TY - JOUR
T1 - Inhibition of the NLRP3 inflammasome improves lifespan in animal murine model of Hutchinson–Gilford Progeria
AU - González-Dominguez, Alvaro
AU - Montañez, Raúl
AU - Castejón-Vega, Beatriz
AU - Nuñez-Vasco, Jéssica
AU - Lendines-Cordero, Débora
AU - Wang, Chun
AU - Mbalaviele, Gabriel
AU - Navarro-Pando, José M.
AU - Alcocer-Gómez, Elísabet
AU - Cordero, Mario D.
N1 - Publisher Copyright:
© 2021 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2021/10/7
Y1 - 2021/10/7
N2 - 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.
AB - 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.
KW - NLRP3 inflammasome
KW - aging
KW - progeria
UR - http://www.scopus.com/inward/record.url?scp=85113509800&partnerID=8YFLogxK
U2 - 10.15252/emmm.202114012
DO - 10.15252/emmm.202114012
M3 - Article
C2 - 34448355
AN - SCOPUS:85113509800
SN - 1757-4676
VL - 13
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 10
M1 - e14012
ER -