Department of Neurology in the Third Affiliated Hospital of Guizhou Medical University, PR China; Medical Laboratory Center in the Third Affiliated Hospital of Guizhou Medical University, PR China.
Medical Laboratory Center in the Third Affiliated Hospital of Guizhou Medical University, PR China; Department of Psychiatry in the Third Affiliated Hospital of Guizhou Medical University, Duyun, PR China.
Exp Cell Res. 2018 Jan 1;362(1):180-187. doi: 10.1016/j.yexcr.2017.11.015. Epub 2017 Nov 28.
Oxidative stress-mediated activation of NLRP3 inflammasome in microglia is critical in the development of neurodegerative diseases such as Alzheimer's disease (AD), Parkinson disease (PD). However, the mechanism underlying oxidative stress activates NLRP3 inflammasome remains exclusive. Here we demonstrated cathepsin B (CTSB) as a regulator of the activation of NLRP3 inflammasome by HO·HO induced IL-1β secretion in NLRP3 inflammasome-dependent manner·HO treatment increased CTSB activity, which in turn activated NLRP3 inflammasome, and subsequently processed pro-caspase-1 cleavage into caspase-1, resulting in IL-1 β secretion. Genetic inhibition or pharmacological inhibition of CTSB blocked the cleavage of pro-caspase-1 into caspase-1 and subsequent IL-1 β secretion induced by HO. Importantly, CTSB activity, IL-1β levels and malondialdehyde (MDA) were remarkably elevated in plasma of AD patients compared to healthy controls, while glutathione was significantly lower than healthy controls. Correlation analyses showed that CTSB activity was positively correlated with IL-1β and MDA levels, but negatively correlated with GSH levels in plasma of AD patients. Taken together, our results indicate that oxidative stress activates NLRP3 through upregulating CTSB activity. Our results identify an important biological function of CTSB in neuroinflammation, suggesting that CTSB is a potential target in AD therapy.
氧化应激介导的小胶质细胞中 NLRP3 炎性体的激活在神经退行性疾病（如阿尔茨海默病（AD）、帕金森病（PD））的发展中至关重要。然而，氧化应激激活 NLRP3 炎性体的机制尚不清楚。在这里，我们证明组织蛋白酶 B（CTSB）作为 HO·HO 诱导的 IL-1β 分泌中 NLRP3 炎性体激活的调节剂，以 NLRP3 炎性体依赖性方式起作用。HO 处理增加了 CTSB 的活性，进而激活了 NLRP3 炎性体，随后将前半胱天冬酶-1 切割成半胱天冬酶-1，导致 IL-1β 分泌。CTSB 的遗传抑制或药理学抑制阻断了 HO 诱导的前半胱天冬酶-1 切割成半胱天冬酶-1和随后的 IL-1β 分泌。重要的是，与健康对照组相比，AD 患者血浆中的 CTSB 活性、IL-1β 水平和丙二醛（MDA）显着升高，而谷胱甘肽显着降低。相关性分析表明，AD 患者血浆中 CTSB 活性与 IL-1β 和 MDA 水平呈正相关，与 GSH 水平呈负相关。总之，我们的研究结果表明，氧化应激通过上调 CTSB 活性激活 NLRP3。我们的研究结果确定了 CTSB 在神经炎症中的重要生物学功能，表明 CTSB 是 AD 治疗的潜在靶点。
