LRH‐1/NR5A2 targets mitochondrial dynamics to reprogram type 1 diabetes macrophages and dendritic cells into an immune tolerance phenotype
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<sup>+</sup>/CD25<sup>+</sup>/FoxP3<sup>+</sup> 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
- Beatriz Fernández‐Santos (ORCID: https://orcid.org/0000-0002-1447-8115)
- Daniel Salas‐Lloret (ORCID: https://orcid.org/0000-0001-7336-2887)
- Lorenzo Piemonti (ORCID: https://orcid.org/0000-0002-2172-2198)
- Akaitz Dorronsoro (ORCID: https://orcid.org/0000-0001-6141-8484)
- Alejandro Martín Montalvo
- Silvia Rodríguez-Fernández (ORCID: https://orcid.org/0000-0001-8429-4293)
- Marta Vives‐Pi (ORCID: https://orcid.org/0000-0003-3735-0779)
- Mireia Ramos-Rodríguez (ORCID: https://orcid.org/0000-0001-8083-2445)
- Sandra Marín‐Cañas (ORCID: https://orcid.org/0000-0003-3612-5908)
- Eugenia Martin Vázquez
- Raquel Araujo Legido (ORCID: https://orcid.org/0000-0003-3333-8086)
- María Isabel García Sánchez
- Ana I. Arroba (ORCID: https://orcid.org/0000-0002-5136-1725)
- Román González‐Prieto (ORCID: https://orcid.org/0000-0001-8997-2321)
- Petra I. Lorenzo
- Antônio Carlos Ligocki Campos (ORCID: https://orcid.org/0000-0001-5080-8380)
- Alfred C.O. Vertegaal (ORCID: https://orcid.org/0000-0002-7989-0493)
- Livia López–Noriega (ORCID: https://orcid.org/0000-0002-2905-9490)
- Christian Claude Lachaud (ORCID: https://orcid.org/0000-0001-8698-4589)
- Décio L. Eizirik (ORCID: https://orcid.org/0000-0003-2453-5889)
- Benoit R. Gauthier (ORCID: https://orcid.org/0000-0001-8146-7486)
- Carmen Espejo Serrano
- Luis Hidalgo (ORCID: https://orcid.org/0000-0002-9959-0658)
- Maria Asuncion Martínez‐Brocca
- Rita Nano
- Nadia Cobo‐Vuilleumier (ORCID: https://orcid.org/0000-0002-8164-3416)
- Lorenzo Pasquali (ORCID: https://orcid.org/0000-0003-2423-1826)
- Franz Martı́n (ORCID: https://orcid.org/0000-0002-5745-8704)
- Nila van Overbeek (ORCID: https://orcid.org/0000-0002-0431-3595)
- Manuel Aguilar‐Diosdado (ORCID: https://orcid.org/0000-0001-9657-5949)
- Raúl López‐Fernández‐Sobrino (ORCID: https://orcid.org/0000-0002-2418-2123)
- Jaime M. Franco (ORCID: https://orcid.org/0000-0002-4227-9391)
- Carmen Mateo‐Rodríguez
Institutions
- Universitat Autònoma de Barcelona (ES)
- Université Libre de Bruxelles (BE)
- Universitat Pompeu Fabra (ES)
- Leiden University Medical Center (NL)
- Universidad de Cádiz (ES)
- Hospital Universitario Virgen Macarena (ES)
- Centro de Investigación Biomédica en Red Diabetes y Enfermedades Metabólicas Asociadas (ES)
- Biomedical Research and Innovation Institute of Cadiz (ES)
- IRCCS Ospedale San Raffaele (IT)
- Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES)
- Centro Andaluz de Biología Molecular y Medicina Regenerativa (ES)
- Universidad de Sevilla (ES)
- Junta de Andalucía (ES)
- Universidad Pablo de Olavide (ES)
Publication Details
- Journal
- Clinical and Translational Medicine
- Published
- 2024-12-01
- DOI
- https://doi.org/10.1002/ctm2.70134
- Citations
- 8
- Primary Topic
- Diabetes and associated disorders
- Type
- article
- Field-Weighted Citation Impact
- 4.40
Funders
- Human Islet Research Network
- Ministerio de Ciencia e Innovación
- National Institutes of Health
- Agencia Estatal de Investigación
- National Institute of Diabetes and Digestive and Kidney Diseases