Pennington Biomedical Research Center, LSU System, Baton Rouge, LA 70808, USA.
Cell Metab. 2013 Oct 1;18(4):519-32. doi: 10.1016/j.cmet.2013.09.010.
Despite a wealth of clinical data showing an association between inflammation and degenerative disorders in the elderly, the immune sensors that causally link systemic inflammation to aging remain unclear. Here we detail a mechanism by which the Nlrp3 inflammasome controls systemic low-grade age-related "sterile" inflammation in both periphery and brain independently of the noncanonical caspase-11 inflammasome. Ablation of Nlrp3 inflammasome protected mice from age-related increases in the innate immune activation, alterations in CNS transcriptome, and astrogliosis. Consistent with the hypothesis that systemic low-grade inflammation promotes age-related degenerative changes, the deficient Nlrp3 inflammasome-mediated caspase-1 activity improved glycemic control and attenuated bone loss and thymic demise. Notably, IL-1 mediated only Nlrp3 inflammasome-dependent improvement in cognitive function and motor performance in aged mice. These studies reveal Nlrp3 inflammasome as an upstream target that controls age-related inflammation and offer an innovative therapeutic strategy to lower Nlrp3 activity to delay multiple age-related chronic diseases.
尽管有大量的临床数据表明炎症与老年人退行性疾病之间存在关联，但导致系统性炎症与衰老相关的确切免疫传感器仍不清楚。在这里，我们详细描述了一种机制，即 Nlrp3 炎性小体独立于非典型 caspase-11 炎性小体控制外周和大脑中与年龄相关的全身性低度“无菌”炎症。Nlrp3 炎性小体的缺失可保护小鼠免受与年龄相关的固有免疫激活增加、中枢神经系统转录组改变和星形胶质细胞增生。与全身性低度炎症促进与年龄相关的退行性变化的假设一致，缺乏 Nlrp3 炎性小体介导的半胱天冬酶-1 活性可改善血糖控制并减轻骨丢失和胸腺衰竭。值得注意的是，IL-1 仅介导 Nlrp3 炎性小体依赖性改善老年小鼠的认知功能和运动表现。这些研究揭示了 Nlrp3 炎性小体作为一个上游靶点，可控制与年龄相关的炎症，并提供了一种创新的治疗策略，以降低 Nlrp3 的活性，从而延缓多种与年龄相关的慢性疾病。
