González-Dominguez, AlvaroMontañez, RaúlCastejón-Vega, BeatrizNuñez-Vasco, JéssicaLendines-Cordero, DéboraWang, ChunMbalaviele, GabrielNavarro-Pando, José M.Alcocer-Gómez, ElísabetCordero, Mario D.2022-11-172022-11-172021-08-27González-Dominguez A, Montañez R, Castejón-Vega B, Nuñez-Vasco J, Lendines-Cordero D, Wang C, et al. Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria. EMBO Mol Med. 2021 Oct 7;13(10):e1401234448355http://hdl.handle.net/10668/4355Inflammation is a hallmark of aging and accelerated aging syndromes such as Hutchinson-Gilford progeria syndrome (HGPS). In this study, we present evidence of increased expression of the components of the NLRP3 inflammasome pathway in HGPS skin fibroblasts, an outcome that was associated with morphological changes of the nuclei of the cells. Lymphoblasts from HGPS patients also showed increased basal levels of NLRP3 and caspase 1. Consistent with these results, the expression of caspase 1 and Nlrp3, but not of the other inflammasome receptors was higher in the heart and liver of Zmpste24-/- mice, which phenocopy the human disease. These data were further corroborated in LmnaG609G/G609G mice, another HGPS animal model. We also showed that pharmacological inhibition of the NLRP3 inflammasome by its selective inhibitor, MCC950, improved cellular phenotype, significantly extended the lifespan of progeroid animals, and reduced inflammasome-dependent inflammation. These findings suggest that inhibition of the NLRP3 inflammasome is a potential therapeutic approach for the treatment of HGPS.enAtribución 4.0 Internacionalhttp://creativecommons.org/licenses/by/4.0/AgingNLRP3InflammasomeProgeriaCaspase 1LongevityFibroblastsPhenotypeLamin AEnvejecimientoProteína con dominio pirina 3 de la familia NLRInflamasomasCaspase 1LongevidadFibroblastosFenotipoLamina tipo AMedical Subject Headings::Organisms::Eukaryota::AnimalsMedical Subject Headings::Diseases::Animal Diseases::Disease Models, AnimalMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::HumansMedical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::InflammasomesMedical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Nuclear Matrix-Associated Proteins::Lamins::Lamin Type AMedical Subject Headings::Phenomena and Processes::Physiological Phenomena::LongevityMedical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::MiceMedical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::ProgeriaMedical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 1Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::InflammationMedical Subject Headings::Anatomy::Cells::Connective Tissue Cells::FibroblastsMedical Subject Headings::Phenomena and Processes::Genetic Phenomena::PhenotypeMedical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animalresearch article34448355open access10.15252/emmm.2021140121757-4684