Necroptosis increases with age in the brain and contributes to age-related neuroinflammation.
Necroptosis increases with age in the brain and contributes to age-related neuroinflammation.
复制标题
脑坏死随着年龄的增长而增加，并导致与年龄相关的神经炎症。
DOI：
10.1007/s11357-021-00448-5
复制
发表时间：
2021-10
期刊：
影响因子：
5.6
通讯作者：
Deepa SS
中科院分区：
文献类型：
--
作者：
Thadathil N;Nicklas EH;Mohammed S;Lewis TL Jr;Richardson A;Deepa SS
中枢神经系统（CNS）的慢性炎症（称为神经炎症）是衰老的标志，也是与衰老相关的认知能力下降的中介因素。神经炎症的特征是小胶质细胞（中枢神经系统的先天免疫细胞）的持续激活，损伤相关分子模式（DAMP）是众所周知的小胶质细胞激活剂之一。由于坏死性凋亡是一种通过释放 DAMP 诱导炎症的细胞死亡途径，因此我们假设与年龄相关的坏死性凋亡增加会导致神经炎症随着年龄的增长而增加。坏死性凋亡标记物、磷酸化形式的 MLKL (P-MLKL) 和坏死性凋亡途径中的激酶（RIPK1、RIPK3 和 MLKL）显示，随着年龄的增长，大脑中的区域特异性增加，特别是在小鼠的皮质 V 层和海马 CA3 区域。同样，与年轻小鼠相比，老年小鼠皮质和海马中引起膜结合和透化的 MLKL 寡聚物显着增加。近 70% 至 80% 的 P-MLKL 免疫反应性位于神经元，不到 10% 位于小胶质细胞，而星形胶质细胞中未检测到 P-MLKL。神经元中的 P-MLKL 表达是在体细胞中检测到的，而不是在突中检测到的。使用Mlkl−/−小鼠阻断坏死性凋亡可减少老年小鼠大脑中的神经炎症标志物（Iba-1和GFAP），而使用坏死性凋亡抑制剂necrostatin-1s进行短期治疗可减少老年小鼠海马中促炎细胞因子IL-6和IL-1β的表达。因此，我们的数据首次证明，脑坏死性凋亡随着年龄的增长而增加，并导致小鼠出现与年龄相关的神经炎症。在线版本包含可在 10.1007/s11357-021-00448-5 获取的补充材料。
Chronic inflammation of the central nervous system (CNS), termed neuroinflammation, is a hallmark of aging and a proposed mediator of cognitive decline associated with aging. Neuroinflammation is characterized by the persistent activation of microglia, the innate immune cells of the CNS, with damage-associated molecular patterns (DAMPs) being one of the well-known activators of microglia. Because necroptosis is a cell death pathway that induces inflammation through the release of DAMPs, we hypothesized that an age-associated increase in necroptosis contributes to increased neuroinflammation with age. The marker of necroptosis, phosphorylated form of MLKL (P-MLKL), and kinases in the necroptosis pathway (RIPK1, RIPK3, and MLKL) showed a region-specific increase in the brain with age, specifically in the cortex layer V and the CA3 region of the hippocampus of mice. Similarly, MLKL-oligomers, which cause membrane binding and permeabilization, were significantly increased in the cortex and hippocampus of old mice relative to young mice. Nearly 70 to 80% of P-MLKL immunoreactivity was localized to neurons and less than 10% was localized to microglia, whereas no P-MLKL was detected in astrocytes. P-MLKL expression in neurons was detected in the soma, not in the processes. Blocking necroptosis using Mlkl−/− mice reduced markers of neuroinflammation (Iba-1 and GFAP) in the brains of old mice, and short-term treatment with the necroptosis inhibitor, necrostatin-1s, reduced expression of proinflammatory cytokines, IL-6 and IL-1β, in the hippocampus of old mice. Thus, our data demonstrate for the first time that brain necroptosis increases with age and contributes to age-related neuroinflammation in mice. The online version contains supplementary material available at 10.1007/s11357-021-00448-5.
登录
查看更多内容
耦合的增殖和凋亡维持成人大脑中小胶质细胞的快速离职。
影响因子：
8.8
作者：
Askew K;Li K;Olmos-Alonso A;Garcia-Moreno F;Liang Y;Richardson P;Tipton T;Chapman MA;Riecken K;Beccari S;Sierra A;Molnár Z;Cragg MS;Garaschuk O;Perry VH;Gomez-Nicola D
通讯作者：
Gomez-Nicola D
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
7.8
作者：
Baar EL;Carbajal KA;Ong IM;Lamming DW
通讯作者：
Lamming DW
DOI：
10.1016/j.bbadis.2018.03.019
发表时间：
2018-06-01
影响因子：
6.2
作者：
Carvajal, Francisco J.;Mira, Rodrigo G.;Cerpa, Waldo
通讯作者：
Cerpa, Waldo
影响因子：
11.4
作者：
Ferrada, Luciano;Barahona, Maria Jose;Nualart, Francisco
通讯作者：
Nualart, Francisco