Cathepsin B links oxidative stress to the activation of NLRP3 inflammasome

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 H2O2 center dot H2O2 induced IL-1 beta secretion in NLRP3 inflammasome-dependent mannerH(2)O(2) treatment increased CTSB activity, which in turn activated NLRP3 inflammasome, and subsequently processed pro-caspase-1 cleavage into caspase-1, resulting in IL-1 beta secretion. Genetic inhibition or pharmacological inhibition of CTSB blocked the cleavage of pro-caspase-1 into caspase-1 and subsequent IL-1 beta secretion induced by H2O2. Importantly, CTSB activity, IL-1 beta 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-1 beta 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.