Muela-Zarzuela Ines, Suarez-Rivero Juan M, Gallardo-Orihuela Andrea, Wang Chun, Izawa Kumi, de Gregorio-Procopio Marta, Couillin Isabelle, Ryffel Bernhard, Kitaura Jiro, Sanz Alberto, von Zglinicki Thomas, Mbalaviele Gabriel, Cordero Mario D
bioRxiv. 2023 Mar 28:2023.02.06.527254. doi: 10.1101/2023.02.06.527254.
Senescence is a cellular aging-related process triggered by different stresses and characterized by the secretion of various inflammatory factors referred to as the senescence-associated secretory phenotype (SASP). Here, we present evidence that the inflammasome sensor, NLRP1, is a key mediator of senescence induced by irradiation both in vitro and in vivo. The NLRP1 inflammasome promotes senescence by regulating the expression of p16, p21, p53, and SASP in Gasdermin D (GSDMD)-dependent manner as these responses are reduced in conditions of NLRP1 insufficiency or GSDMD inhibition. Mechanistically, the NLRP1 inflammasome is activated downstream of the cytosolic DNA sensor cGMP-AMP (cGAMP) synthase (cGAS) in response to genomic damage. These findings provide a rationale for inhibiting the NLRP1 inflammasome-GSDMD axis to treat senescence-driven disorders.
衰老 是一种与细胞衰老相关的过程，由不同应激触发，其特征是分泌各种炎症因子，即衰老相关分泌表型（SASP）。在此，我们提供证据表明，炎性小体传感器NLRP1是体外和体内辐射诱导衰老的关键介质。NLRP1炎性小体通过以Gasdermin D（GSDMD）依赖的方式调节p16、p21、p53和SASP的表达来促进衰老，因为在NLRP1功能不足或GSDMD抑制的情况下，这些反应会减弱。从机制上讲，NLRP1炎性小体在细胞溶质DNA传感器cGMP-AMP（cGAMP）合酶（cGAS）下游被激活，以响应基因组损伤。这些发现为抑制NLRP1炎性小体-GSDMD轴治疗衰老驱动的疾病提供了理论依据。
