ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation.
ATP exposure stimulates glutathione efflux as a necessary switch for NLRP3 inflammasome activation.
复制标题
ATP暴露刺激谷胱甘肽流出作为NLRP 3炎性小体激活的必要开关。
DOI：
10.1016/j.redox.2021.101930
复制
发表时间：
2021-05
期刊：
影响因子：
11.4
通讯作者：
Sawa T
中科院分区：
文献类型：
--
作者：
Zhang T;Tsutsuki H;Islam W;Ono K;Takeda K;Akaike T;Sawa T
NLRP 3炎性体是一种多蛋白复合物，负责白细胞介素（IL）-1β和IL-18的前体形式成熟为活性促炎细胞因子。越来越多的证据表明，氧化还原稳态的调节有助于NLRP 3炎性体的激活。然而，具体的机制细节仍不清楚。我们在这里证明，ATP暴露引起巨噬细胞中谷胱甘肽（GSH）水平的急剧下降，这导致NLRP 3炎性小体激活。我们检测到培养上清液中GSH水平的增加与巨噬细胞中GSH的减少相当，这表明暴露于ATP刺激GSH流出。外源性添加P2 X7受体拮抗剂，GSH，或氧化形式GSSG衰减这种流出。此外，外源性GSH或GSSG强烈抑制体外和体内NLRP 3炎性小体活化。这些数据表明，GSH外排控制NLRP 3炎性小体激活，这可能会导致NLRP 3炎性小体相关疾病的新的治疗策略的发展。ATP通过P2 X7受体刺激谷胱甘肽（GSH）快速流出。GSH流出是NLRP 3炎性体复合物组装的上游事件。外源性GSH减弱ATP引起的GSH外排和NLRP 3炎性体激活。GSH或GSSG抑制炎症小鼠模型中白细胞介素-1 β的产生。
The NLRP3 inflammasome is a multiprotein complex responsible for the maturation of precursor forms of interleukin (IL)-1β and IL-18 into active proinflammatory cytokines. Increasing evidence suggests that modulation of redox homeostasis contributes to the activation of the NLRP3 inflammasome. However, specific mechanistic details remain unclear. We demonstrate here that ATP exposure evoked a sharp decrease in glutathione (GSH) levels in macrophages, which led to NLRP3 inflammasome activation. We detected an increase in GSH levels in culture supernatants that was comparable to the GSH decrease in macrophages, which suggests that exposure to ATP stimulated GSH efflux. Exogenous addition of P2X7 receptor antagonist, GSH, or the oxidized form GSSG attenuated this efflux. Also, exogenous GSH or GSSG strongly inhibited NLRP3 inflammasome activation in vitro and in vivo. These data suggest that GSH efflux controls NLRP3 inflammasome activation, which may lead to development of novel therapeutic strategies for NLRP3 inflammasome-associated disorders. ATP stimulates rapid glutathione (GSH) efflux via the P2X7 receptor. GSH efflux is an upstream event for NLRP3 inflammasome complex assembly. Exogenous GSH weakens ATP-caused GSH efflux and NLRP3 inflammasome activation. GSH or GSSG suppressed interleukin-1β production in an inflammatory mouse model.
登录
查看更多内容
影响因子：
8.8
作者：
Hughes, Mark M.;Hooftman, Alexander;O'Neill, Luke A. J.
通讯作者：
O'Neill, Luke A. J.
影响因子：
30.5
作者：
通讯作者：
--
DOI：
10.1038/nri2938
发表时间：
2011-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
56.9
作者：
Dostert, Catherine;Petrilli, Virginie;Tschopp, Jurg
通讯作者：
Tschopp, Jurg
影响因子：
10.4
作者：
Golladay, SA;Park, SH;Aust, AE
通讯作者：
Aust, AE