LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype
Clinical and Translational Medicine, vol. 14, pp. e70134
Abstract
Abstract 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.
Authors 31
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Consejo Superior de Investigaciones Científicas · Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · Centro de Investigación Biomédica en Red · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Nadia Cobo‐Vuilleumier and Petra I Lorenzo Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
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Universitat Autònoma de Barcelona · Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
Affiliation as printed
Immunology Department Germans Trias i Pujol Research Institute Autonomous University of Barcelona Badalona Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · Centro de Investigación Biomédica en Red · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Nadia Cobo‐Vuilleumier and Petra I Lorenzo Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Université Libre de Bruxelles · Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
ULB Center for Diabetes Research Medical Faculty Université Libre de Bruxelles (ULB) Brussels Belgium
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Consejo Superior de Investigaciones Científicas · Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · Centro de Investigación Biomédica en Red · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Nadia Cobo‐Vuilleumier and Petra I Lorenzo Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Daniel Salas‐Lloret Aachen
Leiden University · Leiden University Medical Center
Affiliation as printed
Cell and Chemical Biology Leiden University Medical Centre Leiden The Netherlands
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Nila K. van Overbeek Aachen
Leiden University · Leiden University Medical Center
Affiliation as printed
Cell and Chemical Biology Leiden University Medical Centre Leiden The Netherlands
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Affiliation as printed
Pompeu Fabra University Barcelona Spain
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Hospital Universitario Virgen Macarena
Affiliation as printed
Department of Endocrinology and Nutrition University Hospital Virgen Macarena Sevilla Spain
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Affiliation as printed
ULB Center for Diabetes Research Medical Faculty Université Libre de Bruxelles (ULB) Brussels Belgium
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Affiliation as printed
Diabetes Research Institute IRCCS Ospedale San Raffaele Milan Italy
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Universidad de Cádiz · Biomedical Research and Innovation Institute of Cadiz · Hospital Universitario Puerta del Mar
Affiliation as printed
Department of Endocrinology and Nutrition University Hospital Puerta del Mar, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA). University of Cádiz (UCA) Cádiz Spain
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Alfred C.O. Vertegaal Aachen
Leiden University · Leiden University Medical Center
Affiliation as printed
Cell and Chemical Biology Leiden University Medical Centre Leiden The Netherlands
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
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Consejo Superior de Investigaciones Científicas · Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · Centro de Investigación Biomédica en Red · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Nadia Cobo‐Vuilleumier and Petra I Lorenzo Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
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Universidad de Cádiz · Biomedical Research and Innovation Institute of Cadiz · Hospital Universitario Puerta del Mar
Affiliation as printed
Department of Endocrinology and Nutrition University Hospital Puerta del Mar, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA). University of Cádiz (UCA) Cádiz Spain
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Affiliation as printed
Diabetes Research Institute IRCCS Ospedale San Raffaele Milan Italy
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Affiliation as printed
Pompeu Fabra University Barcelona Spain
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Consejo Superior de Investigaciones Científicas · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Department of Cell Biology Faculty of Biology University of Sevilla Sevilla Spain
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Affiliation as printed
Biobank of the Andalusian Public Health System Node Hospital Virgen Macarena Sevilla Spain
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Affiliation as printed
ULB Center for Diabetes Research Medical Faculty Université Libre de Bruxelles (ULB) Brussels Belgium
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Universidad de Cádiz · Biomedical Research and Innovation Institute of Cadiz · Hospital Universitario Puerta del Mar
Affiliation as printed
Department of Endocrinology and Nutrition University Hospital Puerta del Mar, Institute of Research and Innovation in Biomedical Sciences of Cádiz (INiBICA). University of Cádiz (UCA) Cádiz Spain
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Universitat Autònoma de Barcelona · Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol
Affiliation as printed
Immunology Department Germans Trias i Pujol Research Institute Autonomous University of Barcelona Badalona Spain
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Benoit R. Gauthier corresponding
Consejo Superior de Investigaciones Científicas · Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas · Centro de Investigación Biomédica en Red · Centro Andaluz de Biología Molecular y Medicina Regenerativa · Universidad de Sevilla · Universidad Pablo de Olavide
Affiliation as printed
Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville Spain
Nadia Cobo‐Vuilleumier and Petra I Lorenzo Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM) Madrid Spain
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