeutic approach.
Key Points
LRH-1/NR5A2 activation in inflammatory cells of individuals with type 1 diabetes (T1D) reduces pro-inflammatory cell surface markers and cytokine release.
LRH-1/NR5A2 promotes a mitohormesis-induced immuno-resistant phenotype to pro-inflammatory macrophages.
Mature dendritic cells acquire a tolerogenic phenotype via LRH-1/NR5A2-stimulated mitochondria turnover.
LRH-1/NR5A2 agonistic activation expands a CD4+/CD25+/FoxP3+ T-cell subpopulation.
Pharmacological activation of LRH-1/NR5A2 improves the survival iPSC-islets-like organoids co-cultured with PBMCs from individuals with T1D.
期刊介绍：
Clinical and Translational Medicine (CTM) is an international, peer-reviewed, open-access journal dedicated to accelerating the translation of preclinical research into clinical applications and fostering communication between basic and clinical scientists. It highlights the clinical potential and application of various fields including biotechnologies, biomaterials, bioengineering, biomarkers, molecular medicine, omics science, bioinformatics, immunology, molecular imaging, drug discovery, regulation, and health policy. With a focus on the bench-to-bedside approach, CTM prioritizes studies and clinical observations that generate hypotheses relevant to patients and diseases, guiding investigations in cellular and molecular medicine. The journal encourages submissions from clinicians, researchers, policymakers, and industry professionals.
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