LRH-1/NR5A2 targets mitochondrial dynamics to reprogramtype 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype

Nadia Cobo-Vuilleumier; Silvia Rodríguez-Fernandez; Livia López-Noriega; Petra I. Lorenzo; Jaime M. Franco; Christian C. Lachaud; EugeniaMartin 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 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

doi:10.1002/ctm2.70134

Clinical and Translational Medicine ›› 2024, Vol. 14 ›› Issue (12) : e70134 DOI: 10.1002/ctm2.70134

RESEARCH ARTICLE

LRH-1/NR5A2 targets mitochondrial dynamics to reprogramtype 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype

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¹. Andalusian Center of Molecular Biology and Regenerative Medicine-CABIMER, Junta de Andalucía-University of Pablo de Olavide-University of Seville-CSIC, Seville, Spain

². Nadia Cobo-Vuilleumier and Petra I Lorenzo, Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain

³. Immunology Department, Germans Trias i Pujol Research Institute, Autonomous University of Barcelona, Badalona, Spain

⁴. ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), Brussels, Belgium

⁵. Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands

⁶. Pompeu Fabra University, Barcelona, Spain

⁷. Department of Endocrinology and Nutrition, University Hospital Virgen Macarena, Sevilla, Spain

⁸. Diabetes Research Institute, IRCCS Ospedale San Raffaele, Milan, Italy

⁹. 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

¹⁰. Department of Cell Biology, Faculty of Biology, University of Sevilla, Sevilla, Spain

¹¹. Biobank of the Andalusian Public Health System, Node Hospital Virgen Macarena, Sevilla, Spain

benoit.gauthier@cabimer.es

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Abstract

	•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.

Keywords

autoimmune diseases / drug development / immune tolerance / pancreatic islets

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Nadia Cobo-Vuilleumier,Silvia Rodríguez-Fernandez,Livia López-Noriega,Petra I. Lorenzo,Jaime M. Franco,Christian C. Lachaud,EugeniaMartin 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 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 reprogramtype 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype. Clinical and Translational Medicine, 2024, 14(12): e70134 DOI:10.1002/ctm2.70134

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2024 The Author(s). Clinical and Translational Medicine published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.