NLRP1 inflammasome promotes senescence and senescence-associated secretory phenotype.

Autor: Muela-Zarzuela I; Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013, Seville, Spain., Suarez-Rivero JM; Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013, Seville, Spain., Gallardo-Orihuela A; Instituto de Investigación E Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain., Wang C; Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA., Izawa K; Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan., de Gregorio-Procopio M; Instituto de Investigación E Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain., Couillin I; Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355, CNRS, University of Orleans, Orléans, France.; IDM, University of Cape Town, Cape Town, South Africa., Ryffel B; Laboratory of Experimental and Molecular Immunology and Neurogenetics (INEM), UMR 7355, CNRS, University of Orleans, Orléans, France.; IDM, University of Cape Town, Cape Town, South Africa., Kitaura J; Atopy (Allergy) Research Center, Juntendo University Graduate School of Medicine, Tokyo, Japan., Sanz A; School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G12 8QQ, UK., von Zglinicki T; Ageing Research Laboratories, Newcastle University, Biosciences Institute, Newcastle, UK., Mbalaviele G; Division of Bone and Mineral Diseases, Washington University School of Medicine, St. Louis, MO, 63110, USA., Cordero MD; Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013, Seville, Spain. mdcormor1@upo.es.; Ageing Research Laboratories, Newcastle University, Biosciences Institute, Newcastle, UK. mdcormor1@upo.es.; CIBER de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III, 28220, Madrid, Spain. mdcormor1@upo.es.
Jazyk: angličtina
Zdroj: Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2024 Aug; Vol. 73 (8), pp. 1253-1266. Date of Electronic Publication: 2024 Jun 21.
DOI: 10.1007/s00011-024-01892-7
Abstrakt: Background: Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as senescence-associated secretory phenotype (SASP), some of which are produced by the NLRP3 inflammasome. Here, we present evidence that the NLRP1 inflammasome is a DNA damage sensor and a key mediator of senescence.
Methods: Senescence was induced in fibroblasts in vitro and in mice. Cellular senescence was assessed by Western blot analysis of several proteins, including p16, p21, p53, and SASP factors, released in the culture media or serum. Inflammasome components, including NLRP1, NLRP3 and GSDMD were knocked out or silenced using siRNAs.
Results: In vitro and in vivo results suggest that the NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP factors in a Gasdermin D (GSDMD)-dependent manner. Mechanistically, the NLRP1 inflammasome is activated in response to genomic damage detected by the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS).
Conclusion: Our findings show that NLRP1 is a cGAS-dependent DNA damage sensor during senescence and a mediator of SASP release through GSDMD. This study advances the knowledge on the biology of the NLRP1 inflammasome and highlights this pathway as a potential pharmcological target to modulate senescence.
(© 2024. The Author(s).)
Databáze: MEDLINE
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