eprintid: 111 rev_number: 14 eprint_status: archive userid: 2 importid: 0 dir: disk0/00/00/01/11 datestamp: 2021-06-01 23:55:06 lastmod: 2023-06-30 23:30:17 status_changed: 2021-06-01 23:55:06 type: article succeeds: 0 commentary: 0 metadata_visibility: show item_issues_count: 0 sword_depositor: 0 creators_name: Alcocer-Gómez, Elísabet creators_name: Castejón-Vega, Beatriz creators_name: Nuñez-Vasco, Jéssica creators_name: Lendines-Cordero, Débora creators_name: Navarro-Pando, José M. creators_name: Cordero, Mario D. creators_id: creators_id: creators_id: creators_id: creators_id: jose.navarro@uneatlantico.es creators_id: mario.cordero@uneatlantico.es title: NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model ispublished: unpub subjects: uneat_bm divisions: uneatlantico_produccion_cientifica full_text_status: none note: Inmunology abstract: Inflammation is a hallmark of aging and accelerated aging syndromes. In this context, inflammation has been associated to the pathophysiology of Hutchinson–Gilford progeria syndrome (HGPS). In this study, we report that progeroid skin fibroblasts and animal models present an hyperactivation of the NLRP3-inflammasome complex. High expression of NLRP3 and caspase 1 was also observed in skin fibroblasts from HGPS associated to the nuclei morphology. Lymphoblast from HGPS also showed increased basal levels of NLRP3 and caspase 1 independent to the induction from metabolic factors. Consistent with these results, Zmpste24−/− showed high expression of Nlrp3 and caspase 1 in heart, liver and kidney and reduced levels of Nlrc3, however these changes were not observed in other inflammasomes. We also show that pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved cellular phenotype, significantly extends the lifespan of these progeroid animals and reduced inflammasome-dependent inflammation. These findings suggest the NLRP3-inflammasome comples as a therapeutic approach for patients with HGPS. date: 2020-09 date_type: published publication: bioRxiv (preprints) pages: 0 id_number: doi:10.1101/2020.09.09.288290 refereed: FALSE book_title: NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model official_url: http://doi.org/10.1101/2020.09.09.288290 num_pieces: 0 gscholar_impact: 0 gscholar_datestamp: 0000-00-00 00:00:00 access: open language: en citation: Artículo Materias > Biomedicina Universidad Europea del Atlántico > Investigación > Producción Científica Abierto Inglés Inflammation is a hallmark of aging and accelerated aging syndromes. In this context, inflammation has been associated to the pathophysiology of Hutchinson–Gilford progeria syndrome (HGPS). In this study, we report that progeroid skin fibroblasts and animal models present an hyperactivation of the NLRP3-inflammasome complex. High expression of NLRP3 and caspase 1 was also observed in skin fibroblasts from HGPS associated to the nuclei morphology. Lymphoblast from HGPS also showed increased basal levels of NLRP3 and caspase 1 independent to the induction from metabolic factors. Consistent with these results, Zmpste24−/− showed high expression of Nlrp3 and caspase 1 in heart, liver and kidney and reduced levels of Nlrc3, however these changes were not observed in other inflammasomes. We also show that pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved cellular phenotype, significantly extends the lifespan of these progeroid animals and reduced inflammasome-dependent inflammation. These findings suggest the NLRP3-inflammasome comples as a therapeutic approach for patients with HGPS. metadata Alcocer-Gómez, Elísabet; Castejón-Vega, Beatriz; Nuñez-Vasco, Jéssica; Lendines-Cordero, Débora; Navarro-Pando, José M. y Cordero, Mario D. mail SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, jose.navarro@uneatlantico.es, mario.cordero@uneatlantico.es (2020) NLRP3 inflammasome inhibition rescues Hutchinson-Gilford Progeria cellular phenotype and extend longevity of an animal model. bioRxiv (preprints). (Inédito)