LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype
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/...
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2024-12-01
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| author | 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 vanOverbeek Mireia Ramos‐Rodriguez Carmen Mateo‐Rodríguez Lucia Hidalgo Sandra Marin‐Canas Rita Nano Ana I. Arroba Antonio Campos Caro Alfred CO Vertegaal Alejandro Martín‐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 |
| author_facet | 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 vanOverbeek Mireia Ramos‐Rodriguez Carmen Mateo‐Rodríguez Lucia Hidalgo Sandra Marin‐Canas Rita Nano Ana I. Arroba Antonio Campos Caro Alfred CO Vertegaal Alejandro Martín‐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 |
| author_sort | Nadia Cobo‐Vuilleumier |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-c5769c438c404765859eb6683cbbb639 |
| institution | Kabale University |
| issn | 2001-1326 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
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| series | Clinical and Translational Medicine |
| spelling | doaj-art-c5769c438c404765859eb6683cbbb6392025-01-30T03:56:55ZengWileyClinical and Translational Medicine2001-13262024-12-011412n/an/a10.1002/ctm2.70134LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotypeNadia Cobo‐Vuilleumier0Silvia Rodríguez‐Fernandez1Livia López‐Noriega2Petra I. Lorenzo3Jaime M. Franco4Christian C. Lachaud5Eugenia Martin Vazquez6Raquel Araujo Legido7Akaitz Dorronsoro8Raul López‐Férnandez‐Sobrino9Beatriz Fernández‐Santos10Carmen Espejo Serrano11Daniel Salas‐Lloret12Nila vanOverbeek13Mireia Ramos‐Rodriguez14Carmen Mateo‐Rodríguez15Lucia Hidalgo16Sandra Marin‐Canas17Rita Nano18Ana I. Arroba19Antonio Campos Caro20Alfred CO Vertegaal21Alejandro Martín‐Montalvo22Franz Martín23Manuel Aguilar‐Diosdado24Lorenzo Piemonti25Lorenzo Pasquali26Roman González Prieto27Maria Isabel García Sánchez28Decio L. Eizirik29Maria Asuncion Martínez‐Brocca30Marta Vives‐Pi31Benoit R. Gauthier32Andalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainImmunology Department Germans Trias i Pujol Research Institute Autonomous University of Barcelona Badalona SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainCell and Chemical Biology Leiden University Medical Centre Leiden The NetherlandsCell and Chemical Biology Leiden University Medical Centre Leiden The NetherlandsPompeu Fabra University Barcelona SpainDepartment of Endocrinology and Nutrition University Hospital Virgen Macarena Sevilla SpainDepartment of Endocrinology and Nutrition University Hospital Virgen Macarena Sevilla SpainULB Center for Diabetes Research Medical Faculty Université Libre de Bruxelles (ULB) Brussels BelgiumDiabetes Research Institute IRCCS Ospedale San Raffaele Milan ItalyDepartment 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 SpainDepartment 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 SpainCell and Chemical Biology Leiden University Medical Centre Leiden The NetherlandsAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainDepartment 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 SpainDiabetes Research Institute IRCCS Ospedale San Raffaele Milan ItalyPompeu Fabra University Barcelona SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainBiobank of the Andalusian Public Health System Node Hospital Virgen Macarena Sevilla SpainULB Center for Diabetes Research Medical Faculty Université Libre de Bruxelles (ULB) Brussels BelgiumDepartment 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 SpainImmunology Department Germans Trias i Pujol Research Institute Autonomous University of Barcelona Badalona SpainAndalusian Center of Molecular Biology and Regenerative Medicine‐CABIMER Junta de Andalucía‐University of Pablo de Olavide‐University of Seville‐CSIC Seville SpainAbstract 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.https://doi.org/10.1002/ctm2.70134autoimmune diseasesdrug developmentimmune tolerancepancreatic islets |
| spellingShingle | 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 vanOverbeek Mireia Ramos‐Rodriguez Carmen Mateo‐Rodríguez Lucia Hidalgo Sandra Marin‐Canas Rita Nano Ana I. Arroba Antonio Campos Caro Alfred CO Vertegaal Alejandro Martín‐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 LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype Clinical and Translational Medicine autoimmune diseases drug development immune tolerance pancreatic islets |
| title | LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| title_full | LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| title_fullStr | LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| title_full_unstemmed | LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| title_short | LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| title_sort | lrh 1 nr5a2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype |
| topic | autoimmune diseases drug development immune tolerance pancreatic islets |
| url | https://doi.org/10.1002/ctm2.70134 |
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