Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria
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 wi...
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| Format: | Article |
| Language: | English |
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Springer Nature
2021-08-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202114012 |
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| author | Alvaro González‐Dominguez Raúl Montañez Beatriz Castejón‐Vega Jéssica Nuñez‐Vasco Débora Lendines‐Cordero Chun Wang Gabriel Mbalaviele José M Navarro‐Pando Elísabet Alcocer‐Gómez Mario D Cordero |
| author_facet | Alvaro González‐Dominguez Raúl Montañez Beatriz Castejón‐Vega Jéssica Nuñez‐Vasco Débora Lendines‐Cordero Chun Wang Gabriel Mbalaviele José M Navarro‐Pando Elísabet Alcocer‐Gómez Mario D Cordero |
| author_sort | Alvaro González‐Dominguez |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-741ada3b7d4b430aadbd36423e7df82b |
| institution | DOAJ |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2021-08-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-741ada3b7d4b430aadbd36423e7df82b2025-08-20T03:05:53ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842021-08-0113101710.15252/emmm.202114012Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford ProgeriaAlvaro González‐Dominguez0Raúl Montañez1Beatriz Castejón‐Vega2Jéssica Nuñez‐Vasco3Débora Lendines‐Cordero4Chun Wang5Gabriel Mbalaviele6José M Navarro‐Pando7Elísabet Alcocer‐Gómez8Mario D Cordero9Instituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del MarInstituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del MarInstitute of Molecular, Cell and Systems Biology, University of GlasgowInstituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del MarInstituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del MarDivision of Bone and Mineral Diseases, Washington University School of MedicineDivision of Bone and Mineral Diseases, Washington University School of MedicineCátedra 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)Departamento de Psicología Experimental, Facultad de Psicología, Universidad de SevillaInstituto de Investigación e Innovación Biomédica de Cádiz, INiBICA, Hospital Universitario Puerta del MarAbstract 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.https://doi.org/10.15252/emmm.202114012agingNLRP3 inflammasomeprogeria |
| spellingShingle | Alvaro González‐Dominguez Raúl Montañez Beatriz Castejón‐Vega Jéssica Nuñez‐Vasco Débora Lendines‐Cordero Chun Wang Gabriel Mbalaviele José M Navarro‐Pando Elísabet Alcocer‐Gómez Mario D Cordero Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria EMBO Molecular Medicine aging NLRP3 inflammasome progeria |
| title | Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria |
| title_full | Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria |
| title_fullStr | Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria |
| title_full_unstemmed | Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria |
| title_short | Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria |
| title_sort | inhibition of the nlrp3 inflammasome improves lifespan in animal murine model of hutchinson gilford progeria |
| topic | aging NLRP3 inflammasome progeria |
| url | https://doi.org/10.15252/emmm.202114012 |
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