Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013, Seville, Spain.
Instituto de Investigación E Innovación Biomédica de Cádiz (INiBICA), Hospital Universitario Puerta del Mar, Cádiz, Spain.
Inflamm Res. 2024 Aug;73(8):1253-1266. doi: 10.1007/s00011-024-01892-7. Epub 2024 Jun 21.
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.
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.
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).
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.
衰老（senescence）是一种由不同应激引发的与细胞衰老相关的过程，其特征是分泌各种被称为衰老相关分泌表型（SASP）的炎症因子，其中一些由 NLRP3 炎性小体产生。在这里，我们提供的证据表明 NLRP1 炎性小体是一种 DNA 损伤传感器，也是衰老的关键介质。
在体外和体内诱导成纤维细胞衰老。通过 Western blot 分析培养物中或血清中释放的几种蛋白质（包括 p16、p21、p53 和 SASP 因子）来评估细胞衰老。使用 siRNA 敲除或沉默炎性小体成分，包括 NLRP1、NLRP3 和 GSDMD。
体外和体内结果表明，NLRP1 炎性小体通过调节 p16、p21、p53 和 SASP 因子的表达，以依赖 GSDMD 的方式促进衰老。从机制上讲，NLRP1 炎性小体在细胞质 DNA 传感器 cGMP-AMP（cGAMP）合酶（cGAS）检测到基因组损伤时被激活。
我们的研究结果表明，NLRP1 是衰老过程中 cGAS 依赖性 DNA 损伤传感器，通过 GSDMD 介导 SASP 释放的介质。本研究推进了 NLRP1 炎性小体生物学的知识，并强调了该途径作为调节衰老的潜在药物靶点。
