Publication: Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson-Gilford Progeria
Identifiers
Date
2021-08-27
Authors
González-Dominguez, Alvaro
Montañez, Raúl
Castejón-Vega, Beatriz
Nuñez-Vasco, Jéssica
Lendines-Cordero, Débora
Wang, Chun
Mbalaviele, Gabriel
Navarro-Pando, José M.
Alcocer-Gómez, Elísabet
Cordero, Mario D.
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
EMBO Press
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Abstract
Inflammation 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.
Description
MeSH Terms
Medical Subject Headings::Organisms::Eukaryota::Animals
Medical Subject Headings::Diseases::Animal Diseases::Disease Models, Animal
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Inflammasomes
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Nuclear Matrix-Associated Proteins::Lamins::Lamin Type A
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Longevity
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::Progeria
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 1
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation
Medical Subject Headings::Anatomy::Cells::Connective Tissue Cells::Fibroblasts
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal
Medical Subject Headings::Diseases::Animal Diseases::Disease Models, Animal
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans
Medical Subject Headings::Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Inflammasomes
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Proteins::Nuclear Proteins::Nuclear Matrix-Associated Proteins::Lamins::Lamin Type A
Medical Subject Headings::Phenomena and Processes::Physiological Phenomena::Longevity
Medical Subject Headings::Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice
Medical Subject Headings::Diseases::Congenital, Hereditary, and Neonatal Diseases and Abnormalities::Genetic Diseases, Inborn::Metabolism, Inborn Errors::Progeria
Medical Subject Headings::Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases, Initiator::Caspase 1
Medical Subject Headings::Diseases::Pathological Conditions, Signs and Symptoms::Pathologic Processes::Inflammation
Medical Subject Headings::Anatomy::Cells::Connective Tissue Cells::Fibroblasts
Medical Subject Headings::Phenomena and Processes::Genetic Phenomena::Phenotype
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Animal
DeCS Terms
CIE Terms
Keywords
Aging, NLRP3, Inflammasome, Progeria, Caspase 1, Longevity, Fibroblasts, Phenotype, Lamin A, Envejecimiento, Proteína con dominio pirina 3 de la familia NLR, Inflamasomas, Caspase 1, Longevidad, Fibroblastos, Fenotipo, Lamina tipo A
Citation
González-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):e14012