Cathepsin B links oxidative stress to the activation of NLRP3 inflammasome

Journal Article · Mon Jan 15 04:00:00 EST 2018 · Experimental Cell Research

DOI:https://doi.org/10.1016/J.YEXCR.2017.11.015· OSTI ID:23082521

Bai, Hua ^[1]; Yang, Bo ^[2]; Yu, Wenfeng; Xiao, Yan ^[3]; Yu, Dejun ^[2]; Zhang, Qifang ^[3]

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1. Department of Neurology in the Third Affiliated Hospital of Guizhou Medical University (China)
2. Medical Laboratory Center in the Third Affiliated Hospital of Guizhou Medical University (China)
3. Key Laboratory of Medical Molecular Biology in Guizhou Medical University, Beijing Road 9, Guiyang city, Guizhou 550004 (China)

Highlights: • Oxidative stress induces apoptosis and upregulates CTSB expression in mouse microglia. • Inhibition of CTSB expression using special shRNA markedly or its inhibitor markedly decreases H2O2-induced apoptosis. • CTSB accelerates oxidative stress-induced apoptosis by activating NLRP3/IL-1β signaling. 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 H{sub 2}O{sub 2}·H{sub 2}O{sub 2} induced IL-1β secretion in NLRP3 inflammasome-dependent manner·H{sub 2}O{sub 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 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 H{sub 2}O{sub 2}. 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.

• OSTI ID: 23082521
• Journal Information: Experimental Cell Research, Journal Name: Experimental Cell Research Journal Issue: 1 Vol. 362; ISSN 0014-4827; ISSN ECREAL
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
CATHEPSINS
GLUTATHIONE
HYDROGEN PEROXIDE
MICE
NERVOUS SYSTEM DISEASES
OXIDATION
THERAPY