Cathepsin B links oxidative stress to the activation of NLRP3 inflammasome

Area of Science:

• Neuroinflammation
• Molecular mechanisms of neurodegeneration
• Innate immunity

Background:

• NLRP3 inflammasome activation in microglia by oxidative stress is crucial for neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD).
• The precise mechanism by which oxidative stress triggers NLRP3 inflammasome activation remains unclear.

Purpose of the Study:

• To elucidate the role of cathepsin B (CTSB) in oxidative stress-induced NLRP3 inflammasome activation.
• To investigate CTSB as a potential therapeutic target for Alzheimer's disease.

Main Methods:

• Investigated the effect of hydrogen peroxide (H₂O₂) on NLRP3 inflammasome activation and IL-1β secretion.
• Assessed the impact of genetic and pharmacological inhibition of CTSB on H₂O₂-induced inflammatory responses.
• Measured CTSB activity, IL-1β, malondialdehyde (MDA), and glutathione (GSH) levels in plasma from AD patients and healthy controls.

Main Results:

• H₂O₂ treatment increased CTSB activity, leading to NLRP3 inflammasome activation, caspase-1 cleavage, and subsequent IL-1β secretion.
• Inhibition of CTSB abrogated H₂O₂-induced IL-1β secretion.
• AD patients exhibited elevated plasma CTSB activity, IL-1β, and MDA, with decreased GSH compared to controls. CTSB activity correlated positively with IL-1β and MDA, and negatively with GSH.

Conclusions:

• Oxidative stress activates the NLRP3 inflammasome by upregulating CTSB activity, highlighting CTSB's role in neuroinflammation.
• CTSB represents a potential therapeutic target for Alzheimer's disease and other neuroinflammatory conditions.