Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria

Autor: José M. Navarro-Pando, Débora Lendines-Cordero, Mario D. Cordero, Raúl Montañez, Gabriel Mbalaviele, Alvaro González-Dominguez, Jéssica Nuñez-Vasco, Elísabet Alcocer-Gómez, Beatriz Castejón-Vega, Chun Wang
Přispěvatelé: Universidad de Sevilla. Departamento de Psicología Experimental, Junta de Andalucía, [González-Dominguez,A, Montañez,R, Nuñez-Vasco,J, Lendines-Cordero,D, Cordero,MD] Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del Mar, Cádiz, Spain. [Castejón-Vega,B] Institute of Molecular, Cell and Systems Biology, University of Glasgow, Glasgow, UK. [Mbalaviele,G] Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, USA. [Navarro-Pando,JM] Cátedra de Reproducción y Genética Humana del Instituto para el Estudio de la Biología de la Reproducción Humana (INEBIR), Universidad Europea del Atlántico (UNEATLANTICO)-Fundación Universitaria Iberoamericana (FUNIBER), Seville, Spain. [Alcocer-Gómez,E] Departamento de Psicología Experimental, Facultad de Psicología, Universidad de Sevilla, Sevilla, Spain., This study was supported by a grant from the Progeria Research Foundation PRF 2021- 80 grant, Andalusian regional government (Grupo de Investigacion Junta de Andalucia CTS113 and Consejer ıa de Salud de la Junta de Andalucia: PI-0036-2014). Dr. Gabriel Mbalaviele was supported by NIH/NIAMS AR068972 and AR076758 grants.
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Medicine (General)
Phenomena and Processes::Genetic Phenomena::Phenotype [Medical Subject Headings]
Inflammasomes
Envejecimiento
Phenomena and Processes::Physiological Phenomena::Longevity [Medical Subject Headings]
QH426-470
Inflammasome
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]
Basal (phylogenetics)
Mice
Organisms::Eukaryota::Animals [Medical Subject Headings]
Receptor
Chemicals and Drugs::Amino Acids
Peptides
and Proteins::Proteins::Nuclear Proteins::Nuclear Matrix-Associated Proteins::Lamins::Lamin Type A [Medical Subject Headings]
Progeria
integumentary system
Anatomy::Cells::Connective Tissue Cells::Fibroblasts [Medical Subject Headings]
Lymphoblast
Caspase 1
Lamin Type A
Phenotype
NLRP3inflammasome
Molecular Medicine
Chemicals and Drugs::Enzymes and Coenzymes::Enzymes::Hydrolases::Peptide Hydrolases::Cysteine Proteases::Cysteine Endopeptidases::Caspases::Caspases
Initiator::Caspase 1 [Medical Subject Headings]
medicine.symptom
Fenotipo
medicine.drug
congenital
hereditary
and neonatal diseases and abnormalities
Immunology
Longevity
Diseases::Congenital
Hereditary
and Neonatal Diseases and Abnormalities::Genetic Diseases
Inborn::Metabolism
Inborn Errors::Progeria [Medical Subject Headings]
Inflammation
Biology
Inflamasomas
Lamina tipo A
Analytical
Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models
Animal [Medical Subject Headings]
R5-920
NLRP3
Report
NLR Family
Pyrin Domain-Containing 3 Protein
Genetics
medicine
Animals
Humans
Phenocopy
Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Rodentia::Muridae::Murinae::Mice [Medical Subject Headings]
aging
nutritional and metabolic diseases
progeria
Fibroblasts
medicine.disease
NLRP3 inflammasome
Fibroblastos
Diseases::Animal Diseases::Disease Models
Animal [Medical Subject Headings]
Disease Models
Animal
Chemicals and Drugs::Macromolecular Substances::Multiprotein Complexes::Inflammasomes [Medical Subject Headings]
Longevidad
Lamin A
Cancer research
Genetics
Gene Therapy & Genetic Disease
Proteína con dominio pirina 3 de la familia NLR
Diseases::Pathological Conditions
Signs and Symptoms::Pathologic Processes::Inflammation [Medical Subject Headings]
Zdroj: EMBO Molecular Medicine, Vol 13, Iss 10, Pp n/a-n/a (2021)
EMBO Molecular Medicine
ISSN: 1757-4676
Popis: 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.
This study reveals a critical role of the NLRP3‐inflammasome complex in the pathogenesis of Hutchinson‐Gilford Progeria (HGPS). Targeting NLRP3 may be a novel potential therapeutic strategy for progeria treatment.
Databáze: OpenAIRE
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